Part 10. Metabolic Disease

넬슨 요약

PART X  Metabolic Disease

Chapter 70. An Approach To Inborn Errors Of Metabolism

* Sign and Symptom

    - metabolic acidosis

    - persistent vomiting

    - failure to thrive

    - developmental abnormalities

    -blood or urine level; amino acid or ammonia

    - peculiar odor

           93 Table 70-1

    - hepatomegaly

Neonatal Period

; usually severe, often lethal

; 89Sx & Sg

    - *lethrgy, poor feeding, convulsions, vomiting

; infection, pylotic stenosis, hypoglycemia, hypocalcemia DDX

; physical exam., CNS Sx

    - nonspecific

; hepatomegaly - common

; 93unusual odor - Table 70-1

; Dx

    - ammonia, bicarbonate, pH

    - Fig 70-1 

Children After The Neonatal Period

; mental retardation, motor deficit, convulsion

    - most constant finding

; Considered in any child with one or more of the following manifestations

    1. unexplained mental retardation, developmental delay, motor deficit, or convulsion

    2. unusual odor

    3. intermittent episodes of unexplained vomiting, acidosis, mental deterioration or coma

    4. hepatomegaly

    5. renal stones

♥표8-3, 8-4, 8-5(p156-158)

Chapter 71. Defects in Metabolism of Amino Acids

71.1 Phenylalanine(PA)

; dietary phenylalanine not utilized

; etiology

    - *deficiency of phenylalanine hydroxylase --> classic

    - *deficiency of cofactor(=tetrahydrobiopterin deficiency)

Fig 71-1

Classic phenylketonuria (PKU)

; 87,89 pathogenesis

    - complete or near complete def. of PA hydroxylase

           phenylalanine

           phenylpyruvic acid, phenylethylamine

           disrupt normal metabolism

           brain damage

94 Clinical Manifestations

; normal at birth

; mental retardation

    - *gradually, IQ 50 by the end of the 1st yr

    - *생후1개월이내에 치료를 개시하면 이와같은 증상은 나타나지 않는다

; *vomiting

; hyperactive with purposeless movement, rhythmic rocking, athetosis

; *blonder, fair skin, blue eyes

; *seborrheic or eczematoid skin

    - disappears as the child grows older

; musty, mousym wolf like odor due to *phenylacetic acid

; *hypertonic with hyperactive DTR - most

; seizure - 1/4

; EEG abnormalities - 1/2

; micorcephaly, prominent maxilla with widely spaced teeth enamel hypoplasia, growth retatdation

Diagnosis

; Guthrie method

    - positive as early as 4hr after birth

    - but recommend blood sampling after 48-72hr of life & feeding protein

    - bacterial inhibitory assay, 고초균 bacillus subtillis

    - (+)시에는 plasma phenylalanine, tyrosine 측정

; 86,94 Criteria for diagnosis of classic PKU

    - plasma phenylalanine level above 20mg/dl (1.2mM)

    - normal plasma tyrosine level

    - urinary level of metbolite of phenylalanine

           / phenylpyruvic acid and o-hydroxyphenylacetic acid

    - normal of conc. of the cofactor tetrahydrobiopterine

# 10% ferric chloride(FeCl3) + urine

    ; *olive green color (phenylpyruvic acid)

    ; 신생아기는 phenylpyruvic acid excretion 적어서 반응(-)

    ;91,93 Disease

           - PKU, ASA, Phenothiazine, MSD, Histidinemia

# Guthrie test 사용하는 inhibitor

    - PKU; phenylalanine

    - MSUD; leucine

    - homocystinuria; methionine

    - histidinemia; histidine

Treatment

; Diet low in phenylalanine

    - optimal serum level *3-15mg/dl

; 지나친 식이 제한

    - lethargy, anorexia, rash, diarrhea, anemia, even death

; tyrosine 충분한 공급

; *relaxed diet after 6 yr

Pregnancy in mother with PKU

; spontaneous abortion, mental retardation, microcephaly, congenital heart anomaly

; low phenylalanine diet before concenption

    - *below 10mg/dl through pregnancy

Hyperphenylalaninemia due to deficiency of cofactor tetrahydrobiopterin(BH4)

; hyperphenylalaninemia *2%

; etiology

    - *defect of BH4

           /cofactor for phenylalanine, tyrosine, tryptophan hydroxylase

           /cofactor for nitric oxide synthase

           /synthesized from guanosine triphosphate

           /converted to 4α-hydroxytetrahydrobiopterin

    - *deficiency of enzyme related BH4

           /6-PTS(=6-pyruvoyltetrahydropterin synthase)

           /guanosine triphosphate cyclohydratase

           /carbinolamine dehydratase

           /dihydropteridine reductase

; clinical Manifestation

  - similar to PKU

    - neurologic manifestation after 3 mo despite adequate dietary therapy

; diagnosis

    - body fluid(esp, urine, plasma, CSF)에서 neopterin biopterin 측정

    - BH4 loading test

    - enzyme assay

    - gene study

; treatment

    - low phenylalanine diet; not prevent neurologic damage

    - Neurotransmitter precusors

           / *L-dopa, 5-hydroxytryptophan

           / *most effective, prevent neurologic damage if early started

           / *all pt with PKU and hyperalaninemia should be tested for BH4 def.

    - BH4 replacement

           / high dose (20-40mg/kg/24hr)

           / may be neurologic damage progress due to not cross BBB

Benign hyperphenylalaninemia(10-20mg/dl)

; 1-35%정도의 phenylalanine hydroxylase activity 가짐

; simple reduction of dietary protein or low diet만으로 serum phenlyala. 조절가능

Transient phenylalaninemia

; transient tyrosinemia of newborn에서 있다.

; absence or delayed maturation of PA transaminase

Genetics and Prevalence

; AR, 1:10,000~1:20,000 live birth

; gene for        PA hydroxylase; long arm of ch. 12

; carbinolamine dehydratase; logn arm of ch. 10

; dihydropteridine reductase; short arm of ch. 4

87,89,93 초기 발견 치료로 지능 장애 예방 가능한 ds.

    PKU

    galactosemia

    urea cycle disorder          

    hypothyroidism

    homocystinemia                    

    histidinemia

# 식이요법으로 호전되는 선천 대사 질환

    ; PKU, MSUD, galactosemia, homocystinuria, histidinemia, propionic acidemia

# metabolic orgin of dwarfism

    ; Hurler syn., GSD, galactosemia, idiopathic infantile HECa++

# persistent acidosis in IN+CH, PCO2 <10mmHg, large anion gap

      inbor error metabolism 의심

71.2 Tyrosine

; precusor of dopamine, NE, EP, melanine, thyroxine

; excess tyrosine CO2+H2O metabolite

; protein synthesis

Tyrosinemia type I(Tyrosinosis, Hereditary Tyrosinemia, Hepatorenal Tyrosinemia)

; AR

; severe involvement of *liver, kidney, CNS

; accumulation of metabolites of tyrosine

; caused by deficiency of enzyme *fumarylacetoacetate hydrolase

Clinical Manifestation

1. acute form

    ; *6개월내 증상 발현후 2세내 간부전으로 사망

    ; failure to thrive, developmental delay, vomiting, diarrhea, fever

    ; *hepatomegaly, jaundice, hypoglycemia, bleeding tendency (melena, hematuria, ecchymosis)

    ; *cabbage-like odor(metabolite of methionine)

2. chronic form

    ; 1세이후 증상발현하여 10년내 사망

           - *간부전 혹은 간암

    ; failure to thrive, dev. delay, progressive cirrhosis, Fanconi syn., vit D resistent ricket

    ; episode of acute polyneuropathy- resembling acute porphyria

; Lab

    1) normocytic anemia

    2) elevation of s. bil., AST, ALT, α-fetoprotein

    3) increased of plasma tyrosine, methionine

           - *I : 6~10mg% < II : 20~50mg%

    4) increased of urine and serum succinyl acetoacetate, succinyl acetone(diagnostic)

    5) measurement of fumarylacetoacetate H activtiy at liver bx specimen      or fibroblast cell

Treatment

    1) trial of diet low in tyrosine, phenylalanine, methionine

           diet만으로 질병의 진행을 막지 못함.

    2) 간이식

Tyrosinemia type II(Richter-Hanhart syn., oculocutaneous tyrosinemia)

Clinical Manifestation

    ; MR

    ; palmar and plantar punctate hyperkeratosis

    ; herpetiform corneal ulcers

2) Lab;      1. hypertyrosinemia(20-50mg%), tyrosinuria

                   2. L and RFT, other aminoacid; normal

3) 기전; hepatic tyrosine aminotransferase cytosol fraction aminotransferase 결핍

                   * gene for tyrosine aminotransferase; chromosome 16q

4) Tx; diet low in tyrosine and phenylalanine effective

Transient tyrosinemia of NB

; NB 0.5-10%에서 2주동안 plasma tyrosine 증가

    - most premature, hyperprotein diet infant

    - as high as 60mg/dl

; *mostly asymptomatic

    - lethargy, poor feeding

; spontaneously resolves during 1mo of life

; pathogenesis

    - delayed maturation of 4-hydroxyphenlypyruvate dioxygenase

; Treatment

    - reducing the amount of protein in diet(2-3g/kg/24hr)

    - administering *vitamine C(200-400mg/24hr)

           / necessary for optimal function of the oxidase

           / scurvy tyrosinemia 가능

Hawkinsinuria

1. due to a deficiency of one of the component of the 4-hydoxyphenylpyruvate

           deoxygenase enzyme complex

2. block in the rearrangement step leads to accumulation of epoxide intermediate

           reduced to form 4-HCAA or react to cyteine (fig 71-1)

; Clinical Manifestation

    - symptomatic only during infancy

    - severe metabolic acidosis, ketosis, failure to thrive, mild hepatomegaly, *unusal odor(like that of swimming pool)

Albinism

; defect in the biosynthesis and distribution of melanin

# 3 type

    1. generalized A ; AR

    2. partial A(piebaldism); AD

    3. ocular A; x-linked R

# memb-bound intracellular organell melanosome안의 tyrosine으로부터 melanocyte melanin 합성

# BH4 ; rate-limiting component for melanine synthesis

# defect in the formation of the pigment melanin

Oculocutaneous(generalized) albinism

; two forms according to ability of plucked hair bulb to form pigment when incubated with tyrosine

    - tyrosinase negative

    - tyrosinase positive

# Tyrosinase Negative Albinism

    ; *severe, 2nd common

    ; AR, chromosome 11-long arm

    ; visual acuity loss, red R loss

# Tyrosinase Positive Albinism

    ; *common

    ; AR, chormosome 15-long arm

    ; visual acuity and red R loss

# Chediac-Higashi syndrome

    ; tyrosinase (+) partial albinism

    ; *abnormal granule in leukocytes and other cells

           --> susceptiblity to inf

    ; *reduced number of melanosomes

    ; *macromelanosome

# Hermansky-Pudlak Syndrome

    ; tyrosinase-positive generlized albinism

    ; *absence of platelet -dense bodies and accumulation of ceroid in tissues

           --> *platelet dysfunction

Ocular albinism

; XR, AR, AD

; nystagmus, decreased visual acuity, photophobia, skin and hair color are within normal limits

Partial albinism (piebaldism)

; AD

Alcaptonuria

; AR

; deficiency of *homogentisic acid oxidase

; accumulation of homogentisic acid in body

Clinical Manifestation

; *ochronosis, arthritis

; not evident until midadult life

; *darkening of the urine almost black color

    - due to oxidation & polymerization of homogentisic acid

    - enhanced with alkaline pH

    - acid urine not darkening

; ochronosis

    - darkening of tissue : cartilage & other mesenchymal tissue

; arthritis

    - large joints(spine, hip, knee)

    - *more severe in men

; heart ds.

    - aortic, mitral valvulitis, calcification of hart valve, mycocardial inf          

Diagnosis

1. Benedict test (+)

2. Fecl3(+)(Fehling test)

cf)  black diper due to phenol poisoning, melanotoic tumor시는 무반응

    homogentisic acid glucose oxidase 반응 없다.

Treatment

no effective therapy

71.3 Methionine

methionine에서 S-adenosyl methionine 으로의 catabolism

  ; cysteine methylation donor 중요

Homocystinuria(Homocysteinemia)

; homocystein - 정상적으로 plasma and urine에서 detect 되지않음

Homocystinuria Due To Cystathionine Synthase Deficiency(=Homocystenuria Type I, Classic Homocystiuria)

; *common of methionine metabolism

; AR inheritance

; 1/200,000 live birth

Etiology

    ; deficiency of cystathione synthase

           - long arm of chromosome 21

  ; *heterozygote carrier

           - *asymptomatic but thromboembolic disease more common

Clinical Manifestation

    ; in infancy

           - nonspecific

           - maybe failure to thrive, developmental delay

    ; *diagnosis usually after 3yr

           - dislocation of occular lense

                   / severe myopia, iridodonesis

    ; astigamtism, glaucoma, staphyloma, cataract, retinal detachement, optic atrophy

    ; progressive mental retardation

           - *affected patient 1/3 normal intelligence

    ; psychiatric disorder ; 50%

  ; convulsion ; 20%

  ; *skelectal anomaly resembling Marfan syndrome

    ; blue eye, peculiar malar flush

    ; X-ray finding

           - generalized osteoporosis

    ; thromboembolic episode

           - esp. brain

           - sequale of optic atrophy, paralysis, seizure disorder, cor pulmonale, severe hypertension

Laboratory Finding

 elevation of methionine, homocystine(or homocystein) in body fluid

  * urine homocystine ; fresh voided urine 으로 검사해야함.

 cystine ; low or absent in plasma

 enzyme assay of

    liver biopsy specemen, cultured fibroblast, phytoheagglutinin stimulated lymphocyte  

 prenatal diagnosis ; enzyme assay of cultured amniotic cell or chorionic villi

Treatment

    ; *high dose Vitamin B6 (200-1000 mg/24hr)

           - dramatic improvement

    ; *folic acid (1-5mg/24hr)

           - vitamin B6 치료에도 반응하지 않는 경우

    ; restriction of methionine with cystein supplementation

    ; *Betaine (trimethylglycine, 6-9g/24hr)

           - methyl group donor

           -lower homocysteine level

       - vitamin B6 반응하지 않는 경우

Fig. 71-3

Homocystinuria Due To Defects In Methylcobalamin Formation (=Homocystinuria Type II)

   a. methylcobalamin ; cofactor of methionine synthase

   b. clinical manifestation

      vomiting, poor feding, letharge, lypotonia, developmental delay

   c. Lab/F

      megaloblastic anemia

      homocystinuria, hypomethininemia

       * megaloblastic anemia, hypomethioninemia ; DDx point

   d. Dx ; fibroblast culture

      Prenatal Dx ; amniotic cell culture

   e. Tx

      Vt.B12 (1-2mg/24hr)

Homocystinuria Due To Deficiency Of Methylenetetrahydrofolate Reductase (=Homocystinuria Type III)

   a. methyenetetrahydrofolate reductase ; gene located chromosome 1

   b. clinical menifestation

     * complete absence of enzymatic activity

       ; neonatal apnea 

         myoclonic seizure

         coma and death

     * partial deficiency

        ; mental retardation, convulsion, microcephaly, spasticity

   c. Lab/F

      moderate homocystinemia, hymocystinuria

      methionine concentration ; low vor low normal

      absence of megaloblastic anemia

      thromboembolic disorder

   d. Dx

       enzyme assay cultured fibroblast and leukocyte

   e. Tx

       folic acid + Vt.B6 + Vt.B12 + methionine supplemeatation

       betaine

Hypermethioninemia

# ★원인

  ; liver disease

  ; tyrosinemia type I

  ; homocystinuria type I

  ; premature and some full-term infants on high protein diet

  ; deficiency of hepatic methionine adenosyltransferase

Cystathinonemia

    * cystathionase ; Vt.B6 cofactor

                     not present in fetal and neonatla liver

                       -> neonatl period cystein 필수아미노산

     * 원인

        a. Vt.B6, Vt.B12 deficiency

        b. liver disease ; galactoseimia

        c. thyrotoxicosis

        d. hepatoblastoma

        e. neuroblastoma. ganglioblastoma

        f. defect in remethylation of homocystein (homocystinuria type II, III)

