Congenital Metabolic Disorders

Question 1

Pyruvate dehydrogenase deficiency

Answer 1

Findings: neurologic defects Enzyme deficient: Pyruvate Dehydrogenase Accumulated substrate: Pyruvate, Alanine Treatment: increase intake of ketogenic nutrients such as fat or lysine and leucine

Question 2

Glucose 6-phosphate dehydrogenase deficiency

Answer 2

Findings: Hemolytic anemia, Heinz bodies (oxidized hemoglobin precipitated within RBCs), Bite cells (from phagocytic removal of Heinz bodies by splenic macrophages) Enzyme Deficient: Glucose-6-phosphate dehydrogenase Deficient cellular molecule: NADPH Precipitating factors: ingestion of fava beans, sulfonamides, primaquine, antituberculosis drugs, infection (inflammatory response produces free radicals, cause oxidative damage to RBCs) Inheritance: XR; most common human enzyme deficiency; more prevalent among blacks, increased malarial resistance

Question 3

Essential fructosuria

Answer 3

Findings: fructose in blood and urine Enzyme Deficient: Fructokinase Inheritance: AR

Question 4

Fructose intolerance

Answer 4

Findings: Hypoglycemia, jaundice, cirrhosis, vomiting Enzyme Deficient: Aldolase B Accumulated substrate: Fructose-1-phosphate Inheritance: AR Phosphorylated fructose builds up in cells causing inhibition of glycogenolysis and gluconeogenesis Treatment: decrease intake of both fructose and sucrose

Question 5

Galactokinase deficiency

Answer 5

Findings: galactose appears in blood and urine, infantile cataracts; failure of child to track objects or to develop a social smile Enzyme Deficient: Galactokinase Accumulated substrate: Galactitol Inheritance: AR

Question 6

Classic galactosemia

Answer 6

Findings: Failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation Enzyme Deficient: Galactose-1-phosphate uridyltransferase Accumulated substrate: Galactitol Inheritance: AR Treatment: exclude galactose and lactose from diet

Question 7

Lactase deficiency

Answer 7

Findings: bloating, cramps, osmotic diarrhea; may follow gastroenteritis Enzyme Deficient: Lactase Treatment: avoid dary products or add lactase pills to diet

Question 8

Ornithine transcarbamoylase (OTC) deficiency

Answer 8

Findings: Orotic acid in blood and urine, decreased BUN, symptoms of hyperammonemia (tremor, vomiting, cerebral edema, blurring of vision) Enzyme Deficient: OTC Accumulated Substrate: ammonia Inheritance: XR Often evident in the first few days of life, may present later.

Question 9

Phenylketonuria

Answer 9

Findings: mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor Enzyme Deficient: phenylalanine hydroxylase OR tetrahydrobiopterin cofactor Inheritance: AR Tyrosine becomes essential. Maternal PKU with lack of dietary therapy results in microcephaly, mental retardation, growth retardation, and congenital heart defects for the infant.

Question 10

Leber’s hereditary optic neuropathy

Answer 10

Findings: progressive loss of central vision and eventual blindness due to degeneration of the optic nerve Enzyme Defect: NADH dehydrogenase (complex 1 of ETC) Inheritance: mitochondrial (maternal) Most common onset in the third decade.

Question 11

Kearns-Sayre syndrome

Answer 11

Findings: degeneration of retinal pigments, ophthalmoplegia, pain in the eyes, and cardiac conduction defects, which may because death. Muscle biopsy reveals ragged red fibers marked by an irregular contour and structurally abnormal mitochondria that stain red. Inheritance: mitochondrial (maternal) Onset occurs before age 20 years.

Question 12

MELAS syndrome

Answer 12

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Question 13

MERRF syndrome

Answer 13

Myoclonus epilepsy with ragged red fibers

Question 14

Von Gierke’s disease

Answer 14

Findings: Severe fasting hypoglycemia, ketosis, hyperlipidemia, lactic acidosis, enlarged liver and kidneys (hepatorenomegaly) Enzyme Deficient: Glucose 6-phosphatase (liver and kidney) Inheritance: AR

Question 15

Pompe’s disease

Answer 15

Findings: Infant and Adult forms: Infant: mental retardation, hypotonia, cardiomegaly leading to death by age 2 Adult: gradual skeletal myopathy Enzyme Deficient: alpha-1,4-Glucosidase (lysosomes) Inheritance: AR

Question 16

Cori’s disease

Answer 16

Findings: Mild hypoglycemia, hepatomegaly; decrease in free glucose after epinephrine challenge Enzyme Deficient: Debranching enzyme (muscle and liver), amylo-alpha-1,6-glucosidase Inheritance: AR Abnormal glycogen structure: many short-branched chains

Question 17

Andersen’s disease

Answer 17

Findings: Hepatosplenomegaly, cirrhosis, liver failure leading to death by age 2 Enzyme Deficient: Branching enzyme (liver and spleen), glucosyl 4,6-transferase Inheritance: AR Abnormal glycogen structure: few long chains with very few branches

Question 18

McArdle’s disease

Answer 18

Findings: Muscle cramping, fatigue, and myoglobinuria with strenuous exercise; no increase in lactic acid after exercise Enzyme Deficient: Muscle glycogen phosphorylase Inheritance: AR

Question 19

Alkaptonuria

Answer 19

Findings: Dark connective tissue, brown pigmented sclera, urine turns black on prolonged exposure to air. Possible debilitating arthralgias. Enzyme Deficient: homogentisic acid oxidase Inheritance: AR Mostly a benign disease.