Inborn Errors of Metabolism

desaisa's version from 2015-07-12 19:46

Defects in Amino Acid Metabolism

PhenylketonuriaDecreased phenylalanine hydroxylase or tetrahydrobiopterin cofactor (AR). Tyrosine is essential. Increased phenylketones in urineMental retardation, fair skin, blue eyes, eczema, musty, mousy, body odorDecreased phenylalanine and increased tyrosine in diet
Alkoptonuria (ochronosis)Deficiency of homogentisic acid oxidase in degradative pathway of tyrosine. AR. BenignDark connective tissue, pigmented sclera, urine turns black upon standing. May have debilitating arthalgias
Homocystinuria1) Cystathionine synthase deficiency, 2) decreased affinity of cystathionine synthase for pryidoxal phosphate, homocysteine methyltransferase deficiencyExcess homocysteine in urine. Cysteine is essential. Mental retardation, osteoporosis, Marfanoid, Vaso-occlusive events , atherosclerosis1) decreased Met and increased Cys, B12, and folate in diet, 2) increased B6 in diet
AlbinismAbsent tyrosinase (AR), Defective tyrosine transporters, lack of migration of neural crest cells; Ocular is X-linkedLack of melanin --> increased risk of skin cancer.
CystinuriaDefect of renal tubular AA transporter for cysteine, ornithine, lysine, and arginine in PCT of kidneysExcess cystine in urine --> ~cystine staghorn caliculiAcetazolamide to alkalinize urine
Maple Syrup Urine DiseaseBlocked decarboxylation of branched amino acids (Ile, Leu, Val). Deficiency in alpha-ketoacid dehydrogenaseIncreased alpha-ketoacids in blood (especially Leu). Poor feeding and vomiting --->Severe CNS defects, mental retardation, death. Urine smells like maple syrup.
Hartnup DiseaseAR, defective neutral AA transporter in renal/intestinal epithelial cellsTryptophan deficiency, Pellagra. Lots of amino acids in the urine

Glycogen Storage Diseases

Very Poor Carbohydrate Metabolism
SyndromeFindingsDeficient Enzyme
Von Gierke's disease (Type I)Doll like face. Hypoglycemic seizures at 3-4 months of age Other abnormalities: hyper: lipids, uric acid, lactate in the blood streamGlucose-6-phosphatase
Pompe's Disease (Type II)Cardiac and skeletal muscle deposits. hypertrophic Cardiomyopathy = death. Also macroglossia, hypotonia, hepatomegaly.
Milder version = myopathy without much cardiac involvement.
Lysosomal alpha-1,4-glucosidase (acid maltase)
Cori's Disease (Type III)Milder form Type I with normal blood lactate levelsDebranching enzyme (alpha-1,6-glucosidase)
McArdle's disease (Type V)Increased glycogen in muscle, cannot break it down --> painful muscle cramps, myoglobinuria with strenuous exercise, elevated CK at rest , then second wind with fatty acid metabolismskeletal muscle glucogen phosporylase
Type I Glycogen Deposits?LIVER and KIDNEY
Type III glycogen deposits?IIIa liver and muscle (85%); IIIb liver only; BOTH: normal kidneys
Type I earlier complicationsHyperlip--> pancreatitis; Hyperuricemia --> gout, frequent nosebleeds (platelet dysfunction), delayed puberty
Type I late complications hepatic adenomas--> can bleed and become cancer; kidney disease, stones, FSGS, fibrosis; osteoporosis
Type Ib classic findingsneutrophil dysfunction and neutropenia --> ulcers in mouth and gut (Mucositis!), recurrent infections