      * AR inheritance

71.4 Cysteine/Cystine

   sulfur-containing nonessential amino acid

   methionine 으로부터 합성됨

   --> cystinuria/cystinosis

Sulfite Oxidase Deficiency (Molybdenum Cofactor Deficeincy)

   a. clinical manefestation

      refused to feed vomiting, seizure (tonic, clonic, myoclonic)

      severe developmental delay

      bilateral dislocation of ocular lense

   b. urine slfite, thiosulfate, S-sulfocystein, xanthine, hypoxanthine

      urine and serum level of uric acid 감소

      urine sulfate 감소

   c. Tx

      뚜렷한 치료방법 없어 보통 생후 2세내 사망

71.5 Tryptophan

Hartnup Disorder

Serotonin Deficiency

Indicanuria(Tryptophan Malabsorption)

71.6 Valine, Leucine, Isoleucine, And Related Organic Acidemia

Deficiency Of Branched-Chain Aminotransferase

Maple Syrup Urine Disease(Msud)

Isovaleric Acidemia

Clinical Manifestation

# acute form

    ; in 1st few days of life

    ; *vomiting, severe acidosis

    ; lethargy, convulsion, coma, death if no therapy

; *odor of “sweaty feet”

Proprionic Acidemia(Propionyl Coa Carboxylase Deficiency)

# propionic acids

    ; intermediate metabolite of isoleucine, valine, threonine, methionine, odd-chain fatty acids, cholesterol catabolism

Clinical Manifestation

; in 1st few days of life

; *poor feeding, vomiting, hypotonia, lethargy, dehydration, acidosis

; rapidly progress to coma & death

; seizures - 30%

Laboratory Finding

; during acute attack

    - severe metabolic acidosis with large anion gap, keosis, neutropenia, thrombocytopenia, hypoglycemia

; hyperammonia

; hyperglycemia

Methylmalonic Acidemia

; similar with proprionic acidemia

; *fulminant neonatal form

    - severe ketosis, acidosis, hyperammonemia, neutropenia, coma, death

    - *more common than proprionic acidemia

71.7 Glycine

Hyperglycinemia

Sarcosinemia

D-Glyceric Acidemia

Trimethylaminuria

; deficiency of trimethylamine oxidase

; massive excretion of trimethylamine in urine

    --> *foul body odor resembling rotten fish

Hyperoxaluria And Oxalosis

Fig. 71-7

# Secondary hyperoxaluria

    ; pyridoxine deficiency

    ; ingestion of ethylene glycol

    ; high dose of vitamin C

    ; anesthetic agents methoxyflurane

  ; IBD

    ; enteric hyperoxaluria : entensive resection of bowel

    ; ingestion of plants with high oxalic acid contents

           - sorrel, spinach, rhubarb

Primary Hyperoxaluria Type I

; common form of primry hyperoxaluria

; causes

    - deficiency of peroxisomal enzyme alanine-glyoxylate aminotransferase

; Clinical Manifestation

    - *symptomatic before 5yr

    - renal stone, nephronocalcinosis

    - renal colic, asymptomatic hematuria

Primary Hyperoxaluria Type II

71.10 Urea Cycle And Hyperammonemia (Arginine, Citulline, Ornithine)

Fig. 71-10

71.11 Histidine

71.12 Lysine

71.13 Aspartic Acid (=Canavan Disease)

Canavan Disease

; AR

; *spongy degeneration of white matter of the brain

    --> severe form of leukodystrophy

Etiology And Pathology

    ; deficiency of enzyme *aspartoacylase

           --> *accumulation of N-acetylaspartic acid in brain

Clinical Manifestation

    ; no symptoms until 3-6mo

    ; *progressive macrocephaly, severe hypotonia, persistent head lag

    ; *hyper-regflexic and hypotonic

    ; *seizures, optic atrophy

Diagnosis

    ; brain CT & MRI

           - diffuse white matter digeneration, primarily in cerebral hemispheres

    ; *N-acetylaspartic acid in urine & deficiency of aspartocylase in cultured skin fibroblast

Differential Diagnosis

    ; Alexander Disease

           - usually slow

           - hypotonia not pronounced

Chapter 72. Defects in Metabolism Of Lipids

72.1 Disorders Of Mitochondrial Fatty Acid Oxidation

Fig. 72-1

# *common presentations

    ; acute attack of life-threatening coma & hypoglycemia induced by fasting

Defects In The β-Oxidation Cycle

MCAD Deficiency

; *common of fatty acid oxidation disorders

; 85-90% homozygous for single common *mis-sense mutation, A to G transition at cDNA 985

Clinical Manifestation

    ; *present in first 2-3yr

    ; episode of acute illness triggered by prolonged fasting for more than 12-16hr

    ; vomiting, lethargy

           - rapidly progressive to coma or seizures & to cardiorespirtory collapse

    ; why rare attacks until beyond the first few months of life ?

           - *no night fasting & fasting stress

Laboratory Finding

    ; hypoglycemia, low ketone : hypoketotic hypoglycemia

    ; *no acidemia

    ; elevations of transaminases, urate, ammonia, prolonged PT/aPTT

    ; secondary carnitine deficiency

Diagnosis

    ; *increased octanoylcarnitine in plasma or urine

    ; *increased glycine conjugates of hexanoate & phyenylpropionate in urine

    ; deficient MCAD enzyme activity

    ; common A985G mutation in homozygous form              

LCAD/VLCAD Deficiency

SCAD Deficiency

LDHAD(Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase) Deficiency

SCHAD Deficiency

Defects In The Carnitine Cycle

Plasma Meembrane Carnitine Transport Defect(=Primary Carnitine Deficiency)

Carnitine Palmitoyltransferase-1 (CPT-1) Deficiency

Carnitine/Acylcarnitine Translocase (TRANS) Deficiency

Carnitine Palmitoyltransferase-2 (CPT-2) Deficiency

Defects In Electron Transfer Pathway

Electron Transfer Flavoprotein (ETF) And ETF Dehydrogenase (ETF-DH) Deficiencies

Defects In Ketone Synthesis Pathway

72.2 Disorders Of Very Long Chain Fatty Acids

Peroxisomal Disorders

Table 72-1 classification of peroxisomal disorders

Etiology

Epidermiology

Pathology

Pathogenesis

Clinical Manifestation

Group I

# Zellweger syndrome

    ; *severe

    ; typical facial appearance

           - high forehead, unslanting palpabral fissures, hypoplastic supraorbital ridges, epicanthal folds

   ; *severe weakness, hypotonia, neonatal seizures, eye abnormalities (cataracts, glaucoma, corneal clouding, brushfield spots, pigmentary retinopathy, optic nerve dysplasia)

Laboratory Finding

Diagnosis

Complication

Prevention

Treatment

Genetic Counselling

Adrenoleukodystrophy(X-Linked)

Etiology

    ; gene defect in formation of peroxisomal membrane protein

           --> *impaired function of peroxisomal lignoceroyl CoA ligase

    ; *excess hexacosanoic acid(C26:0)

           - *striking & characteristic features

Epidermiology

Pathology

Pathogenesis

Clinical Manifestation

Childhood Cerebral Form

; *first onset between 4 and 8yr

; hyperactivity

    - *common initial symptoms

    - mistaken for ADHD

# Adrenal dysfunction

    ; impaired cortisol response to ACTH stimulation

           - 85%

    ; mild hyperpigmentation

Adolescent ALD

Adrenomyeloneuropathy

    ; onset in late adolescence

    ; progressive paraparesis dueto long tract degeneration in spinal cord

    ; one half involvement of cerebral white matter

Addison Only Phenotype

Laboratory Finding

Diagnosis And Differential Diagnosis

# Definite Diagnosis

    ; demonstration of only excess of very long chain fatty acid & peroxysomal disorder

Complication

Treatment

# BMT

    ; *effective

    ; Indication

           - boys with significant but mild cerebral involvement for whom a donor with a good HLA match

           - *MRI abnormality is combined with moderate deficits in visual or auditory processing or memory/learning

Genetic Counselling And Prevention

72.3 Lipid Storage Disroders

GM1 Gangliosidosis

Tay-Sachs (GM2 Gangliosidosis II)

; *primary involvement of CNS

; *devastating of lipid storage diseases

Etiology

    ; *deficiency of β-hexosaminidase

Clinical Manifestation

    ; normally until about 5mo

    ; hyperacusis : exaggerated strtle response to noise

    ; *by end of 1st yr

           - *severe hypotonia, blindness, hyperacusis

           - *fundus : cherry-red sopt of the macula

           - enlarged head size : more than 50%

Sandhoff Disease (GM2 Gangliosidosis II)

Niemann-Pick Disease

Type A

; AR

; disorder of sphingomyelin and cholesterol storage within lysosomes

Etiology

; *increase of sphingomyelin & cholesterol in bone marrow, liver, spleen, brain

; *deficiency of sphingomyelinase

Clinical Manifestation

; brain CT or MRI

    - *gray matter degeneration, demyelination, cerebellar atrophy

Diagnosis

Type B

Type C & D

Gaucher Disease

; *glucosylceramide is stored in RES

; not involve CNS

    - infantile form : neuropathy

    - juvenile form : late-onset neurologic symptom

Etiology

; *deficiency of β-glucosidase

    - WBC, skin fibroblast에서 검사해야 된다.

Clinical Manifestation

; *splenomegaly

    - characteristics

    - due to RES involvement

    - *usually first sign

; *2nd or 3rd decade되어야 발견된다.

; hypersplesnism, bone marrow failure

    - 출생시에 나타날 수도 있고, 80세가 되어야 나타날 수도 있다.

    - anemia, leukopenia, thrombocytopenia

; *moderate hepatomegaly

; *Gaucher cell in bone marrow or spleen

; radiologic changes

    - *Erlenmeyer flask shape of long bone, esp. distal femora

Diagnosis

; *splenomegaly with mild anemia unexplained

    --> *suspicion

; confirmed by demonstration of deficiency of β-glucosidase

Gengetics

; AR

Treatment

; splenectomy

    - now rarely

; enzyme replacement

    - *ceredase(glucocerebrosidase isolated from human placenta)

    - *cerezyme(genetically engineered enzyme)

    - *15-60units/kg/4wks #2 iv every 2wks

Fabry Disease

; X-linked recessive

; *deficiency of α-glalactosidase

Schindler Disease

; AR neurodegenerative disorders

; *deficiency of α-N-acetylgalactosaminidase

    --> *accumulation of glycolipid with α-N-acetylgalactosamine in brain cortex

    --> axonal degeneration

Metachromatic Leukodystrophy (MLD)

; AR

; deficiency of arylsulfatase A

; *storage of sulfatide in esp. white matter

Multiple Sulfatase Deficiency

Krabbe Disease

; globoid cell leukodystrophy

; *progressive cerebral degenerative disease affecting white matter primarily

Batten Disease

Farber Disease

; AR

; *storage of ceramide in esp. joints

Wolman Disease

Fucosidosis

72.4 Disorder of Lipoprotein Metabolism and Transport

# hyperlipidemia

    ; increased risk for heart disease, but not all

Plasma Lipoprotein Metabolism And Transport

  (cholesterol & TG)

     ; macromolecular complexs lipoprotein 형태로 혈중으로 운반

  (lipoproteins)

    apolipoprotein ; protein component of complexs

    chylomicrons ; dietary lipoprotein  formed in & secreted by small intestine

    VLDL ; synthesized in the liver

    HDL ; secreted as nascent particles by liver & small intestine 

 

 1. Transport of exogenous (dietary) lipids (Fig. 72-10)

     Ingestion of fat-containing meal

     --> hydrolysis by intestine & pancreatic lipase

     --> FFA & cholesterol

     --> re-esterified in intestinal epithelium

     --> TG & cholesterol esters

     --> packed togather with phospholipids, free cholesterol, and

            two apolipoproteins (apoA-I, apoB-48)

     --> chylomicrons 형성

     --> secreted into intestinal lymph,

          pass through thoracic duct into peripheral circulation

     --> acquire additional apoproeins

     +--> TG (constitute most of chylomicron mass)

     |     -> immediately hydrolyzed by lipoprotein lipase at capillary epithelium

     |     -> FFA product

     |            ; transferred primary to adipose tissue for storage as TG,

     |                                 to muscle tissue for beta oxidation 

     +--> chylomicron remnants

           ; lipoprotein particles TG content 상실하여 smaller & more dense

           -> transferred some of apolipoproteins (apoC & apoA-I) to HDL

               apoB-48 & apoE content ; delived to hepatocyte

       chylomicrones & their remnants

          ; very short lived in the circulation

 

 2. Transport of endogenous lipids from the liver (Fig. 72-11)

    1) VDRL (liver secrete) 

       ; contain free & esterified cholesterol, TG, phosphilipids, apoproteins

                                      (apoB-100, apoC, apoE)

    2) TG ; adipose tissue 가서 storage

    3) VDRL remnants or intermediate density lipoproteins

            ; 일부는 hepatic cell membrane receptors 통하여 taken up   

              일부는 남아있는 TG apolipoprotein (apoB-100) 제거하여 LDL conversion 

 

 3. HDL & reverse cholesterol transport

   1) HDL

      nascent discoidal particles liver, small intestine에서 분비되며

              phospholipids protein으로 구성 

      small intestine origin ; rich in apoA-I, apoA-IV  

      deriver from liver ; predominantly apo-I, apo-II & apoE

   2) HDL VLDL, LDL, tissue로부터 cholesterol 받아들임.

         ; via lecithin (cholesterol acyltransferase reaction)

   3) HDL자체는 liver에서 대사되며, tissue-derived cholesterol liver return하는데

        vehicle 역할을 제공

      liver cholesterol bile 분비 

Plasma Lipid & Lipoprotein Levels

Normal

Table 72-6

# 1st few months of life

    ; *LDL 변화로 cholesterol level 상승 

# 15-20 yrs in both sexs

    ; little change in total cholesterol level

    ; mean total cholesterol value

           - fluctuates around 150-165 mg/dl

    ; mean LDL cholesterol levels

           - slightly under 100 mg/dL

    ; HDL cholesterol

           - constant in females

           - *decline markedly during second decade and maintained through adulthood in males

# early adulthood

    ; *marked rise in plasma cholesterol

           - *due to increase of LDL cholesterol

# adulthood

    ; *increasing rate with aging

    ; greater in male than female

    ; lower HDL cholesterol + high LDL cholesterol

           --> *much greater risk in male for atherosclerotic heart disease

# plasma TG

  ; 생후 1년간은 남녀 모두에서 일시적으로 상승하였다가 수년뒤 50-60mg/dl 떨어짐  20세쯤에는 75mg/dl 상승함 

2ndary Hyperlipidemia

   (1) 많은 hypertriglyceridemia 소수의 hypercholesterolemia

       ; 2차적으로 초래하는 exogenous factors & undelying clinical conditions 있음

         (eg, obesity : desiable weight 회복되면 hypertriglycerdemia 대개 normalizer)

   (2) hyperlipidemia 초래하는 pediatric conditions  

       hypothyroidism

       nephrotic syndrome

       renal failure

       storage disease (GSD, Tay-Sachs disease, Niemann-Pick dis)

       diabetes mellitus and occasionally other endocrine and metabolic disorders                               (congenital biliary atresia)

       other cause of cholestasis

       hepatitis

       anorexia nervosa

       SLE 

   (3)  excessive alcohol intake

         ; well known cause of hypertriglyceridemia in adults

   (4) oral contraceptives

         ; increase triglyceride levels

   (5) other drugs

         ; 13-cis-retinoic acid, thiazid diuretics, some beta-adrenergic blocking agents

   (6) treatment of underlying condition or removal of offending drugs

         ; 1st approach to management

Assessment And Treatment Of Primary Hypercholesterolemia  

Risk Of Elevated Cholesterol Levels

   (1) in 1984, Lipid Reserch Clinics Coronary Primary Prevention Trial

        ; plasma cholesterol 1% 감소될 때마다 mycardial infarction incidence 2% 감소      (2) cardiovascular disease ; children & young adult 시작됨

