Inborn Errors of Metabolism Flashcards
AKU
First recognized inborn error of metabolism, rare disorder in which homogentisic acid is excreted in large quantities in the urine, darkens on staining (black urine disease)
Reasons for predominance of metabolic disorders
Reactions are catalyzed by enzymes, most enzymes are produced in mild excess, one good gene is usually sufficient, defective genes can persist in populations
Classes of metabolic disorders
Carbohydrate, amino acid, lipid, organic acid metabolisms, urea cycle disorder, energy production defects, transport defects
Metabolic disorder genetics
Most are autosomal recessive, a few are X-linked, consanguinity a factor, history of miscarriages or neonatal deaths, siblings with developmental delay or autism
Galactosemia
Most common carbohydrate defect (1:55,000), defect in galactose-1-phosphate uridyl transferase, 11 exons, 4 kb, most common missense mutation in exon 6, cannot convert galactose to glucose efficiently
Symptoms of galactosemia
Failure to thrive, hepatic insufficiency, cataracts, developmental delay, long term- poor growth and mental retardation, screening by blood enzyme activity, treatment by dietary restriction
Hereditary fructose intolerance
Appears after adding fruit to diet, defect in fructose 1,6-bisphosphate aldolase, normally in liver, kidney cortex, and small intestine, child may avoid fruit and candy, 1:20,000
Von Gierke disease
Glycogen storage disorder, defect in glucose-6-phosphatase, glucose from glycogen not released from the liver, G-6-P metabolized, hypoglycemia between meals, hepatomegaly
Phenylketonuria (PKU)
Hyperphenylalanemia, high phenylalanine disrupts brain myelination, protein synthesis, produces mental retardation, phenylalanine hydroxylase gene (PAH)
Prevalence of PKU
1:10,000 Caucasians, 1:90,000 Africans, all newborns in US are tested, requires dietary restriction to limit symptoms, high maternal blood levels of phenylalanine will affect fetus
Maple syrup urine disease
Cannot metabolize branched chain ketoacids from branched chain amino acids, 40% of protein is BCAA, named for odor of urine, accumulation of BCAA and byproducts can lead to neurodegeneration and death
Epidemiology of maple syrup urine disease
Rare except in Mennonites of Lancaster county, 1 in 7 are carriers
MCAD deficiency
Medium-chain acyl-coenzyme A dehydrogenase deficiency, most common fatty acid metabolism defect, episodic hypoglycemia after fasting, present with vomiting and lethargy after minor illness, fatty acid intermediates accumulate, insufficient ketone bodies, glycogen gone, most northwest European descent, 90% of mutations are missense A to G lysine to glutamate
Treatment of MCAD
Provide supportive care during episodes, provide usable calories promptly (glucose), avoid fasting, cerebral edema and exhaustion of glucose supplies can be followed by death
Congenital adrenal hyperplasia (CAH)
Block in corticosteroid synthesis, excess precursors can be androgenic or converted to weak androgens, virilizaiton of females in utero, severe forms cause salt-wasting (weight loss, lethargy, dehydration, death)
Zellwegger syndrome
Most severe peroxisome biogenesis disorder, neonatal hypotonia, progressive white matter disease, distinctive face, death in infancy, mutations in proteins needed for peroxisome biogenesis and importing proteins into matrix
Lysosomal storage disorders
Lysosomes degrade mucopolysaccharides, sphingolipids, glycoproteins, and glycolipids, accumulate in tissues when not degraded, can cause cell, tissue, organ dysfunction, most are enzyme defects, some affect transport/targeting
Mucopolysaccharidoses
Reduced degradation of glycosaminoglycans- heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, ten enzymes cause six disoders
Distinguishing MPS
Autosomal recessive except Hunter (X-linked), all have chronic, progressive multisystem deterioration, hearing, vision, joint, cardiovascular problems, mental retardation only in Hunter, Hurler, Sanfilippo
Hurler syndrome
Growth deficiency, coarse facies
Sphingolipidoses
Lysosomal storage diseases (mucolipidoses), sphingolipid degradation deficient, Gaucher, Tay-Sachs, Niemann-Pick
Gaucher
Beta-glucosidase deficiency, rare except Ashkenazi Jews, three types, vary in severity
Tay-Sachs
Beta-hexosaminidase A deficiency, more common in Jewish populations
Niemann-Pick
Sphingomyelinase deficiency
I-cell disease
Lysosomal enzymes target to lysosomes by mannose-6-P and lysosomal receptor, I-cell has deficient phosphotransferase, accumulated products appear as inclusions
Urea cycle disorders
Defects known in each of five major reactions, 4 defects cause accumulation of precursors, lethargy, coma- carbamoyl phosphate synthetase (CPS), ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASA), argininosuccinase (AS)
OTC deficiency
Most common urea cycle defect, X-linked gene, 10 exons, variety of mutations, women can be symptomatic carriers, must provide calories and protein for normal growth and development, prevent hyperammonemia from excess nitrogen
Energy production
Several pathways, lead to OXPHOS system- five multiprotein complexes, 100 polypeptides, on inner mitochondrial membrane
Transport systems
Move molecules between compartments, same transporter may be used in different tissues, bring in nutrients, recover from glomerular filtrate so not lost to urine
Cystinuria
Cystine = 2 cysteines with disulfide bond, transporter for dibasic amino acids, lysine, arginine, ornithine affected, high levels in urine, cystine is least soluble, can form kidney stones, treat by solubilizing cystine with water, high pH, penicillamine
Cystinuria defects
Type I- mutates SLC3A1
Types II and III- SLC7A9
Heavy and light chains of brush border amino acid transporter b, less transport, less amino acids recovered, more in urine
Metal ion transporters
Metals are co-factors for enzymes, required for heme protein function, defects in copper, iron, zinc transport, transport may be in or out of cells, disorders due to deficiency or excess
Wilson disease
Defect in copper excretion to biliary tract, accumulates in liver leading to progressive liver disease and neurological abnormalities
Symptoms of Wilson disease
Acute or chronic liver disease, dysarthria, diminished coordination, arthropathy, cardiomyopathy, kidney damage, hypoparathyroidism, Kayser-Fleischer ring in the eye
Gene for Wilson disease
ATP7B, similar to proteins that make bacteria resistant to heavy metals, preodminant expression in liver and kidney, single missense in 40% of northern European cases
Hereditary hemochromatosis
Excessive iron absorption in intestine, accumulates in liver, kidney, heart, joints, pancreas, common in northern Europeans (1 in 8 is carrier), 1 in 200-400 affected (incomplete penetrance), delayed onset
Symptoms of hemochromatosis
Fatigue common, joint pain, diminished libido, diabetes, increased skin pigmentation, cardiomyopathy, liver enlargement and cirrhosis, diagnosis by liver biopsy with hemosiderin staining
Genetics of hemochromatosis
Found linkage to HLA region, class I-like gene called HFE, binds transferrin receptor on cell surface, inhibits iron uptake, affects sensor for iron in intestine, excess brush border uptake of iron
Mutation in hemochromatosis
Common mutation C282Y, cysteine to tyrosine, cystine part of disulfide bond at beta-2-microglobulin binding domain, iron deficiency is common, increased uptake could alleviate deficiency
