Inborn Errors of Metabolism

Question 1

AKU

Answer 1

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)

Question 2

Reasons for predominance of metabolic disorders

Answer 2

Reactions are catalyzed by enzymes, most enzymes are produced in mild excess, one good gene is usually sufficient, defective genes can persist in populations

Question 3

Classes of metabolic disorders

Answer 3

Carbohydrate, amino acid, lipid, organic acid metabolisms, urea cycle disorder, energy production defects, transport defects

Question 4

Metabolic disorder genetics

Answer 4

Most are autosomal recessive, a few are X-linked, consanguinity a factor, history of miscarriages or neonatal deaths, siblings with developmental delay or autism

Question 5

Galactosemia

Answer 5

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

Question 6

Symptoms of galactosemia

Answer 6

Failure to thrive, hepatic insufficiency, cataracts, developmental delay, long term- poor growth and mental retardation, screening by blood enzyme activity, treatment by dietary restriction

Question 7

Hereditary fructose intolerance

Answer 7

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

Question 8

Von Gierke disease

Answer 8

Glycogen storage disorder, defect in glucose-6-phosphatase, glucose from glycogen not released from the liver, G-6-P metabolized, hypoglycemia between meals, hepatomegaly

Question 9

Phenylketonuria (PKU)

Answer 9

Hyperphenylalanemia, high phenylalanine disrupts brain myelination, protein synthesis, produces mental retardation, phenylalanine hydroxylase gene (PAH)

Question 10

Prevalence of PKU

Answer 10

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

Question 11

Maple syrup urine disease

Answer 11

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

Question 12

Epidemiology of maple syrup urine disease

Answer 12

Rare except in Mennonites of Lancaster county, 1 in 7 are carriers

Question 13

MCAD deficiency

Answer 13

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

Question 14

Treatment of MCAD

Answer 14

Provide supportive care during episodes, provide usable calories promptly (glucose), avoid fasting, cerebral edema and exhaustion of glucose supplies can be followed by death

Question 15

Congenital adrenal hyperplasia (CAH)

Answer 15

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)

Question 16

Zellwegger syndrome

Answer 16

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

Question 17

Lysosomal storage disorders

Answer 17

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

Question 18

Mucopolysaccharidoses

Answer 18

Reduced degradation of glycosaminoglycans- heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, ten enzymes cause six disoders

Question 19

Distinguishing MPS

Answer 19

Autosomal recessive except Hunter (X-linked), all have chronic, progressive multisystem deterioration, hearing, vision, joint, cardiovascular problems, mental retardation only in Hunter, Hurler, Sanfilippo

Question 20

Hurler syndrome

Answer 20

Growth deficiency, coarse facies

Question 21

Sphingolipidoses

Answer 21

Lysosomal storage diseases (mucolipidoses), sphingolipid degradation deficient, Gaucher, Tay-Sachs, Niemann-Pick

Question 22

Gaucher

Answer 22

Beta-glucosidase deficiency, rare except Ashkenazi Jews, three types, vary in severity

Question 23

Tay-Sachs

Answer 23

Beta-hexosaminidase A deficiency, more common in Jewish populations

Question 24

Niemann-Pick

Answer 24

Sphingomyelinase deficiency

Question 25

I-cell disease

Answer 25

Lysosomal enzymes target to lysosomes by mannose-6-P and lysosomal receptor, I-cell has deficient phosphotransferase, accumulated products appear as inclusions

Question 26

Urea cycle disorders

Answer 26

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)

Question 27

OTC deficiency

Answer 27

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

Question 28

Energy production

Answer 28

Several pathways, lead to OXPHOS system- five multiprotein complexes, 100 polypeptides, on inner mitochondrial membrane

Question 29

Transport systems

Answer 29

Move molecules between compartments, same transporter may be used in different tissues, bring in nutrients, recover from glomerular filtrate so not lost to urine

Question 30

Cystinuria

Answer 30

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

Question 31

Cystinuria defects

Answer 31

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

Question 32

Metal ion transporters

Answer 32

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

Question 33

Wilson disease

Answer 33

Defect in copper excretion to biliary tract, accumulates in liver leading to progressive liver disease and neurological abnormalities

Question 34

Symptoms of Wilson disease

Answer 34

Acute or chronic liver disease, dysarthria, diminished coordination, arthropathy, cardiomyopathy, kidney damage, hypoparathyroidism, Kayser-Fleischer ring in the eye

Question 35

Gene for Wilson disease

Answer 35

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

Question 36

Hereditary hemochromatosis

Answer 36

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

Question 37

Symptoms of hemochromatosis

Answer 37

Fatigue common, joint pain, diminished libido, diabetes, increased skin pigmentation, cardiomyopathy, liver enlargement and cirrhosis, diagnosis by liver biopsy with hemosiderin staining

Question 38

Genetics of hemochromatosis

Answer 38

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

Question 39

Mutation in hemochromatosis

Answer 39

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