   (3) now a consensus

        ; cholesterol level 75th percentile 이상이면 hypercholesterolemic으로 분류되며,

          adult heart disease risk

   (4) hypertriglycerdemia

        ; hypercholesterolemia보다 lesser risk이지만 일부에서는 early development of                     atherosclerosis 관계됨

   (5) children에서 moderately raised cholesterol level 경우

       primary genetic defects

       common polymorphic variants of apoE and apoB

       2ndary causes of hyperlipoproteinemia

       inappropriate dietary habits 

Screening For Hypercholesterolemia

# parental history of elevated total cholesterol levels (>240mg/dl)

    incomplete or unavailable family histories

    other risk factors for coronary heart disease

           --> screening test ; measure total cholesterol level

    ; *total cholesterol levels < 170 mg/dl

           - no intervention & re-evaluated at 5yr

    ; *total cholesterol > 200mg/dl

         - *lipid profile performed (total and HDL cholesterol, TG, calculated LDL cholesterol)

    ; borderline cholesterol levels (170-199 mg/dl)

    - another total cholesterol

           - average total cholesterol > 170 mg/dl

           - lipid profile recommand

# family history of premature coronary heart disease (before age of 55 in a parent or grandparent)

    ; *complete lipid profile

97 Lipid profile

obtained after 24-hr fast

*LDL cholesterol = total cholesterol - [HDL cholesterol + (total triglycerides/5)]

average LDL cholesterol levels

    > 130 mg/dL ; considered to have elevated levels

  < 110 mg/dL ; considered acceptable 

  110-130 mg/dL ; borderline

# TG > 95 percentile

  ; further scrutinized

   mark for some patients with genetic forms of hyperlipidemia

Dietary Management Of Hyperlipidemia 

# *hyperlipidemic children (average LDL cholesterol > 110 mg/dL) over 2 yr

    ; best initial intervention dietary modification

# Prudent(Step I) Diet

    ; 30% of total calories as fat

           - equally saturated, monounsaturated, polyunsaturated

    ; no more 100mg cholesterol per 1000 calories (maximum 300 mg/24 hr)    

# minimum goal for dietary intervention

          LDL cholesterol level < 130 mg/dL

          ideal goal < 110 mg/dL

# Step II diet

  step I diet goals 도달하지 못한경우에 고려 

  <7% calroies as saturated fat and

  < 66 mg cholesterol/1000 calroies to a maximum of 200 mg/24hr

Other Dietary Factors

   (1) dietary fiber, especially soluable fiber

       ; modest cholesaerol-lowering effect in hypercholesterolemic individuals

        소아에서 사용할 때는 calories nutrients 부족하지 않도록 주의

   (2) monounsaturated fats

       ; lower LDL cholesterol levels &

         maintaining or even rasing HDL cholesterol level

   (3) vegetarian diets

       ; large significant cholesterol-lowering effects

Drug Therapy

   (1) recommendation

       ; 10 이상에서 적절한 diet therapy (6개월 - 1) 후에도

         LDL cholesterol level 아래 수치 이상일 경우 

      LDL cholesterol 190 mg/dL 

      LDL cholesterol 160 mg/dL and

         (a) positive family history of premature coronary heart disease (before 55yr of age)           (b) two or more other risk factors (children or adolescent) after vigrous attempt

                have been made to control these risk factors

    (diabetes, hypertension, smoking, low HDL  cholesterol, severe obesity, physical inactivity)     (2) drug therapy시는 diet therapy 계속지속함

Other Factors

  ; hypercholesterolemia management시에 other lifestyl factors premature coronary heart

    disease risk 관계있는 conditions 염두에

   (eg) lack of exercise, cigarette smoking, hypertension, obesity, diabetes

     -- controlled, minimized, or eliminated

Risk Of Screening And Intervention

   (1) screening ; completed using reliable laboratories and methods

   (2) psychosocial influence of screening

        ; sickle cell trait, alpha-1 anti-trypsin deficiency, benign heart murmur, hypertension

           -- negative psychosocial impact

Genetic Dyslipidemias

 * 1st myocardial infarction (50 yr in man, 60 yr in woman)

    ; 1/3에서 hyperlipoproteinemia 있슴

      -- 이중 1/2 dominant inharited disorder of lipoprotein metabolism

 * recent 2 yr period at  Lipid-Heart Research Center of Children's Hospital of Philadelphia

    diagnosis was made

     => dominantly inherited disorder of lipoprotein metabolism (75%)

         familial hypercholesterolemia (FH) (21%)

         familial combined hyperlipidemia (FCHL) (67%)

         hypeoapobetalipiprotenemia (11%)

         familial hypertriglycerdemia (FHTG) (1%)

Fammilial Hypercholesterolemia (Fh)

Heterozygous FH 

    ; 1/500 in the general population

    ; *common form of inherited hyperlipidemia in childhood

    ; Etiology

           - *defect in LDL receptor

           - five classes of mutations

                / null, transport defective, binding defective, internalization defective, recycling defective

    ; Clinical Malifestations 

           - premature coronary atherosclerosis

                   / *not typically develop until 3rd or 4th decade

             / peak incidence of myocardial infarction : 4th-5th decades

                   / 여자는 onset 10년정도 늦음

           - *tendon xanthomas

             / nodular swellings involving Achilles and other tendon

                   / initial symptoms in 10-15% of patients

                   / *teenager 나타나면 FH 의심해야한다.

           - *xanthelasmas

                   / deposit in soft tissue around eyelid

                   / rare in childhood

           - *arcus corneae

                   / rare in childhood

    ; Diagnosis

           - strong family history of early myocardial infarctions, tendon xanthomas

           - total cholesterol levels > 300 mg/dL in affected adults

           - affected children

                   / total cholesterol level > 250 mg/dL with LDL cholesterol > 200 mg/dL

    ;Treatment

           weight control

           step I diet followed by step II diet

           cholestyramine or colestipol resin

               - 10 이상에서 지속적으로 LDL cholesterol > 160 mg/dL 경우

               - additional benefit of increasing number of LDL receptors in liver

             - blood로부터 LDL uptake 증가시키고, liver에서 cholesterol 생성을 하향조정

           - (S/E) constipation, abdominal pain, nausea, bloating

                  fat-soluable vit 흡수를 방해 (치료 6개월후 PT 검사요함)

    nicotinic acid ; next drug of choice in adult

       Lavastatin and other HMG-CoA reductase inhibitors

           ; 19 이하에서는 사용 않도록

    * minimal goal for drug therapy

       - LDL cholesterol level of 130 mg/dL and < 110 mg/dL if possible

Homozygous FH (rare & severe FH)

plasma cholesterol level of 600 mg/dL or higher from birth

unique planar cutaneous xanthomas over knee, elbows and buttocks

tendon xanthomas, xanthelasma, and arcus corneae

coronary artherosclerosis ; frequently onset before 10yr of age

most patient die of complications of myocardial infarction before age 30

treatment

 ; regular plasmapheresis and aggresive therapies,

       such as LDL apheresis, ileal bypass surgery and portacaval shunt

   liver trasplantation

Familial Defective ApoB-100

       dominant inherited condition, 1/500 (incidence)

       moderate to marked elevation of plasma LDL cholesterol

           ; result from defective uptake by LDL receptors

       result from a single missense mutation

               causing an amino acid substitution inthe apoB molecule

Familial Combined Hyperlipidemia (FCHL)

; *frequent inherited disorder in adults(1-2 in 100)

; *high risk of mycardial infarction (10% of 1st episodes)

; Clinical Manifestation

    - hypertriglycerdemia (1/3), hypercholeserolemia (1/3), both elevation (1/3)

    - not usually associaed with tendon xanthomas

    - frequently obesity, hyperinsulinism, glucose intolerance

; Treatment

  initial dietary intervention (step I or step II)

  drug therapy

        ; bile acid sequestrants (cholestyramine and colestipol)

  weight loss in overweight child ; help lower triglyceride and choleserol levels

  resin therapy

        ; 10 이상에서 adequate step I therapy후에도 LDL cholesterol

            160 mg/dL 이상일때      

Hyperapobetalipoproteinemia

       plasma apoB level ; significantly increased

       upper normal limit of plasma cholesterol and triglyceride

Elevation Of Lp(A)

       large lipoprotein composed of LDL      

       high level of LP(a)

             ; risk factor for coronary heart disease independent of hyperlipidemia

Familial Dysbetalipoproteinemia

   (1) known as type 3 hyperlipoproteinemia

       abnormal plasma lipoproteins designated beta VLDL or

           floating beta lipoproteins

       plana xanthomas along palmar crease of hands (xanthoma striata palmaris)

            ; diagnostic

       tubereruptive xanthomas of trunk, tuberous xanthomas over elbows and knees,

            and tendinous xanthomas

       coronary heart disease and peripheral vascular disease ; commonly

Diagnosis

       basis of clinical manifestations or

           by demonstrating abnormal lipoprotein by eletrophoresis

       abnormal chemical composition of  paricles  

       cholesteol content ; high

       ratio of VDRL cholesterol to total triglycerides > 0.3

Treatment

       often exquisitely sensitive to dietary intervention

       weight loss to a appropriate for height, coupled with instition of step Idiet

           ; often cause lipid levels to return to normal

Sitosteroiemia (Phytosterolemia)

        tendon and tuberous xanthoma

           ; accelerated atherosclerosis, 특히 young males

       hemolytic episode

       arthritis and arthralgias

       very low cholesterol synthesis ; major biochemical features

       bile acid binding resins ; effective

Familial Hypertriglycerdemia

       lower risk of premature artherosclerosis

       elevaton of fasting plasma TG ; 200-500 mg/dL

       obesity, insulin resistance, hyperinsulinemia,

              glucose intolerance, and hyperyricemia

       2 이상 ; managed with weigh control and use of step I diet

Hyperchylomicronemia Syndromes

Lipoprotein Lipase (LPL) Deficiency

    ; extremely rare

    ; AR

    ; clinical manifestation  

         - eruptive xanthoma over trunk, lipemia retinalis, mild hepatosplenomagaly

           - not increased risk for artherosclerosis

           - recurrent bouts of pancreatitis

                   / *life-threatening

    ; diagnosis

           - measuring enzyme activity in plasma after administration of heparin

 treatment

  making diet low enough long-chain fatty acids

    ; to keep patient asymptmatic and free of recurrent bouts of pain

  using medium-chain-TG oil ; provide sufficient calories for growth

APOC-II Deficiency

Familial Type 5 Hyperlipoproteinemia

       marked elevation of both chylomicron and triglycerides

       eruptive xanthomas, lipidemia retinalis, pancreatitis, and

            abnormal glucose tolerance associated with hyperinsulinism

       treatment

           - primary weight control and dietary modification

           - carbohydrate restriction

           - aggresive dietary measures ; tried before drug therapy

HDL Deficiency States

   increased risk of atherosclerosis

     : extremely low levels of HDL cholesterol (10mg/dl) 많은 환자들이 inherited HDL            deficiency state Tangier disease 이다

Tangier Disease

# Homogygotes for tangier disease

  ; abnormal markedly reduced HDL conc.

    ; extremly low apo-I, low apo II

    ; low to normal LDL cholesterol levels

  ; High plasma TG level

    ; Clinical Manifestation

        - *enlarged yellowish tonsils, splenomegaly, peropheral neurupathy, hepatomegaly, lymphadenopathy, diffuse corneal infiltration

# Heterogygotes for tangier disease

       : 50%에서 HDL cholesterol, apo A-I, apo A-II normal level

         Cl/M homogygote 동일

Lecithin : Cholesterol Acyltransferase(Lcat) Deficiency

    * lipoprotein에서 cholesteryl esterase markedly reduced

    * plasma lipoprotein alteration

       : HDL,LDL -감소

       : TG-증가

       : abnormal electrophoretical mobility

    * Cl/M

       : corneal opacity,anemia,proteinuria

         sea-blue histiocyte in BM& spleen

    * extremely rare (<1,000,000)

    * Tx : no specific

         fat restriction

    * related disorder called fish-eye disease :partial LCAT deficiency

        : corneal opacity, very low level of HDL cholesterol

Other HDL Deficiency Disorders

   * complete absence of HDL(familial analphalipoproteinemia)

      : due to a nonsense mutation of the apoA-I gene

        bilaeral retinopathy,cataracts,spinocerebellar ataxia,tendon xanthomas,

          premature atherosclerosis

    * familial hypoalphalipoproteinemia

      : AD

      : HDL level 작용하는 특별한 therapy 없고 exercise,moderate alcohol intake

         영향을 미친다.

Abetalipoproteinemia And Hypolipoproteinemia

Abetalipoproteinemia

    * rare AR disease

    * childhood 특징적으로 fat malabsorption,diarrhea,retinitis pigmentosa,cerebellar

      ataxia,acanthocytosis 있다

    * Homogygotes for abetalipoproteinemia

       : lack all forms of apoB

         -> no detectable chylomicron,VLDL,HDL

    * Heterogygotes

       : no  apparent clinical or biochemical abnormalities

    * defect

       : apoB-containing lipoprotein abnormal synthesis or secretion

    * Tx

        vitamin E : neurologic& retinal degeneration 진행을 지연

        vitamin A.K

        long chain fat diet restriction

        MCT oil

Hypobetalipoproteinemia

    * AD

    * homozygotes:extremly low plasma cholesterol levels

    * heterozygotes

        : low plasma cholesterol & low -to-normal trygliceride levels

         usually asymptomatic

Chapter 73. Defect in Metabolism of Carbohydrate

73.1 Defect In Intermediary Carbohydrate Metabolism

# Why enzymatic defect affecting one tissue not be demonstrable in another tissue ?

 1. defective enzyme 정상적으로 특정 tissue 없을수 있다.

   : ) glucose-6-phosphatase musle에는 없다.

 2. enzyme activity 다른 tissue에서는 different enzyme protein 가진다.

   : ) glycogen synthetase, phosphorylase, phosphoenzyme

 3. 조직에서만 enzyme activity 측정 가능

   : ) galactokinase RBC에서는 측정 가능하나 liver에서는 측정 불가

 4. in vitro에서는 active하나 in vivo에서는 불활성

   : ) in GSD Ib, glucose-6-phosphatase

 5. enzymatic defiency suboptimal tissue handling 의한 artifact 나타날수 있다.

   : ) liver phosphorylase

73.2 Defect In Galactose Metabolism

Fig. 73-1

Galactosemia

Deficiency Of Galactokinase

# ★특징

    galactosemia

    galactosuria

    *cataract without mental deficiency or aminoaciduria

#* cataract 출생시 부터 시작

    ; *galactose galactitol convert -> cataract 발생

    ; galactose free diet cataract 예방할수 있다

  ; 다른것은 정상이기 때문에 prognosis good

# Diagnosis

  ; erythrocyte galactokinase activity deficient

  ;AR 유전

Deficiency Of Galactose-1-Phosphate Uridyl Transferase

; *classic glactosemia

; incidience -- 1 : 60000

; *accumulation of galactose-1-phosphate in kidney, liver, brain

Clinical Manifestation

    ; jaundice, hepatomegaly, vomiting, convulsion, lethargy, irritability, feeding difficulty, poor weight gain, aminoaciduria, cataract, hepatic cirrhosis, ascites, splenomegaly, mental retardation  

    ; *increased risk for E. coli neonatal sepsis

           - often precedes diagnosis

    ; galactose tolerance test 위험하므로 금지

    ; cautions

  galactose 투여

     -> intracellular galactose-1-phosphate 축적

     -> phosphoglucomutase competitive inhibition

     -> glycogen glucose conversion 억제

     -> hypoglycemia 유발

  Galactose-1-phosphate

     -> hepatotoxicity, M.R. 일으킴

     Galactitol -> catarat 야기

  ovarian toxicity -> hypergonadotropic hypogonadism

     그러나 male gonad에는 영향 없다

Diagnosis

clinitest ;

   urine reducing substance 의해

  ( galactose 대해 specific enzymatic test )

clinistix or testape urine test

   : glucose specific, galactose에는 nonreactive

erythrocyte galactose-1-phosphate 증가

electrophoretic techniques

   -> heterogeneity of defective enzyme

Prognosis

early life부터 diet에서 galactose 제거시

   severe liver cirrhosis, M.R., cataract, hypoglycemia 예방

galactose-1-phosphate level long term outcome 관계 없다

Deficiency Of Uridyl Diphosphogalactose-4-Epimerase

  1) Benign form (AR)

     no Sx

     erythrocyte galactose-1-phosphate 증가

     leukocyte, lymphocyte, RBC 영향

     no treatment

  2) generalized epimerase deficiency ( AR )

     fibroblast에서 epimerase activity 10%감소

        leukocyte, RBC에서도 감소

     Sx : classic galactosemia 유사

     Tx : galactose free diet

73.3  Defect In Fructose Metabolism

Deficiency Of Fructokinase (Benign Fructosuria)

   * reducing substance 포함된 무증상 환아의 소변에서 우연히 발견

   * 증상이 없으면 no Tx.