Lysosomal Storage Diseases

DiseaseFindingsDeficient EnzymeAccumulated substrate
Fabry's Disease (XR)Severe neuropathic pain of hands/feet, angiokeratomas, Renal biopsy = lipids, cardiac involvementalpha-galactosidase Aceramide trihexoside
Gaucher's Disease (AR)TYPE I = Hepatosplenomegaly, avascular necrosis of femur, bone pain, pancytopenia macrophages that look like crumpled tissue paper
less common types can affect the brain
Niemann-Pick disease (AR)Progressive neurodegeneration, hepatosplenomegaly, neonatal jaundice, cherry-red spot on macula, foam cellsSphingomyelinasesphingomyelin
Tay-Sach's Disease (AR)Progressive neurodegeneration, exaggerated startle response, cherry-red spot on macula, no hepatosplenomegaly, lyosomes with onion skinhexoaminidase AGM2 ganglioside
Krabbe's Disease (AR)Peripheral neuropathy, developmental delay, optic atrophy, globoid cellsGalactocerebrosidaseGalactocerebroside
Metachromatic Leukodystrophy (AR)Central and peripheral demyelination with ataxia, dementiaArylsulfatase ACerebroside sulfate


Mucopolysaccharidoses = excessive urinary secretin of GAG
DiseaseFindingsDeficient EnzymeAccumulated substrate
Hurler's Syndrome (AR)Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegalyalpha-L-iduronidaseheparan sulfate, dermatan sulfate
Hunter's syndrome (XR)Mild developmental delay, gargoylism, airway obstruction, hepatosplenomegaly. Aggressive behavior. NO corneal cloudingIduronate sulfataseheparan sulfate, dermatan sulfate

Disorders of Carbohydrate Metabolism

Fructose Metabolism (causes milder symptoms than analogous disorders of galactose metabolism)
DiseaseFindingsDeficient EnzymeAccumulated substrate
Fructose Intolerance (AR)Hypoglycemia, jaundice, cirrhosis, vomiting; seizures, lactic acidosis. Treatment: decrased intake of fructose and sucrosealdolase BFrucose-1-phosphate
Essential fructosuria (AR)Benign, asymptomatic condition. + urine reducing substance, with no symptomsFructokinaseNone


Galactose Metabolism
DiseaseFindingsDeficient EnzymeAccumulated substrate
Classic galactosemia (AR)Failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation. + urine reducing substance, but normal urine odor
!"E coli sepsis"!
Treatment: exclude galactose and lactose from diet
galactose-1-phosphate uridyltransferasetoxic substances, including galactitol
Galactokinase deficiency (AR)Galactose appears in blood and urine, infantile cataracts (may initially present as inability to track objects or develop social smile), Relatively mildgalactokinasegalactitol

Disorders of the Urea Cycle, De Novo Purine and Pyrimidine Synthesis, and Purine Salvage

Urea Cycle
DiseaseFindingsDeficient EnzymeAccumulated substrate
HyperammonemiaInhibition of TCA cycle. Ammonia intoxication -- tremor, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision. Treatment: limit protein in diet. Benzoate or phenylbuyrateAcquired (liver disease) or hereditary (urea cycle enzyme deficiencies)NH4+ (depletion of alpha-ketoglutarate)
Ornithine transcarbamoylase (OTC) deficiency (XR)Orotic acid in blood and urine, decreased BUN, sx of hyperammonemiaornithine transcarbamoylaseorotic acid (from excess carbamoyl phosphate)


De novo Purine and Pyrimidine Synthesis/Purine Salvage
DiseaseFindingsDeficient EnzymeAccumulated substrate
Orotic Aciduria (AR)Orotic acid in urine, megaloblastic anemia that does not correct with administration of B12 or folate, failure to thrive. NO hyperammonemia. Treatment: oral uridine administrationorotic acid phosphoribosyltransferase or orotidine 5'phosphate decarboxylaseorotic acid
Adenosine Deaminase DeficiencySCIDAdenosine deaminase (converts adenosine to inosine)ATP and dATP
Lesch-Nyhan Syndrome (XR)Mental retardation, self-mutilation, aggression, hyperuricemia and gout, choreoathetosisHGPRT (converts hypoxanthine to IMP and guanine to GMP)Uric acid

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