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)