   * AR trait

   * present in liver, intestine, kidney

   * positive clinitest & negative clinistix test

      ; urinary reducing substance 때문

Deficiency Of  Fructose 1,6-Biphosphate Aldolase (Aldorase B) (Hereditary Fructose Intolerance)

; *appears with ingestion of fructose-containing food

    - 보통 이유식

; early clinical manifestation

    - *galactosemia 유사

  - jaundice, hepatomegaly, vomiting, lethargy, irritability, convulsion  

    - acute fructose ingestion : hypoglycemia

    - chronic ingestion : hepatic ds

; fructose-1-phosphate hepatocyte 축적되어 phosphorylase competitive inhibitor로작용

      ; glycogen glucose conversion되는것을 방해하여 hypoglycemia 유발

; fructose-1,6-diphosphate conversion 심한 감소가 있는 경우에는 fructose-free diet에서도 progress liver ds 유발

; AR

; fructose tolerance test 금기

       ( 이유; hypoglycemia, shock, death초래)

; treatment

      ; 식사에서 fructose 완전히 제거

Deficient Muscle Phosphoglycerate Mutate

  1) 증상 ; myoglobinuria, 운동후 cramp외는 정상

           Ischemic exercise후에 혈중 lactic acid농도 증가 (-)

  2) muscle biopsy

     1) glycogen농도와 enzyme activity 정상

     2) phosphoglycerate mutate activity감소

         B ( brain type ) isoenzyme 정상

         M ( muscle type) isoenzyme (-)

Deficient Muscle Type Lactase Dehydrogenase

      ; lactase dehydrogenase (LDH) M unit 합성이 안됨

  1) AR on chromosome 11

  2) 증상 ; fatigue, 운동후에 myogloburinuria

  3) muscle glycogen  pyruvate convert 되나 lactate 전환되지 않고 혈중으로 유리됨

73.4  Defect In Intermediary Carbohydrate Metabolism Associated With Lactic Acidosis

Fig. 73-2

* normal lactic acid농도 < 18 mg/dl or 2mM

  1) hypoxemia

      ; 경우 S - pyrubic acid 농도는 정상 ( < 1.0mg/dl)이므로

        S - lactate, pyruvate 동시에 측정이 필요

  2) thiamine (B1) deficiency

      ;  thiamine pyruvate dehydrogenase reaction 관여

  3) defect of carbohydrate metabolism

     pyruvate 방해 (interfere)  ----> glucose ( glyconeogenesis 경로)

     pyruvate 방해 -----> CO2 & water ( mitochondrial enzyme of citric acid cycle )

 

*  증상

  1) deep sighing respiartion of Kussmaul variety

      ; acute metabolic acidosis from hypolactic acidemia

        -> 교정하지 않으면

     coma

     respiratory failure

     cardiovascular collapse

     renal insuffiency

     death

  2) infant & child에서 unexplained acidosis 있으면서 anion gap 16 mM이상이면

        -->  blood lactic acid 측정

* 종류

Deficiency Of Glucose-6-Phosphate (GSD I)

     ; GSD I significant lactic acidosis 관련된 glycogenesis 12 type 하나           

Deficiency Of Fructose-1,6-Diphosphatase

     1) 모유만 먹는 경우에는 증상이 나타나지 않는다.

     2) formular 혹은 fructose, sucrose 과포함된 식이시

         ; intermittent hypoglycemia, shock, coma, convulsion, metabolic acidosis 초래

     3) 10시간 이상 fasting하면 hypoglycemia & lactic acidosis 초래

Deficiency Of Pyruvate Decarboxylase

       ; first enzyme(E1) of pyruvate dehydogenase complex

     1) neonatal onset

       lethal lactic acidosis

       white matter cystic lesion

       corpus callosum agenesis

       most severe enzyme deficiency

     2) infantile onset

       lethal 할수 있다

       psychomotor retadation

       chronic lactic acidosis

       brain anomaly & cystic lesion

       brain stem & basal ganglia pathology of Leigh ds

     3) old child

       ataxia c high carbohydrate diet

       intelligence 정상

Deficiency Of Dihydrolipoyl Transacetylase

      ; 2nd enzyme (E2) in pyruvate dehydrogenase complex

Deficiency Of Dihydrolipoyl Dehyrogenase

; E3

     1) 증상 ; severe

        lethargy, hypertonia, irritabilty, optic atrophy,

            hyperactive reflex with muscular hypotonia

            lower extrimity spasticity, irregular respiration

        persistent lactic acidosis high thiamine or fat diet 교정되지 않는다.

        hypoglycemia alanine 의해 relieve

     2) Lab finding

        pyruvate, lactate, alpha - ketoglutarate 혈중 농도 증가

        liver function test 정상

        tissure dihydrolipoyl dehydrogenase activity 정상의 5%이하

     3) pathology of brain

          : cavitation & lack of myelination in basal ganglia, thalamus, brain stem

           - Leigh syndrome 유사

Deficiency Of Pyruvate Carboxylase

     1) 증상

        psychomotor retardation    심하면 death

        vomiting, irritability, lethargy, progressive motor mental retardation, hypotonia,

           hyporeflexia, abnormal eye movement, optic ataxia & convulsion.

        Dx of psychomotor retardation & death of sibling

              : suggested Leigh syndrome

     2) Lab

        blood lactate, pyruvate, alanine 농도 증가

        CSF protein 상승

        liver size 정상이고 liver & muscle glycogen증가

             : glycogen 투여후 혈중 glucose 농도는 normal increase

     3) Tx

          : thiamine

Deficiency Of Pyruvate Carboxylase Secondary To Deficiency Of Holocarboxylase Synthetase Or Biotinase

; deficiency of enzymes of biotin metabolism

    - *holocarboxylase, biotinidase

    --> *secondary deficiency of pyruvate carboxylase

; Sx

  - *skin rash, lactic acidosis, alopecia

    - biotinase deficiency protaction

           --> intermittent exacerbation of chronic lactic acidosis, failure of thrive, hypotonia

       --> spasticity, lethargy, coma, death

; reversed by oral biotin, 10mg/24h

Carnitinine Deficiency States

     1) Sx

        recurrent attack of severe metabolic acidosis

             ( lactic & pyruvic acidemia )

        hypoglycemia

        hepatomegaly

        cardiomegaly

     2) untreated persistent psychomotor retardation으로 사망

 

     3) correction of acidosis & IV glucose

          : 12-24시간내에 crisis 중단됨

     4) carnitine concentration

          : reduced in serum, liver, muscle, heart

     5) carnitine def. state primary carnitine def. 같이 나타날 있다

     6) secondary carnitine deficiency에서 serum & tissue carnitine 농도 감소

  

         * two group

            (1) increased loss or decreased intake of carnitine

            (2) carnitine ester 축적

                 : excreted urine, draining carnitine body

   

             (group 1)

                 renal Fanconi syndrome

                 type ? glycogenosis

                 cystinosis

                 Lowe syndrome

                 suboptimal diet

                 renal dialysis

       

             (group 2)

                 defect in oxidation of fatty acid

                 organic acidemia

                 Tx /c anticonvalsant drug(valporic acid)

 

     7) main danger by primary & secondary carnitine def.

          : threat to transfer of fatty acid into mitochondria

             (βoxidation & energy production)

     8) Tx

          : oral L-carnitine in divided dose of up to 200mg/kg/24hr

Deficiency Of Pyruvate Dehydrogenase Phosphatase

    ; found in newborn boy

        - *metabolic acidosis /c high concentration of lactate, pyruvate, free fatty acid

    - no hypoglycemia or hepatomegaly

    ; glucose intake증가시나 fat감소시 acidosis improve

  ; neurologic damage

    - lethargy, convulsion, hypotonia, irritability

    ; 6mo death

Congenital Idiopathic Lactic Acidosis

     1) Sx.

       labored respiration in infant

           : metabolic acidosis from hyperlactic acidemia 연관

       convulsion, hypoglycemia,

           neurogic damage death in infant

            (thiamine, biotin, steroid, lipoic acid 투여에도 불구하고)

     2) pyruvate, lactate, alanine, other aminoacid 혈중농도 감소

Leigh Subacute Necrotizing Encephalopathy (SNE)

     1) 원인 : pyruvate carboxylase

              pyruvate decarboxylase

              pyruvate dehydrogenase def.

     2) 특징

        seizure

        psychomotor retardation

        optic atrophy

        hypotonia

        vomitng

        abnormal movement

        lethargy

        lactic acidosis

     3) critical criteria for pathologic diagnosis

       gliosis, cavitation, capillary proliferation in brain stem, basal ganglia, thalamus

         : visible in CT scan

     4) Treatment

        thiamine

        dichloroacetate

             : correct lactic acidemia

              --> inhibit inactivating kinase for pyruvate dehydrogenase (E1)

        THAM ( tris-hydroxymethyl aminomethadone )

             : acute, life-threatening hyperlactic acidemia

             : 대개 poor prognosis 영향을 주지 못함.

73.5  Glycogen Storage Diseases

 ; result of metabolic errors leading to abnormal concentrations or structure of glycogen

Deficiency Of Glycogen Synthetase(GSD 0)

## 1) typical symptoms

       Early morning convulsions

       hypoglycemia

    2) hyperketonemia & no hepatomegaly

    3) (fasting) hypoglycemia - during periods without food

                                glucagon투여에 not responsive

       After administration of glucose

       -> b-glucose level remains elevaled for longer than usual

    4) ketotic hypoglycemia sx비슷

    5) Dx - hepatic glycogen synthetase assay

            ; deficient glycogen synthetase activity in liver

              (but,  normal in muscle, WBC, RBC)

          - glucose투여후의 persistent hyperglycemia & serum lactate

            ; glycogen synthetase 결핍을 반영

    6) Glycogen concentration in liver ; low (< 2%) but not absent

       (normal in muscle)

    7) Tx - frequent meals rich in protein

            ; hypoglycemic episodes & mental retardation can be avoided

Deficiency Of Glucose-6-Phosphatase (GSD Ia)

(=Von Gierke ds, hepatorenal glycogenosis)

Etiology

; *defective glucose-6-phosphatase activity

; *glycogen conc. in liver, kidney, intestine

Clinical Manifestation

; no primary effect on muscle

  - because *muscle not normally contain glucose-6-phosphatase

; marked hypoglycemia

    - *may be well tolerated

    - b-glucose levels 10mg/dL이하에도 normal behavior보일 수있음

; *hyperlipidemia (producing xanthomas)

; *hyperuric acidemia

    - later gout in adult

; *secondary impairment of plalelet function

    - bleeding tendency

; hepatomegaly

; kidneys moderately enlarged : GSD III DDx에도움(GSDIII - n'l)

; *doll face, stunted growth, normal mental development

hypoglycemia

   galactose or fructose투여 : glucose증가(-)

                                - severe acidosis 초래가능

   iv glucagon or sc Epi. : glucose증가(-)

      * GSD III ; 2hr after meal glucagon투여시 b-glucose증가

; Acute lactic acidosis

    - *recurrent & life-threatening problem

Treatment

   Portacaval shunt : not beneficial

   continuous nighttime feedings by nasopharyngeal or gastrostomy tube

   repeated daily drinking of solution of uncooked cornstarch

   Disease-related post-treatment hypoglycemia may result in convulsions

   frequent meals : gastric tube feedings 유사한  effects

   grow older -> metabolic problems less severe & more easily manageable

6) nuclear glycogenosis

   : hepatocytes many lipid droplets, nucleus glycogen

   GSD Ia

   GSD III

   DM

   Wilson's Ds

7) hepatoma incidence : Abd. exam. by ultrasound or CT scan q 6-12mo

8) Prenatal Dx using amniotic fluid cells 불가

   ##() glucose-6-phosphatase

     정상적으로 cultured skin fibroblasts WBC 없다

GSD Ib (Pseudo-GSD I)

; transport defect of glucose-6-phosphatase at microsomal membrane

; clinically indistingishable from GSD Ia

    - ★다른점

           / *increased incidence of neutropenia, inflammatory bowel disease, infections

           / Neutropenia : responds to G-CSF

Hepatic glycogen concentration

 glucose-6-phosphatase activity

    +- normal in hypotonic homogenates made of frozen liver tissue

   +- decreased in isotonic homogenates made from fresh liver tissue

 --> defect; transport glucose-6-phosphatase across microsomal membranes

GSD Ic

    1) transport of inorganic phosphates at microsomal membrane

    2) Liver glycogen concentration : 9.4%

       but frequent hypoglycemic attacks -> therapeutic glucose adm.

                                         -->increased glycogen concentration

    3) Mauriac synd. in diabetic children Sx 유사

Deficiency Of Lysosomal Acid α-Glucosidase (GSD II)

(=pompe ds, generalized glycogenosis, cardiac glycogenosis)

# GSD IIa

    ; infants - infantile fatal form

  ; lysosomal acid α-glucosidase구조이상

# GSD IIb

    ; older children & adults - late juvenile-adult form

  ; enzyme amount감소

# Abnormal lysosomes

    ; morphologic hallmark

# *GSDII lysosomal ds이고 나머지는 모두 cytoplasmic ds

# gene of acid α-glucosidase : chromosome 17

GSD IIa (=Pompe Ds, Infantile Fatal Form, Classic)

    ; classic form of generalized glycogenosis

    ; always fetal within 2yr after birth

    ; at birth

        - healthy, normal muscle tone & liver size

           - *heart size & EKG

                   / short PR, ventricular hypertrophy

         / *marginally abnormalities

    ; after a few weeks or months

           - *completely flaccid, extreme cardiomegaly, typically only moderately hepatomegaly

           - *alert & normal intelligence

  ; aspiration pneumonia, atelectasis

        - due to cardiomegaly->bronchial compression

    ; death due to failure of respiratory m.

    ; *normal b-glucose concentrations & tolerance tests

    ; Diagnosis

           - *intracellular vesicles(abnormal lysosomes) engorged with glycogen in liver, muscle, heart, most other tissue

        - prenatal Dx : by EM of cells obtained by chorionic villus biopsy or at amniocentesis

GSD IIb (=Late Juvenile-Adult Form)

         skeletal m. weakness : later onset

         respiratory failure can occur during the 3rd or 4th decad

         cardiomegaly(-)

         Dx : EM of skin biopsy

              - abnormal lysosomes packed with glycogen particles

Deficiency Of "Debrancher" Activity (GSD III)

    (limited dextrinosis, debrancher glycogenosis, Cori ds, Forbes ds)

    1) Sx

       hepatomegaly

       muscle involvement : m.dystrophy유사      -+  varying degree

       heart : moderate cardiomegaly, normal EKG -+

       kidneys : normal

       hypoglycemia : rare

       recurrent pneumonia : may be

       Px : usually good

    2) s-uric acid, lactate, ketone, lipids : normal

 ## 3) glucagon 2hr after meal -> glucose증가 (GSD I : not)

       glucagon after overnight fasting -> flat : GSD I & III

    4) "debranching" of glycogen molecule (2 enzymatic reactions)

     +- transferase : transfer 3 glucose units of branched outer chain onto

     |                   straight outer chain

     +- α-1,6-glucosidase

      대개 generalized or liver or mucsle involve

    5) limit dextrin

       : GSD III에서 starvation glycogen within 4 units of branch point

         degradation되는데 이러한 short outer chains 가진 glycogen limit dextrin이라함

    6) DDx c GSD I by LM

        formation of fibrous septa

       more extensive nuclear glycogenosis

       paucity of intracellular lipid droplets

    7) hepatic cirrhosis : not usually

Deficiency Of "Brancher" Activity (GSD IV)

    (Amylopectinosis, brancher glycogenosis, Andersen ds)

    1) Sx

       hepatomegaly & splenomegaly

       hepatic cirrhosis, ascites, death in childhood from liver failure

    2) Tx : corticosteroids - may induce temporary remission

            liver transplantation

    3) cirrhosis may be result of the amylopectin-like glycogen

    4) amylo-1,41,6-transglucosidase,"brancher" enzyme

Deficiency Of Muscle Phosphorylase (GSD V)(=McArdle Syndrome)

; wide clinical spectrum

    - from almost no Sx to recurrent myoglobinuria, attacks of rhabdomyolysis, unremitting muscle pain

; muscular pains & cramps after exercise

    - *characteristics differentiating from other muscle cramp

; Diagnosis

    ischemic exercise test

    blood samples from antecubital v. of the ischemic arm during exercise

   : s-lactate증가없음(;inability to produce lactate from glycogen)

    magnetic resonance spectroscopy : pH, ATP, phosphocreatine측정

   (both aerobic and ischemic exercise후에)

    Molecular diagnosis of DNA from chromosome II

           : characteristic restriction endonuclease mutations

         skeletal m. phosphorylase activity(-)

         peak demand for energy m. glycogen분해안됨

; Treatment

    - excessive exercise피함

  - high protein diet

Deficiency Of Liver Phosphorylase (GSD VI)

; hepatomegaly may be massive

    - otherwise no Sx

; *no hypoglycemia, some elevation of serum lipids & transaminases

; glucose conc. not increase after glucagon

Deficiency Of Muscle Phosphofructokinase (GSD VII)

     1) Sx : GSD V 유사

             but, m. pain & cramping after exercise may be more severe

     2) deficient phosphofructokinase in skeletal m.

        liver : n'l

        RBC : only partially defective

Progressive Brain Disease And Deactivated Liver Phosphorylase Without Demonstrated Enzyme Defect (GSD VIII)

    ; *hepatomegaly without hypoglycemia soon after birth

    ; Clinical Manifestation

           - CNS symptoms : unique

                   / nystagmus & rolling of eyes, ataxia, truncal tremor, hypotonic

                           --> spastic, loss of rapport with environment, unresponsiveness, aspiration Pn

    ; urine epinephrine & norepinephrine : may be

    ; glucagon tolerance test : n'l

Deficiency Of Liver Phosphorylase Kinase (GSD IX)

# 3 forms according to inheritance & tissue distribution

    ; GSD IXa : AR

  ; *GSD IXb : XR

  ; GSD IXc : AR

# IXa & IXb

    ; *not affected skeletal muscle & normal biochemistry

# IXc

    ; deficiency of phosphorylase kinase activity of liver & muscles

 hepatomegaly

 : massive in early life

      -> older, may disappear completely in teenage & adult

 - can be classified as a benign hepatomegaly

 hypoglycemia : unusual

 transaminases : minimally elevated

 glucagon : normal rise in b-glucose

 glucagon tolerance curve remains flat

 no treatment

Deficiency Of Cyclic 3'5'-Amp-Dependent Kinase (GSD X)

     1) marked hepatomegaly at 6 yr of age

        GSD IX유사

        cf) GSD IX DDx : IV glucagon b-sugar curve flat

     2) 6 yr later

         ; m. pain, cramping after exercise, minimal persistent m. weakness

        ischemic exercise test- normal

        hepatomegaly - persistent

     3) doing well without specific therapy

Hepatic Glycogenosis With Stunted Growth (GSD XI)

     1) greatly enlarged liver & markedly stunted growth

     2) s-transaminase & lipid : may be elevated

     3) phosphate supplememation po(-) severe hypophosphatemic rickets

          early in life

     4) After puberty : hepatomegaly may

                        growth rate may (but, remains far below normal)

                        s-phosphate remains normal without supplementation

Prenatal Diagnosis Of GSD

# all AR

  ; except GSD IXb : XR

# assay of cultured amniotic fluid cells(수주간 소요됨)

    ; Ix : GSD IIa & IV

    ; GSDI은불가능

           - glucose-6-phosphatase normal cultured amniotic fluid cells에없다.

           - , liver biopsy prenatal Dx가능

     3) GSD I, GSD III, GSD VI, GSD IX, and GSD X prenatal Dx 불필요

        (  near-normal lives). In GSD Ila and GSD

# 3일내 Dx가능

  ; GSDIla after amniocentesis through EM

           of uncultured amniotic fluid cell or EM of chorionic villous Bx

            ; abnormal intracellular lysosomes

               that are not present in heterozygous

73.6 Deficiency of Xylulose Dehydrogenase (Essential Benign Pentosuria)

 

     1) benign condition : reducing substance in urine (특징적)

                           otherwise healthy (탄수화물대사이상중 임상증상없는것)

     2) pentosuria : react with Clinitest

        but not with glucose oxidase test papers(Testape or Clinistix dipsticks

         3) L-xylulose-+->xylitol-->D-xylulose-->D-xylulose-5-phosphate=>pentose phosphate

                  |                                                  shunt

            L-xylulose dehydrogenase

        this enzyme deficiency ; L-xylulose in blood and urine

     4) most common in Jews

        No Tx

73.7 Deficiency of Acid α-Mannosidase

     (Mannosidosis)

     : Hurler synd.유사

     1) hepatosplenomegaly in this lysosomal ds

     2) lymphocytes contain vacuoles

     3) dysostosis multiplex(bone x-ray)

     4) frequent infections(esp. middle ear & lungs)

     5) corneal or lenticular opacities and psychomotor retardation

     6) No available treatment

Chapter 74. Disorders Of Mucopolysaccharide Metabolism

; inherited disorders caused by

   incomplete degradation and storage of acid mucopolysaccharides

       (glycosaminoglycans).

     ; Specific degradative lysosomal enzyme deficiencies for all MPS

 2) 특징          

   a. Dermatan sulfate, heparan sulfate, and keratan sulfate

       ; major mucopolysaccharides in the pathogencsis of the MPS.

   b. mucopolysaccharidcs  connective tissue intercellular substance 주요

      성분이므로 bony changes MPS 특징이다.

     - skeletal deformities seen in rentgenograms ; dysostosis multiplex

   c. CNS affect --> progressive mental retardation

   d. In addition, CV system, liver, spleen, tendons, joints, and skin involved

# 유전양식

       대부분 ; autosomal recessive

        예외 ;  X- linkcd recessive ---- Hunter syndrome

  ** mental retardation & corneal clouding 유무에 주의 ! 

Hurler Syndrome (MPS IH)

; *severe of the mucopoIysaccharidoses

; relentless progression --> death by the early teenage years.

Etiology And Pathology

; deficiency of *α-L-iduronidase

        --> *accumulation of the dermatan and heparan sulfates in tissues and their urinary excretion

Clinical Manifestations

    ; appear normal at birth,

  ; during the 1st yr of life

           - only slight developmental delays

    ; Physical examination

     1) hepatosplenomegaly

     2) exaggerated kyphosis

     3) *persistent nasal discharge, noisy breathing.

     4) facial features

               - progressively coarser after the 1st yr of life

                   - head

                           : large and dolichocephalic, frontal bossing and prominent sagittal and metopic sutures

                   - depressed bridge of the nose, broad and flat nose

                   - *clouding of the corneas : evident at about 1 yr of age.

      5) Umbilical and inguinal hernias

    ; mental retardation becomes obvious

  ; downhill course continues rapidly after the 2nd or 3rd yr of life

Roentgenographic Changes

.( dysostosis multiplex)

    - large dolichocephalic skull and thickened calvarium

      hyperoslosis of the cranium

      sella turcica ; boot or J shaped

    - medial third of clavicle ; thickened

    - vertebral bodies

        ; ovoid in the lower thorax and upper lumbar regions

        ; beaklike projections on their lower anlerior margins,

          while their upper portions remain hypoplastic (Fig. 74-2)

          --> gibbus deformity commonly seen in these patients.

    - ribs ; spatulated or oar shaped

    - pelvis ; flaring of the iliac bones, with shallow acetabulae

    - hips ; progressive coxa valga deformity,

    - hands

        tapering of the terminal phalanges

        widening at the distal ends and tapering at the proximal ends

        of the metacarpals.

       ( 5th metacarpal -- the first to show these changes) (Fig. 74-3)

    - the articular surfaccs of the radius and the ulna ; V forming

      ( Fig. 74-3).

Diagnosis

    -  suggested by presence of clinical and X-ray finding

    -  furthur support; urinary excretion of dermatan and heparan sulfate

    -  definitive diagnosis

            ; detection of α-L-iduronidase deficiency

             in WBC,serum or cultured skin fibroblast

Genetics

    - AR

    - Chromosoma] loca]ization of the iduronidase gene;short arm of chromosome 4

       (4p16.3)

    - most frequent mutation associated with Hurler disease

       ; substitution of AA tryptophan  with a stop codon in position 402

Scheie Syndrome (MPS IS)

; *mildest of MPS

; distinct clinical and genclic entity

    - *enzyme deficiency ofα-L-iduronidase (same as Hurler ds) but specific for dermatan sulfate

Clinical Manifestations

    - normal intelligence

    - mild facial coarsening with striking prognathism

    - joint stiffness typified by claw hands, and carpal tunnel syndrome

    - Corneal clouding ; constant feature (--> loss of visual acuity)

    - Aortic regurgitatiun;  common

    - 임상증상은  5 지나서 나타나며, 거의 정상 생존보이고,정상 키를 가진다.

Roentgenographic Changes

    - mild dysostosis multiplex, without vertebral changes or the gibbus

      deformity

Diagnosis

    - Early clinical diagnosis ; dilficult

    - helpful; Detection of urinary dermatan sulfate

    - confirmed; deficiency of α-L-iduronidase in WBC or in cultured skin

      fibroblasts.

Genetics

    - mildest form of iduronidase deficiency diseases

Hurler-Scheie Syndrome (MPS IH/IS)

Etiology

    - α-L-iduronidase deficiency specific for dermatan sulfate

    - recent work ; as an allelic mutation of the iduronidase gene

Clinical Manifestations

    - mental development ; normal

    - mild coarseness of facial features, corneal clouding, shortness

      of stature, joint contractures, hepatosplenomegaly, hernias,

      cardiac valvular lesions,

      primarily mitral insufficiency (Fig. 74-4)

    - first 2 yr of life  early childhood 시작됨.

    - compatible with long life

Roentgenographic Features

    - severe dysostosis multiplex with findings identical to Hurler syndrome,

                                                 except no gibbus.

Diagnosis

    - findings of dermatan sulfate in the urine and α-L-iduronidase deficiency

    - SCHEIE disease 차이

      ; clinical pattern of onset of joint involvement and

        the severity of skeletal deformities

Genetics

    - mutations with moderate phenotype severity

      ; mutation R89Q (arginine is substituted for glutamine)

Hunter Syndrome (MPS II)

; *only X-linked disorder among the MPS

; milder than Hurler syndrome with respect to the skeletal and mental defects

; enzyme deficiency of *iduronosulfate sulfatase in tissues

    --> *dermatan and heparan sulfate ( stored in tissues and excreted in the urine)

Type A

    ; "classic" form of hunter syndrome

    ; *coarseness of facial features, shot stature, joint stiffness, hepatosplenomegaly, hernia

    ; mental retardation ; severe

  ; Hurler syndrome 비해 

       - slow progressive disease process

           - mild dysostosis multiplex

    ; corneal clouding ; usually absent

    ; common hearing loss

    ; Skin changes

           - also frequent,

    - small raised papules in shoulders, scapulas, and lower back

    ; Cardiac involvement; often

    ; no gibbus deformity

  ; Life expectancy ; usually extends into the late teens or early 20s.

Type B

      - milder disease than type A

      - Retardation ; usually lacking or very minimal

      - physical-features ; similar to but milder than type A

      - longer life expectancy

      - AW obst caused by mucopolysaccharide accumulation in the trachea

         and bronchi

           ; complicating feature of type B

Diagnosis

      - physical features, dysostosis multiplex, and dermatan and heparan

         sulfaturia

        ; suggest either Hurler or Hunter syndrome

     but sex-linked inheritance & iduronosulfate sulfatase deficiency in serum,

                                   white blood cells, or cultured fibroblasts

          --> confirm diagnosis of Hunter syndrome

Genetics

      -  X-linked disease

      -  gene localized to the Xq28 region close to the fragile X sile

      -  Southern blot analyses of genomic DNA

          ; gross deletion of the iduronosulfatase gene

Sanfilippo Syndrome (MPS III)

; *excessive urinary excretion of exclusively heparan sulfate

; coarse facial appearance and skeletal involvement

  - milder than Hurler and Hunter syndromes

; four enzymatic variants

Clinical Manifestations

      - delayed developmental milestones and usually hyperaclive

      - 1st decade말경, rapid neurologic delerioration; unsteady gait, bedridden

         -->대개 10 중반에 사망

      - Mental retardation, some joint stiffening, hepatosplenomega]y,

        hernias, dysostosis multiplex ;  common

   ***- dwarfism and corneal clouding ; rare.

Diagnosis

    - considered ;  heparan sulfaturia, hepatosplenomegaly, mental retardation,

                      dysostosis multiplex

    - confirm;  different enzymatic variants by specific enzyme assays

Sanfilippo A Syndrome (MPS III A)

    ; *Sulfamidase deficiency

Sanfilippo B Syndrome (MPS 111 B)

 -- α-N-acetylhexosaminidase deficiency

Sanfilippo C Syndrome (MPS III C)

 -- acetyl CoA deficiency:

α-glucosaminide N-acetyltransferase.

Sanfilippo D Syndrome (MPS III D)

-- N-acetylglucosamine-6-sulfatase deficiency

Genetics

    - AR caused by four different enzyme defects

    - genc localized to the long arm of chromosome 12 (12q14); Sanfillipo D

Morouio Syndrome (MPS IV)

; *keratan sulfaturia & skeletal dysplasia

; accumulation of keratan sulfate & chondroitin-6-sulfate in tissue

Clinical Manifestations

 mental involvement 결여

  severs somatic manifestation나타냄.

 출생시는 인지되지않음

  1세경에  Joint laxity  short stature나타남

 Skeletal abnormalilies; flat vertebrae,  short neck, genu valgum,

                            flat feet,

                       large and unstable knee joints, large elbow joints,

                       and large wrists with ulnar deviation

                       short trunk and short stature

 odontoid process ; underdeveloped

         --> atlantoaxial subluxation or translocation, with spinal cord

             compression.     

 - Corneal clouding ; apparent at  early age

 Hepalosplenomegaly ; not as pronounced as in  other MPS

 Cardiac manileslations; secondary to respiratory failure

                   caused by kyphoscoliosis and restricted chest movements

                    ( aortic regurgitation 합병되기도함)

 - usually die in their 3rd or 4th decade from cor pulmonale by the severe                                              abnormalities of the chest and spine.

Roentgenographic Changes

     - vertebral bodies ; height loss and ant tonguelike projections

                  ( 2yr  platyspondyly 명확해진다)

     - long bone ; short  / metaphyses ; irregular

     - pelvis ; wide acetabulae with progressive sub & dis of the lemoral heads

     - metacarpal bones ; short and wide with conical tapering

                          of their proximal ends

     - distal ends of the radius and ulna face one another

Diagnosis

     - spondyloepiphyseal dysplasias may mimic the signs of Morquio syndrome

                                    both clinically and roentgenographically.

     - Screening tests for acid mucopolysaccharides in the urine ; negative

        있기때문에 질적보다는 양적인 isolation method 선호된다.

     - enzyme determination; essential for differentiating

Morquio Syndrome Type A (MPS IV A)

    ; deficiency of *N-acetylgalactosamine-6-sulfate sulfatase

Morquio Syndrome Type B (MPS IV B)

    ; deficiency of *β-galactosidase

  ; 2 Type 중요한 임상적 감별점

           - *lack of enamel hypoplasia in type B

 Genetics

     - autosomal recessive

     - type A ; gene locus at long arm of chromosome 16 (16q24.3)

     - type B ; gene locus at  short arm of chromosome 3 (3p21.33)

Keratan And Heparan Sulfaturia (MPS VIII)

     - Urinary studies; excessive excretion of both keratan and heparan sulfates

.    - Enzymatic assays ; N-acetylglucosamine-6-sulfate sulfatase deficiency

                           specific for keratan sulfate

Maroteaux-Lamy Syndrome (MPS VII)

     ** 임상적으로 Hurler disease 유사하나, mental retardation 없다.

     *  two clinical types

             severe form - type A,

             milder form, with less pronounced skeletal deformities - type B.

Clinical Manifestations

       -  Coarse facial features ; typical

       -  head ; enlarged,

          neck and trunk ; short.

          chest ; pectus carinatum deformity

          Claw hands and other joint contractures ; common

          abdomen protrudes owing to hepatosplenomegaly (Fig. 74-5)

          Umbiiical hernias and corneal opachies ; frequent

          Mental ability ; usually not impaired

            although hydrocephalus and increased ICP - sometimes associated

          Cardiac involvement includes mitral insufficiency

              and aortic regurgitation

       -  roentgenographic findings are those of dysostosis multiplex seen

            in Hurler synd.        

Diagnosis

; *elevated urinary dermatan sulfate

; *N-acetylglucosamine-4-sulfate sulfatase (arylsulfatase B) deficiency

Genetics

       - autosomal recessive

       - gene localized on the long arm of chromosome 5 (5q13-5q14)

β-Glucuronidase Deficiency (MPS VIII)

 HSM, umbilical hernia, thoracolumbar gibbus, and mental retardation

 roentgenographic changes ; dysostosis multiplex

 biochemical findings ; mucopolysacchariduria of chondroitin 4/6 sulfate

 definitive diagnosis ; β-glucuronidase deficiency in WBC &

                                           in cultured skin fibroblasts.

Genetics

          ; AR

          ; gene localized to chromosome 7 (7q 21.11)

Differential Diagnosis Of The MPS

   1.multiple sulfatase deficiecy

         - mimic in its clinical, X-ray, mucopolysacchariduria

         - mental and neurologic deterioration ; usu more rapid

         - severe ichthyosis, hepatomegaly ; 질환의심.

  2.GM1 gangliosidosis (generalized gangliosidosis) 

         - lipid and mucoplysaccharide storage diseases

  3.Mannosidosis

         - psychomotor retardatiion, hearing loss, coarse features( Hurler-like)

           hepalosplenolnegaly, muscular hypotonia, mild dysostosis multiplex

         - no mucopolysacchariduria, but mannose-rich oligosaccharide

           in the urine

  4.fusidosis

  5.Aspartylglucosaminuria (AGU)

  6.Mucolipidose I, II, III, IV

  7.spondyloepiphyseal dysplasia ; lack of mucopolysacchariduria

  8.Kneist syndrome

         - usually confused with Morquio syndrome

         - radiologic findings ; generalized osteoporosis with poor modeling

         - keratan sullaturia

         - specilic enzyme deficiency of Morquio synd ; (-)

                    table 74-1

Treatment Of The Mucopolysaccharidoses

  ;Bone marrow transplantation

     --> mucopolysaccharide in serum ana urine (-),intellectual improvement,

         clear cornea,smaller liver & spleen

         Skeletal changes 개선되지않음.

         (그러나 transplant 일찍시행하면 skeletal deterioration minimal)

       

   * Prenatal diagnosis and carrier delection

              ; available for all the MPS

74.1 Mucolipidoses

 : lipidoses mucopolysaccharidoses cl/m 보임

 : little evidence of true storage of lipids or mucopolysaccharides

 : Fucosidosis, GM1 gangliosidosis, multiple sulfatase deficiency 포함됨

 : AR traits. no specific treatment

Mucolipidosis (ML-I), Lipomucopolysaccharidosis, Or Sialidosis Type 2 (Infantile Onset)

  - 생후 1년에 Sx. evelop

  - Hurler-like features with dysostosis multiplex, moderate mental retardation,

    visceromegaly, corneal clouding, cherry-red spot, seizures,

    vacuolated lymphocytes, and coarse fibroblast inclusions,

     but no mucopolysacchariduria

  - 일부 appear relatively normal at birth

    but all - develop progressive severe clinical marfifestattons

  - also a congenital type 2 form

      : characterized by hydrops fetalis, neonatal ascites, hepatosplenomegaly,

                        stippling of the epiphyses, periosteal cloaking,

                        stillbirth or death during infancy

  - Infantile and congenital : isolated neuraminidase deficiency

  - "juvenile" type 2 form of sialidosis (ML1)

     : galactosialidosis

     : 특징 primary β-galactosialidase & neuraminidase deficiencydeficiency

     : 임상 양상은 infancy에서 adulthood까지 어느 때나 발생 가능

    +- In early infancy - a phenotype similar to gangliosidosis

    |                     edema, ascites, skeletal dysplasia, cherry-red spot

    +- Later - dysostosis multiplex, visceromegaly, mental retardation,

               dysmorphism, corneal clouding, progressive neurologic

               deterioration, bilateral cherry-red spots

  - storage compounds : predominantly sialylated oligosaccharides

       similar to those excreted by children with other types of sialidose

  * Sialidosis type 1

      : cherry red spot, myoclonus phenotype and the absence of somatic

        features(coarse facies and dysostosis multiplex)

      : onset age : variable

                    but usuallyoccurs in the 2nd decade of life

  * Sialidosis types 1 and 2

     : result from inherited deficiencies neuraminidase

     : at least 2 forms

     : urine에서 large amount acid terminal oligosaccharides,

          sialylglycopeptides

     : Kupffer cells, hepatocytes : vacuolated

     : Sural nerve biopsy - metachromatic myelin degeneration

     : deficient in glycoprotein sialidase activity

     : Ganglioside sialidase : normal

     : Diagnosis - based on measurement of neuraminidase activity

                   in fibroblasts or white blood cells

     : Prenatal diagnosis - can be made using cuhured amniotic cells.

     : expression of the glycoprotein-specific neuraminidase 관련된

       2 genes

       - sialidase deficiency type 2 : mutation in a structural gene

           on chromosome 10

       - neuraminidase deficiency in a galactosialidosis

           : caused by a mutation on a gene located on chromosome 20

ML-II Or I-Cell

 - first few mo 증상 발현

 - Hurler syndrome GM1 gangliosidosis (type 1) 비슷한 임상 양상

 - 동반 이상 : CDH(congenital dislocation of the hips), inguinal hernias,

              hypertrophy of the gums, restriction of motion in the shoulders,

              generalized hypotonia, thick and tight skin, hepatomegaly

 - coarse facial features 나이가 들면서 뚜렷해짐

 - Progressive, severe psychomotor retardation 발생

 - Characteristic bone changes - severe dysostosis multiplex 연관되어 발생

    -+-> cloaking of the appearance of long tubular bones

     +-> shortening of vertebral bodies

     +-> other significant changes in the pelvis, hands, ribs, skull

 - 2-8 pneumonia or CHF 사망

 - Urine - mucopolysaccharides : normal

         - sialyloligosaccharides : elevated

 - Fibroblast cultures - characteristic inclusions

 - Enzyme stuldies

     : greatly increased lysosomal enzymes in serum

         - whereas values in leukocytes : near the normal range

     : Activities of almost all lysosomal enzymes

          - deficient in cultured skin fibroblasts

          - whereas the culture medium has an excess of these enzymes compared

            with those of control fibroblast lines

   * Normally, the targeting of lysosomal enzymes to lysosomes is mediated

     by receptors that bind mannose-6-phosphate recognition markers

       on the enzymes

   * The marker is synthesized in a two-step reaction in the Golgi complex.

      UDP-N-acetylglucosamine : defectve in ML-II and ML-III

            - lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase,

            - the enzyme catalyzing the first step in this process,

            --> newly formed lysosomal enzymes cannot be phosphorylated.

 - specific phosphotransferase activity (measured in fibroblast cultres)

   --> specific Dx. test for +- patient

                             +- carriers identification

                             +- prenatal dlagnosls

 - Tx. : no effectlve treatment

         one patient : responded favorably to bone marrow transplantation

         Supportwe medlcal and orthopedic care : important

ML-III or Pseudo-Hurler Polydystrophy

 - milder form of ML-II

 - After possibly delayed early psychomotor development

    affected 3-4 yr-old children에서

       progressive joint stifness, short stature, mild dysostosis multiplex,

       mild gingival hyperplasia, normal urinary mucopolysaccharide levels

 - Corneal cloudlng or nystagmus : may be present

 - IQ : 50에서 normal까지

 - Px. : unknown, 일부에서 20대까지 생존

 - Orthopedic treatment : may be indicated in some cases

 - I cell disease 같이 serum lysosomal enzymes - elevated

   cultured skin fibroblasts

   --> characteristic inclusions and decreased activities for many lysosomal

        enzymes

 - Measurement of UDP-N-acetylglucosamine-1-phosphotransferase activity

    using exogenous substrate

   --> more residual activity than in ML-II

 - Prenatal diagnosis

    <-- exam. of cultured amniotic fluid cells

 - Tx

     : no effective treatment

       but supportive medical and orthopedic management - may be helpful

ML-IV

  - recently described mucolipidosis

  - Most cases : in children of Ashkenazi Jewish descent

  - 출생직후부터 affected children bilateral corneal opacitics, strabismus보임

  - Corncal clouding : appear after several years

  - Retinal degeneration

  - After 6 mo

     : hypotonia and psychomotor retardation

  - Surviving pts --> retarded to about the 1-yr level

  - no skeletal dysplasia or excess excretion of opolysaccharides in the urine

  - grossly abnormal storage bodies in the cells

      of the liver, brain, conjunctiva, fibroblasts

  - prognosis : uncertain

                One patient has reached 24 yr of age

  - Treatment

     : to correct the corneal opacities --> may improve the vision

     : but no other treatment is available

  - Diagnosis

     : examining fibroblast cultures

        for the characteristic lamellated multivesicularvmembrane bodies

     : partial deficiency of ganglioside sialidase activity

     : some obligate heterozygotes : less than normal activity

 - Prenatal diagnosis

 : examining cultured amniotic fluid cells for the characteristic storage bodies

Chapter 75. Defects In Metabolism Of Purines And Pyrimidins

 purines and pyridines; heterocyclic nitrgen-containing compounds purines pyrimidines form the elements of RNA and DNA the ability to synthesize the purine ringring denovo is virtually universal among living organisms.purine bases; adenine andguanine the important pyrimidines arethymine,cytosine,and uracil

Gout

; elevation of serum uric acid concentration

; *primarily affect adult male(95%)

    - rarely in children *except GSD type I

Etiology

; abnormally active production denovo of uric acid

; reduction in the renal clearance of uric acid

; combination of these two major factors

# Active Production

    ; *reduced hypoxanthine guanine phosphoribosylpyrophosphate transferase

           - complete deficiency : Lesch-Nyhan syndrome

    ; *high activity of PRPP synthetase

# both enzyme is transmitted as *X-linked recessives

# gouty arthritis depends on the severity and duration of hyperuricemia

Lesch-Nyhan Syndrome

; usually normal at birth

; first abnormality

    - delay in motor development in the first few months

; life later

    - extrapyramidal choreoathetoid movements, hyper-reflexia, ankle clonus, spasticity of the legs

; dramatic compulsive self-destructive behavior

    - *striking clinical abnormality

    - unknown mechanism

    - *self-mutilation

Gouty tophi and gouty arthritis ; in older children

Tophi ; accumulation of sodium urate crystals, extensor surfaces of the elbows, knees, fingers, and toes

serum uric acid concentrations ;

     total absence of hypoxanthine guanine phosphoribostyltransferase activity in many tissues(erythrocytes and fibroblasts)

PRPP synthetase activity increase, giving rise to accelerated purine production denovo and to excesses of uric acid

The salvage pathway may be important in the synthesis of nucleotides within the brain; X-linked condition

The gene for hypozanthine-guaninie phosphoryltransferase is located on the X-chromosome(q26-q27, consists of nine exons and eight introns totaling 57kD). mutations, D1-dopamine antagonists have been proposed as the cause of the self-destructive behavior

Other Abnormalities Of Uric Acid Metabolism

Hyperuricemia : a marked increase in cell number and cell destruction, as in myeloproliferative disease

(A) Hyperuricemia; occur in any condition in which renal clearance is reduced

    β-hydroxybutyrate and acetoacetate are increased, as in starvation and diabetic ketoacidosis

    salicylates(in low doses) may reduce renal clearance and produce hyperuricemia

    Down syndrome display modest hyperuricemia

(B) Hypouricemia; due to an increase of uric acid occurs in proximal renal tubular disease(e.g., Fanconi syndrome).

    caused by an isolated defect of renal tubular reabsorption of uric acid

    is also prominent feature of xanthinuria and nucleoside phosphorylase deficiency

Treatment Of Hyperuricemia

Avoidance of foods high in purines(such as sweetbreads)

Probenecid; effective in increasing uric acid clearance, may be used to treat hyperuricemia in patients with normal renal function

Allopurinol; an inhibitor of xanthine oxidase, is also widely used

           in Lesch-Nyhan syndrome ; allopurinol treatment reduces uric acid concentrations; there is no effect on the severe neurologic problems.

High urine volumes be maintained  and that  urine pH be kept near neutral(7.0); polycitra 사용하는데 Bivon 보다 효과적)

  이유; pH 5.0 : the solubility of uric acid 15mg/dL

    pH 7.0 : the solubility 200mg/dL

The hyperuricemia is associated with type I glycogen storage disease respond to allopurinol

Xanthinuria

Xanthine ; the immediate precursor of uric acid(from purine)

       hypoxanthine - intermediary formed from others.

       oxidations of hypoxanthine to xanthine(by xanthine oxidase)

Xanthinuria is uncommon.

Serum uric acid levels ; undetectable(0.1 - 0.8 mg/dL)

Low lwvels of hypoxanthine and uric acid

Xanthine is less soluble - urinary calculi 생김(The stones are radiolucent)

Muscular pain(deposits of xanthine crystals in muscle)

Genetic heterogeniety

lack aldehyde oxidase activity(converts the drug allopurinol to oxypurinol)

Tx.

High fluid intake

Dietary restriction of purines

Alkalinization of urine

Prognosis

Excellent

Adenosine Deaminase Deficiency

    Severe Combined Immunodeficiency(SCID) : 환자의 절반에서 있다.

Nucleoside Phosphorylase Deficiency

Gene : long arm of chromosome 14

cellular immunity 감소

CNS dysfunction : prominent clinical feature

Adenine Phosphoribosyltransferase

Prominent clinical feature ; urinary calculi composed of 2,8-dihydroxyadenine and calcium oxalate

Orotic Aciduria

Orotic acid: intermediate metabolite in the synthesis of pyrimidines

rare disorder of children

block in the further metabolism of orotic acid

megaloblastic anemia(unresponsive to vitamine C, folic acid, vitamine B12)

retarded in growth and development but the hematologic manifestations are more dramatic clinical features ( RNA and  DNA is so necessary for normal hematopoiesis)

 

<Tx>

Steroid

 

Orotidylic acid pyrophosphorylase and orotidylic acid decarboxylase activities are deficient

The administaration of pyrimidine deriatives lowers the urinary excretion of orotic acid ( by feedback inhibition control)

신생아기에 uridine으로 치료한 경우, 청소년기에 정상인 보고가 있다.

Primary genetic defects in the urea cycle; orotic acid excretion 증가함

Orotic aciduria is also seen in nucleoside phosphorylase deficiency

Other Defects Of Enzymes And Proteins

Defects In Plasma Proteins

Analbuminemia

very rare

receesively inherited trait

homozygotes, heterozygotes have intermediate levels of albumin

usually no treatment

보상으로 다른 plasma protein 증가하므로 Sx. 없다.

Haptoglobin Deficiency

Haptoglobin ; α2-globulin

numerous phenotypic variations

Abetalipoproteinemia

Analphalipoproteinemia(Tangier Disease)

Absece Of Transferrin

siderophilin

congenital absence of transferrin

a physically retarded girl with hepatomegaly, splenomegaly, and anemia

not respond to any treatment

PB ; hypochromic

BM ; many immature erythroblasts

Sudden death ; hemosiderosis

autosomal recessive transmission

Carbohydrate-Deficient Glycoprotein(CDG) Syndrome

basic biochemical defect is unknown

abnormalities of the structure of numerous glycoproteins(increased amounts of carbohydrate-deficient serum transferrin 진단에 도움을 준다.)

include growth failure, dysmorphic facies, liver dysfunction, lipocutaneous abnormalities, ataxia and cerebellar hypoplasia, peripheral neuropathy, lower limb atrophy, strabismus and retinal degeneration, hypotonia, and skeletal abnormalities related to neurologic involvement. Strokelike episodes, coma, and cerebral infarctions (coagulopathies)

Only supportive treatment

C1 Esterase Inhibitor

Complement Deficiencies

α-Antitrypsin Protein Deficiency

Transcobalmin Ii Deficiency

Vit. B12 binding 하는 2개의 serum protein

Transcobalamin I( an α-globulin) deficient ; without clinical or hematologic sequale

Transcobalamin II (a β-globulin) ; severe megaloblastic anemia and neurological manifestations

Treatment ; parenteral administration of large doses of vitamin B12

Defects In Plasma Enzymes

Pseudocholinesterase

in plasma, liver, and neural tissue

physiologic function is poorly understood

Numerous allelic forms are known

Lecithin-Cholesterol Acyltransferase Deficiency

Carosinase Deficiency

γ-Glutamyl Transpeptidase Deficiency

moderately retarded adult male with increased levels of glutathione in blood and urine

No other abnormality in amino acid excretion

Hypophosphatasia

Genetic abnormalities of alkaline phosphatase

Elevated Alkaline Phosphatase

Elevated serum ALP - liver, bone disease

Defects Of Proteins In Other Tissue

Menkes Kinky Hair Syndrome

Molybdenum Cofactor Deficiency

molybdenum cofactor sulfite oxidase xanthine dehydrase aldehyde oxidase 활성화에 필수적.

sulfite oxidase deficiency and xanthinuria ; ocular abnormalities( dislocated lenses, Brushfield spots. and nystagmus), neurologic findings ( tonic-clonic seizures), and mental retardation.

Treatment restricting sulfur-containing amino acids

         administering allopurinol

Myoglobin

heme protein in muscle

the intracellular transport of oxygen

Myoglobinuria may occur in a number of disorders of muscle metabolism such as dificient phosphorylase activity, dificient phosphofructokinase activity, dificient lactase dehydrogenase activity absent carnitine palmity transferase activity

X-Linked Ichthyosis

 Chapter 608 for discussion of steroid sulfatase dificiency

Xeroderma Pigmentosum

 See Chapter 606

Dynein Arm Dificiency

 . The absence of thic specific ATPase is discussed in Chapter 364

Receptor Proteins

 Most if not all communications between cells within the same organ or across organ systems are mediated by specific proteins found on the surface of the cell receiving the message.

example the absence of a functional receptor for the formone vitamin D3, which leads to vitamin D-dependent rickets type II ( see Chapter 649). One gorm of diabetes mellitus os due to a defect in the specific receptor for insulin (see Part XXVI, Section 6).

Pancreatic Enzyme Deficiencies

discribed in whom malabsorption  appears to result from a specific defect involving a pancreatic enzyme or proenzyme ( see Chapter 296). They have none of the pulmonary or electrolyte abnormalities of cystic fibrosis

Lipase Deficiency. Congenital absence of active pancreatic lipase leads to malabsorption of lipids and fatty (and sometines malodorous) stools.

Treatment with pancreatin is effective

Trypsinogen Deficiency. Severe malnutrition, growth failure, and hypoproteinemic edema kwashiorkor are associated with lack of the ability to synthesize pancreatic trypsinogen.

As a result, chymotrypsin and carboxypeptidase activities are also low because these enzymes need to be formed from the corresponding proenzymes by trypsin activity.Treatment with a protein hydrolysate diet and exogenous pancreatic enzymes.

Amylase Deficiency

Less defined deficiencies pancreatic lipase

Intestinal Enterokinase Deficiency

Enterokinase, an enzyme secreted by the small intestine, initiates the reactions for the conversion of the pancreatic proenzymes to their active forms.

recommended treatment for deficient enterokinase activity in children are identical to those described above for trypsinogen deficiency.

Almost all of the infants presented at birth with failure to thrive and diarrhea.

Hypoproteinemia and edema are present in 50% of patients.

Collagen Metabolism

Collagens are the major structural proteins of skin, tendons, cartilage, and bone.

Collagen contains large amounts of glycerine, hydroxylysine, and hydroxyproline.

disorders involve collagen metabolism

Numerous variants of both osteogenesis imperfecta and Ehlers Danlos syndrome, Martin syndrome

Myoadenylate Deaminase Deficiency

Approximately 2% of all Caucasians and African-Americans : homozygous for a mutation(nonsense) in exon 2 of the myoadenylate deaminase(AMPD1-AMP deaminase) gene.

most AMP1 deficient patients are asymptomatic.

Symptoms of muscle cramps, easy fatigability, and muscle pain

At any time from infancy to adulthood

The enzyme normally converts AMP to IMP(inosine-monophosphate) with the liberation of ammonia.

The IMP formed is then normally recycled back to AMP.

In the absence of AMP deaminase activity this cycle is broken.

Mitochondrial Myopathies

See also Chapter 562.4

the defects that exist in mitochondrial myopathies:

    (1) defects in substrate utilization as in carnitine deficiency

    (2) defects in coupling of mitochondrial respiration to phosphorylation

    (3) deficiencies of components of the mitochondrial respiratory chain

Some patients go for many years without any signs or symptoms.

Others become sick early age, and still others have been described with a form that is rapidly fatal in the neonatal period.

the drug zidovudine(AZT) : used to treat AIDS, induces a DNA-depleting mitochondrial myopathy.

Acatalasia

Catalase is found in most tissues

Persons with a decrease of catalase activity , to less than 1% of normal

autosomal recessive

heterozygote

Aspartylglycosaminuria

The compound 2-acetamido-1(β-L-aspartamido)-1,2-dideoxyglucose(AADG) is a substituted hexose that forms one of the linkage points between the carbohydrate moiety and the amino acid groups of many glycoproteins.

Mental retardation, petite mal seizures, manic-depressive psychosis

vaculoated lymphocytes, hepatomegaly, lenticular opacities

chromosome 4q21-4qter

Acid Phosphatase Deficiencies

Two groups of patients

either decreased or absent activity of lysosomal acid phosphatase clinical picture characterized by intermittent vomiting, hypotonia, lethargy, opisthotonos, terminal bleeding, and death within the 1st yr of life.

Patients with total deficiency exhibit the same symptoms and die in infancy.

True Cholinesterase

True holinesterase, an enzyme essential for neural and muscular function, is also found in erythrocytes

Function is unkown

Chapter 76. Porphyrias

the inherited and acquired disorder in which the activites of the enzymes of the heme biosynthetic pathway are partially or almost completely deficient  abnormally elevated levels of porphyrins and their precursors are produced,accumulated in tissues, and are excreated

in urine and stool.

Heme Biosynthetic Pathway

the steps involved in the heme biosynthetic pathway are illusted in figure 76-2. he first step and the last three steps occur in mitochondrias;the intermediate steps take place in the cytosol. the two major organs liver and the erythroid bone marrow ,and inherited enzymatic defects in the porphyrias are mainly expressed in these tissues.

Formation of ( ALA)

 ALAS activitty is very low,rate limiting for heme formation. the gene locus for the human ALAS-N is at chromosome 3p21 and inherited deficiency of ALAS-E is associated with X-linked sideroblastic anemia

Formation of porphobilinogen(PBG) from ALA

ALA dehydratase to a monopyrrole, PBG. ALAD deficiency porphyria(ADP)ALAD gene is localized at chromosome 9q34

Formation of hydroxymethylbilane(HMB) from PBG

porphobilinogen deaminase(PBGD) catalyzes the condensation of four molecules of PBG

Formation of uroporphyrinogen III from HMB

Homozygous deficiency of Uro'Cos is associated with congenital erythropoietic porphyria(CEP)

Formation of Coproporphyrinogen(Copro') from Uro'

Uroporphyrinogen decarboxylase catalyzes the sequential removal of the four caqrboxylic groups of the carboxymethyl side chains in Uro' to yield copro's

Porphyria cutanea tarda(PCT) is due to a partial(or heterozygous) deficiency of Uro'D, while hepatoerythropoietic porphyria(HEP)

Formation of coproporpyrinogen oxidase(Copro'OX) is a mitochondrial enzyme that catalyze the removal of the carboxyl group

Formation of Protoporphyrin from Protoporphyrinogen ( Porto )

Proto 에서 Protoporphyrin Oxidation Porphyriongen nucleolus로부터 6 H+ 제거를 촉매하는 Portophyringen oxidase 의해 매개된다. Variegate porphyria (Vp) Porto'Ox 부분적 결핍 때문에 일어난다. 이것은 cDNA cloning 연구되지 못한 heme biosynthetic pathway 있어 유일한 효소이다.

Formation of heme from Protoporphyrin

heme 생합성의 마지막 단계는 Portoporphyrin으로 iron 삽입하는 것이다.

반응은 ferrochelatase(Fe C) 효소에 의해 촉매된다. heme  합성의 다른 단계되는 달리, 효소는 substrate로써 이것의 환원형태보다는 portoporphyrin X 사용한다. 그러나  특히이 효소는 ferrous (Fe++) iron 필요로 한다.human FeC gene chr.18q21.3 assign되어 있다. Erythropoietic portophyria (EPP) FeC 부분적 결핍 때문에 발생한다.

Regulation Of Heme Synthesis

간에서 heme 생합성은 ALAS (ALAS-N)형성속도에 의해 조절된다. 효소의 활성도는  (정상간에서) 매우 낮으며 다양한 화학치료에 대한 반응으로써 간에서 보다 많은 heme 요구할때는 dramatic 하게 수치가 증가한다. 이효소의 합성은 생합성단계의 마지막 산물인 heme 의해 feedback으로 조절된다.heme 농도가 높을때는 이것은 ALAS-N 합성을 억제해서 heme microsomal heme ozygenase 유도하고 자신의 이화를 촉진한다..heme 농도는 heme의조절영향하에 있는 ALAS-N heme oxygenase 두가지의 합성의 균형에 의해 유지된다.반면에 ALAS-E 합성(erythroid cell에서) heme치료에 반응이 없거나 그런치료에 의해 자극되기도 한다.

Pathophysiologic Consequence Of Porphyrins And Their Precursors

Photosensitiviry

free porphyrin  정상조직에서는 적은양으로 있지만 porphyria에서는 수치가 아주 증가한다.

400nm파장에서의 조명과 산소존재하에 porphyrin  조직,세포,subcellular element그리고 singlet oxygen형성을 위한 biomolecules photodynamic 손상을 초래한다.

Neurologic Disturbance

Acrte hepatic Porphyria에서 ADP,ALP,HCP and VP 신경학적 장애에 의해 특징지워진다.

가장 흔한 증상들로는 복통,장운동에 장애,dysesthesia,muscular paralysis,치명적인 호흡부전등이있다. porphyria에서 신경학적 장애의 정확한 특징은 불분명하다.

Porphyria에서 과도한 porphyin precursors involvement, heme 합성의 결핍 ,hepatictryptophan pyrolase 활성도의 감소로 인한 CNS에서 tryptophan 증가를 포함한 여러 이론들이 제거되었음에도 불구하고 정확한 특징의 신경학적장애는 불분명하다.

Classification Of Porphyria

Table 76-1

Table 76-2

ALAD(δ-aminolevulinic acid dehydratase) Deficiency Porphyria (=ADP)

; *autosomal-recessive

; *rare form

; similar to AIP

Clinical Manifestation

ADP환자는 vomiting,손발의 통증,stress,alcohol,food intake감소에 의해 악화되는 신경증상을 보이다.출생시부터 general muscle hypotonia 호흡부전을 포함하는 임상경과가 보고된 ADP 환아는 드물다.

Laboratory Finding

Urinary ALA 배설은 놀랍도록 증가되어있고 반면에 urinary PBG 정상법위에 있다.

urinary erythrocyte porphyrins 100 가량 증가되어있고,어떤것도 이들 관찰을 만족스럽게 설명하지 못한다. fecal porphyrin 배설응 정상이거나 아주 증가되어있다.A 환자는 nonerythroidcell 뿐만아니라 erythrocyte에서 ALAD 활성도가 아주 감소되어있다.그리고 그들의 부모에서는 효소의 활성도가 거의  50%감소되는 것을 본다.

Genetics

성인에서 시작한 환자는분리된 point mutation 하였고, 각각은 각각의 ALAD allele에서발생하였다. 하나는 base transition으로 G820-> A,Ala274->Thr 이고 다른 것은 A.A 변화를 일으키는 C718->T, Arg240-Try 이다,. 전자의 mutations 효소활성도 감소와 동반되고후자는 효소의 instability 동반되었다.이들은 proband's cell에서는 효소활성도가 거의 완전히 없고,그의 family members로부터의 cell 에서는 정상의 1/2 가량의 활성도가 있다고 설명했다. 위에서 언급된 porband 구별되는 point mutation 가진 다른 복합 heterozygote ADP 가진 Child에서 설명되어졌다. Two pedigrees에서 4개의 구별되는 point mutation disorder 에서 mutation matked heterogeneity 보여준다.

Diagnosis

확진은 손상된 ALAD activity erythrocyte 에서 효소단백의 결핍의 증명에 위존한다.

supporting evidence sms urinary ALA 증가를 포함한다. ADD 임상증상은 단지homozygous 환자에서만 발생하고 반면에 부모와 어떤 porband siblings heterozyguos subfect unaffected 하다.

Treatment

ADD prudent 치료는 AIP management line 아마도 같을 것이다.

Acute Intermittent Porphyria (AIP)

; autosomal dominant

; *partial PBGD(porphobilinogen deaminase) deficiency

;그러나 15%이하의 subjects에서는 단지 nonerythroid cell에서만 효소의 결핍을 보인다.

이들 genetic enz. 결핍을 가진 90% 개개인들은 임상적생화학적으로 정상으로 보인다.

질병의 임상적표현은 영양상태 steroid 다른 endogenous or exogenous origen 화학품과같은 환경적 후천적 인자에 연관되어있다. 질환의 pathobiology peripheral ANS.CNS 영향을 주는 신경학적 장애이다.

Epidemiology

AIP 모든 유전적 porphyria 가장 흔한 형태이다.비록 많은 인종에서 reported 되었지만 특히Lapland,United Kingdom에서 높은 유병율을 나탄낸다. AIP 유병율은 유럽에서 100,000명당1-2 명이다. 낮은 PBGD 활성도의 빈도는 AIP Latent gene Carrier 가진 부모들을 포함해서Finland general population에서 500명당 1명이다.disorder 사춘기이후 그리고 남자보다는 여자에서 보다 임상적으로 많이 발현된다.

Clinical Manifestation

    ; *abdominal pain

           - generalized or localized

           - *common symptom

    ; other GI symptoms

           - N/V, constipation or diarrhea, abdominal distension, ileus

    ; urinary retention, incontinence, dysuria

40%이상의 환자에서 고혈압은 acute attack사이에서 유지된다. Neuropathy AIP 흔한증상이다. muscle weakness leg proximal 에서 시작하고, arms or distal extremities involve한다.motor neuropathy cranial N. involve해서 bulbar paralsis,호흡부전,사망으로 이르게한다.sensory patchy neuropathy 또한 발생한다.AIP acute attack Seizure 동반되는데 특히vomiting, 부적절한 fluid Tx. SIADH 의한 hyponatremia 가진 환자에서 흔하다.AIP acute attack 과정은 개개인과 부모사이, 수일에서 수개월 지속되는등 아주 다양하다.

이들 효소의 결핍은 어떤 피부증상도 보이지 않는다. asymptomatic heterozygotes porphyrin precursor 농도와 임상증세에서 어떠한 이상도 보이지 않는다. latent or 이전의 임상적으로AIP expressed 개인들은 endogenous or exogenous 환경인자에 의해 acute attack으로precipitating factor 있다.(1) ALAS-N 활성도의 증가와 관련이 있다.ALA 과도생성은 국소적으로PBGD activity rate liniting 시킨다. (2) endocrine factor : 임상질병은 특히 mens기의 여자에서 흔하다.(3) Calorie intake : Reduced calorie intake 종종 AIP 악화시킨다.additional calories PBG분비를 감소시키고 임상증상을 suppress시킨다.(4) Drug and foreign materials;porphyria 악화시키는 barbiurate,sex steroid,other foreign chemical 같은 많은 화학품은 cytochrome P450 induce 시킬수 있다.heme합성을 위해 enhanced resultanthepatic ALAS-N induction 시킨다.(5) stress : stress hemeozygenase gene upregulate시키고 AIP 악화시키는 것으로 알려져 있다. stress 다른 형태인 intercurrent illness,감염alcoholic excess,surgery모두는 이들  disorder acute attack genesis 영향을 주는것으로 알려져있다.

Laboratory Finding

AIP 보이는 환자들은 (latent AIP 가진 몇몇의 사람들을 포함해서)attack사이에 urine에서ALA PBG 양이 증가된다.많은 경우에서 acute attack 시작은 이들 precursor excretion 증가하는 것과 동반된다. acute attack 정상적으로는 detectable 할수 없는 ALA,PBG,porphyrins 혈청농도의 증가와 연관되어있다.

stool porphyrins 정상이거나 약간 증가된다.Watson-Schwartz test urinary PBG 대한 screening test 사용된다.그러나 특이하게도 정랑적이지 않아서 이들결과는 Mauzerall Granick column method 의해 확진되고 정량되어져야 한다. Hb bilirubin형성은 AIP에서는 정상이다.

Genetics

AIP 가진 환자들은 3가지 subsets 분류된다.Type mutation 가진 환자들은CRIM-negative PBGD mutation 의해 특징지워진다. 그들은 intermediate하게 효소 활성도의감소와 단백성분의 감소를 나타낸다. Type mutation 모든 AIP 15%이상에서 관찰되고nonerythroid cell에서 PBGD activity 감소와 erythroid PBGD 정상적 activity 특징지워진다. Type mutation 가진 환자들은 효소활성도의 감소와 구조적으로 이상한 효소단백의 존재를 나타내는 CRIM-positive mutation 의해 특징되어진다.human PBGD gene 다양한mutation AIP 가진 환자에서 설명되어지고 Table 76-2에서 요약되어져 있다.

Type AIP 에서 발견된 mutation single base substituion이거나 single A.A 변화나

truncated protein 유발하는 deletions 이다.

Type AIP 에서 발견된 mutation exon 1 exon / intron boundary에서 발생하는 single base substitutios 으로 erythroid cell에서 gene transcription mutation site 에서 downstream 으로 start 하기 때문에 erythroid-specific PBGD에서는 영향을 주지않고 단지PBGD nonspecific form 영향을 주는 splicing defect 유발한다.

Diagnosis

TypeⅠ과 Type ALP 진단은 85%이상의 환자에서 erythrocyte에서 PBGD activity 감소를 증명함으로써 된다.반면에 latent status 임상적으로 표현된 AIP 사이의 차이는 urinary PBG,ALA excretion 증가로 증명된다.

ALA PBG level 증가는  HCP VP 에서 또한 있다. urinary and stool porphyrins 측정은 AIP 부터 이들 condition 구분시켜준다.

Type AIP 진단은 nonerythroid cell 에서 PBGD 결핍과 mutation 대한 allele-specificoligonudeotide specific 이용한 DNA hybridization 증명을 요구한다.

Treatment

ADP,HCP,VP AIP 치료는 근본적으로 동일하다.attack 사이의 치료는 충분한 영양공급과 porphyria 악화시키는 drug 피하고 다른 intercurrent diseaseor infection 적절한 치료등으로 구성된다. 반응을 보이지 않는 심한 경우는 24시간동안 최소 300g carbohydrate 제공하기위한 IV carbohydrate dextrose 투여로 치료되어야한다.IV hematin crutailing acute attack에서 뿐만아니라 ALA,PBG excretion 감소시키는데 효과적이다.

LHRH long-acting agnostic analogs nasal or subcutaneous administration ovulation 억제하고,이병의 cyclic exacerbation 보이는 몇몇여성에서 AIP perimenstrural attack 유병을 감소시키는 것으로 보인다.synthetic heme analogs, 예를들면 Sn-nesoporphyrin 또한 AIP,VP환자에서 ALA,PBG,porphyrin output 감소시키는 것으로 보인다.

Congenital Erythropoietic Porphyria (CEP)

(= Gunther's disease)

; autosomal recessive

; decreased activity of Uro'CoS

Epidemiology

200 case 이하로 reported 되고있고, 이들경우의 몇몇은 실제로 PCT or HEP 가지고 있었다.인종적으로나 성별로 명확한 차이는 없다.

Clinical Manifestation

CEP 진단은 출생시 urine 에서 다량의 porphyrins 때문에 infant 기저귀가 Pink to dark brown staining 됨으로써 의심된다.Cutaneous photosensitivity early onset 특징적이고 햇빛에 노출됨으로써 악화된다.subepidermal bullous lesion crusted erosions 되고 scarring 이나 과색소침착 혹은 저색소화로 healing 된다.hypertrichosis alopecia 빈번하고 erythrodontia CEP Pathognomic 하다.

환자는 hemolytic anemia,splenomegaly,porphyrin-rich gall stones Sx Sg 보인다.

BM erythroid hyperplssia 보이고 이것은 병적골절이나 vertebral compression-collapse 신장의 단축 등을 유발한다.비록 CEP 증상의 시작이 early infancy에서 대부분 관찰되지만 몇몇환자에서는 성인때 증상을 보이기도 한다.

Pathogenesis

효소걸핍의 expression site BM이다.porphyrin축적에 이차적으로 fluorescence 다양하게 분포되나 invariably하게 표현된다.

Laboratory Finding

  .urinary porphyrins-정상치의 20-40(항상증가)

  .uroporphyrin and coproporphyrin-대개 type I isomers

Genetics

  .CEP환자의 Uro'CoS gene heterogeneity mutations.

Diagnosis

  .pink urine and/or onset of severe cutaneous photosensitivity 

   ->CEP 진단을 추측 있다.

 .   urinary, fecal and erythrocyte porphyrins            

     type I isomers of uroporphyrin and coproporphyrin   ; 진단가능

  .def. Uro'CoS activity 증명 ; 확진

Treatment

  .Sunlight, skin trauma, infection 피한다.

  .topical sunscreens -> B-carotene 경구요법과 병용시 약간의 효과는 있다.

  .packed erythrocytes transfusions.

    ;   .transiently decrease hemolysis

        .porphyrin excretion

        .its attendant drive to increased erythropoiesis

  .splenectomy - short-term reductions in hemolysis, porphyrin excretion and skin                                manifestations.

  .Charcoal ; lowered porphyrin levels and induced complete clinical remission

     Porphyria Cutanea Tarda (PCT) and Hepatoerythropoietic Porphyria (HEP)

  .PCT ; due to heterozygous def of Uro'D

  .HEP ; due to homozygous def of Uro'D

      (Fig 76-3, Table 76-1)

PCT

  .hepatic Uro'D activity

  .erythrocyte Uro'D activity 감소 수도 감소되지 않을수도 있음 (type 따라 결정됨)

      -.Type I PCT ;   hepatic        

                         Nl erythrocyte   Uro'D activity

       .Type II PCT ;   .AD inherited

                        .Uro'D activity in all tissues

       .Type III PCT ;   .inherited

                         .결함은 liver erythrocyte 한정됨

Epidemiology

  .최근 여자에서 발생빈도가 증가되는 것은 contraceptive steroids, estrogen, alcohal 섭취에

   기인됨

Clinical Manifestations

  .formation of vesicles - sun-exposed areas of the skin (특히 손등)

  .facial hypertrichosis

  .hypopigmented indurated plaques of skin

  .photoonycholysis

  .PCT에서는 neurologic dysfunction 없다

Pathogenesis

  .skin phototoxic porphyrin 대개 liver에서 나온것이며 어느 정도 피부에 국한적으로 형성된다.

  .irradiation 후에 activation of complement system 나타나는 것은 reactive oxygen species     발생 때문이다.

 

  .bullous fluid contain   .PGE2

                         .photoactivation of uroporphyrin damages lysosomes.

  .PCT 환자의 liver

      -  .fatty changes

         .necrosis

         .chronic inflammatory changes

         .granuloma formation

  .PCT 환자는 B, C 간염의 발생이 정상에 비해 높다.

Laboratory Finding

  .PCT 환자의 소변내에서 uroporphyrin(대부분 isomer I) 7-carboxylic porphyrins(isomer III)    농도가 증가되어있고 그보다는 적은 정도로 coproporphyrin 5 6-carboxylic porphyrins     증가소견을 보임.

  .대변내에서 혈청이나 소변내에서 비해 현저한 isocoproprophyrin증가를 보이는 것은 중요한        PCT 진단 criteria이다. 

  .특히 photoactivation 차단된 부위에서 Skin porphyrins증가

  .혈청 iron ferritin농도 증가

Diagnosis

  .D.Dx-other porphyric and nonporphyric disease.

  .ultraviolet 하의 urinary fluorescence

  .separation and identification of porphyrins

  .plasma porphyrins

  .fecal porphyrins-증가

Treatment

   .identification and avoidance of precipitating factors

   .phlebotomy-  .소변 porphyrin 농도를 내려줌

                 .induction of clinical remission         

   .low-dose chlorquine therapy

    -  +  치료는 부작용 빈도를 줄여줌

HEP

  .rare form of porphyria

  .homozygous defect of Uro'D

Clinical Manifestations

  .CEP 유사

  .Pink urine, severe photosensitivity

  .sclerodermoid changes

  .hypertrichosis, erythrodontia, anemia, hepatosplenomegaly.

  .PCT와는 달리 혈청 iron 농도는 대개 정상이고, phlebotomy 별로 효과가 없다.

Laboratory Finding

  .urinary porphyrins (대개 isomer type I uroporphyrin)

  .소변과 대변내 isocoproporphyrin 농도 증가

  .erythrocyte Zn-protoporphyrin (Table 76-2)

Diagnosis

  .진단 criteria - fecal or urinary isocoproporphyrin and erythrocyte Zn-protoporphyrin

  .D.Dx-EPP (urinary porphyrins 정상이고 임상적으로도 HEP보다 경하다)

  .erythrocyte or fibroblast Uro'D activity-정상보다 2-10%정도 감소되어 있다.

Treatment

  .Avoidance of the sun

  .topical sunscreens

Hereditary Coproporphyria (HCP)

  .caused by heterozygous def. of Copro'Ox activity

  .AD (Fig 76-3 and table 76-1)

  .Photosensitivity

Clinical Manifestations

  .Neurovisceral symptomatology-ADP AIP에서 나타나는것과 구별이 힘듬

  .Abdominal pain, vomiting, constipation

  .neuropathies, psychiatric manifestations

  .cutaneous photosensitivty-30%

  .precipitating factor ;

                       .Pb (mc)

                       .pregnancy

                       .menstrual cycle

                       .contraceptive steroids

Laboratory Finding

  .urine feces coproporphyrin (주로 type III) 과다 배출

  .fecal protoporphyrin

  .Hyperexcretion of ALA, PBG, uroporphyrin into the urine.

  .Copro'OX activity -   .heterozygotes ; 50%감소

                         .homozygotes ; 90-98%감소

Genetics

  .two pt's -    homozygous for the CPO def               

                 heterozygous   "      "

Diagnosis

  .acute hepatic porphyrias 임상증상들을 가질 의심.

                                (ADP,AIP,HCP,VP)

  .heme precursor 소변으로의 배출은 VP 유사하지만 fecal coproporphyrin 보이면 HCP    추정할수 있다.

Treatment

  .악화인자를 확인하고 피하는 것이 중요

  .AIP Tx 유사

Variegate Porphyria(VP)

  .caused by a heterozygous deficiency in Proto'Ox activity

  .AD      

  *Epidemiology

  .incidence of VP ; 3/1000 in South Africa.

  .전세계적 분포

  .VP<AIP

Clinical Manifestations

  .photosensitivity

  .Cutaneous manifestations ;   .vesicles, bullae, hyperpigmentaion

                               .milia, hypertrichosis

                                .skin fragility

  .precipitating factors ;   .barbiturates, dapsone

                         .pregnacy etc

Pathogenesis

  .Proto'Ox activity ; 50%이상감소

Laboratory Finding

  .fecal porphyrin증가 (대개 protoporphyrin IX coproporphyrin 보다 많다)

  .fecal X-porphyrins

  .porphyrin - peptide conjugates

  .urinary coproporphyrin (typeIII) ALA, PBG

                  ;    Between attack-often Nl

                       acute attack-markedly ↑↑

Diagnosis

  .PBGD activity-Nl

  .특정적인 plasma porphyrin fluorescence

  .fecal porphyrin analysis

  .fibroblast lymphocytes에서 Proto'ox def 증명 있음

Treatment

  .회피요법

  .Neurovisceral symptom치료는 AIP 동일하다

Erythropoietic Protoporphyria (EPP)

  .partial def of FeC

  .AD )

  .massive accumulations of protoporphyrin in erythrocytes, plasma, feces

  .CEP보다 피부 병변부위는 경하다

Clinical manifestations

    ; *stinging or painful burning sensations in skin within 1hr of sun exposure

           --> several hour later erythema, edema

  .인공조명으로 photosensitivity 일어날 있다 (수술방 전등불)

  ., 여름에 심해짐

  .지속적이고 반복적인 sun exposure

         -onycholysis, leathery hyperkeratotic skin, scarring

  .Gallstones, hepatic disease 드물게 있을수 있다.

  .알려진 악화 요인이나 neurovisceral manifestations 없다

Pathogenesis

  .400nm light-trigger photosensitivity reactions in the skin

  .light excited porphyrins  free radical singlet oxygen 발생시킴

          ->lipid peroxidation, membrane protein cross-linking

          ->deformability of erythrocytes

          ->hemolysis

 

  .EPP환자 전박에 irradiation

     ->complement activation, polymorphonuclear chemotaxis

     ->pathogenesis of skin lesions in EPP

Laboratory Finding

    ; *excessive protoporphyrin in erythrocytes, plasma, bile, feces

           - hallmark

           - *not in urine due to poor solubility

  .BM newly released erythrocytes protoporphyrin 농도 상승의

                       Major source

Genetics

  .far skipping of exon 2,7,9,10 and three poing mutation 보고됨.

Diagnosis

    Photosensitivity : 진단 가능성 제시

    free protoporphyrin in erythrocytes, plasma, stool

    Nl urinary porphyins

       +   확진

Treatment

  .회피요법

  .oral B carotene 투여 ;

         -serum level ; 600-800ug/dl

         -doses       ;120-180mg/day

         -치료 1-3개월후 효과 나타남

         -mechanism ; quenching of activated oxygen radicals

Chapter 77. Hypoglycemia

Definition

Significance And Sequelae

Substrate, Enzyme, And Hormonal Integration Of Glucose Homeostasis

In The Newhorn

In Older Infants And Children

Clinical Manifestation Of Hypglycemia

Classification Of Hypglycemia In Infants And Children

Neonatal

Transient

Small For Gestational Age And Premature Infants

Infants Born To Diabetic Mothers

Hypoglycemia In Infants And Children

Hyperinsulinemia

leucine-sensitive hypoglycemia

    ; leucine treggered hypglycemic attack

Endocrine Deficiency

Substrate Limited

Ketotic Hypoglycemia

    ; *common form of childhood

    ; usually 18-5yr

           - *spontaneous remission by 8-9yr

    ; hypoglycemic attack

           - ketonemia, ketonuria

           - low insulin level : 5-10uU/ml

    ; intact glycogenolysis pathways & gluconeogenic pathways

    ; Etiology

           - *hypoalaninemia

           - defect in any of complex steps involved in protein catabolism, oxidative deamination of amino acids, transmination, alnine synthesis, alanine efflux from muscle

    ; Treatment

           - frequent feedings of high-protein, high carbohydrate diet