Glycolytic Pathway Disorders Hexokinase – rare autosomal recessive, nonspherocytic hemolytic anemia. Phosphoglucose isomerase – rare autosomal recessive, hemolytic anemia, less common neurological problems. Phosphofructokinase – (Glycogen storage disease type VII; Tarui disease) rare autosomal recessive, three subtypes (classic, infantile onset, and late onset), myoglobinuria, hyperuricemia, hemolytic anemia when erythrocyte isoform is involved. Avoid high carbohydrate meals. Adolase – rare autosomal recessive, three genes (ALDOA, mainly muscle; ALDOB, mainly liver, some kidney and intestine; ALDOC, mainly brain), ALDOA has myopathy and hemolytic anemia. ALDOB (hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis, treat by restricting fructose. Triosephosphate isomerase – rare autosomal recessive, congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy. Glyceraldehyde-3-phosphate dehydrogenase – rare autosomal recessive, very little information available.
Glycolytic Pathway Disorders Bisphosphoglycerate mutase/phosphatase – rare, hemolytic anemia, polycythemia, increased hemoglobin affinity for O 2. Phosphoglycerate kinase – rare X-linked recessive, two forms, chronic hemolytic anemia, myopathic (myoglobinuria) with muscle symptoms especially upon exercise. Phosphoglycerate mutase – rare autosomal recessive, mainly affects skeletal muscle. Enolase – rare autosomal recessive, affects muscle, exercise intolerance. Pyruvate kinase – autosomal recessive, most common inherited cause of nonspherocytic hemolytic anemia (normochromic, normocytic, and reticulocytosis), pallor, jaundice, fatigue, dyspnea, tachycardia and splenomegaly. Treatment is primarily supportive, avoid impact sports with splenomegaly, avoid large doses of salicylates, supplement with folic acid and B vitamins, use blood transfusions with decreased hemoglobin concentrations. Lactate dehydrogenase – rare autosomal recessive, two forms, LDHA is mainly skeletal muscle, LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB subunits. LDHA deficiency symptoms include fatigue, muscle pain, exercise intolerance, rhabdomyolysis, and myoglobinuria. LDHB deficiency is asymptomatic.
Pentose Phosphate Pathway Disorders Glucose-6-phosphate dehydrogenase – X-linked recessive, most common disease- producing enzymopathy, hemolytic anemia most often triggered by bacterial or viral infections, oxidative drugs (sulfonamides and malarials), or eating fava beans (favism). Treatment is supportive, bed rest and oxygen, avoid triggers (drugs, diet, environmental). Ribose-5-phosphate isomerase – very rare (single report), leukoencephalopathy and peripheral neuropathy. Transketolase – very rare (single report), liver cirrhosis and hepatosplenomegaly.
Fructose Pathway fructose fructose-1-phosphate glyceraldehydeglyceraldehyde-3-phosphate dihydroxyacetone phosphate ATP Fructokinase Aldolase B Triose kinase Triose phosphate isomerase
Fructose Pathway Disorders Fructokinase – autosomal recessive, benign. Aldolase B – autosomal recessive, (hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis. Treatment by restricting fructose intake.
Urea Cycle Disorders N-Acetylglutamate synthase – very rare autosomal recessive, lethargy, poorly- controlled breathing rate or body temperature, seizures, coma, hyperammonemia, increased serum alanine and glutamine urine orotic acid within reference range. Treatment is low protein intake. Carbamoylphosphate synthetase – rare, autosomal recessive, early-onset lethargy, seizures, hyperammonemia, serum ammonia concentrations are usually 10-20 times higher than reference range. Treatment is reduced protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Ornithine transcarbamoylase – rare, X-linked recessive, early- or late-onset, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased urine orotic acid, enzyme assays. Treatment is restricted protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate.
Urea Cycle Disorders Argininosuccinate synthetase – rare, autosomal recessive, two forms (type I more common than II). Type I lethargy, poor feeding, vomiting, seizures, and loss of consciousness, type II confusion, restlessness, memory loss, abnormal behaviors (such as aggression, seizures, and coma, hyperammonemia, increased serum citrulline, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is restricted protein diet and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Argininosuccinate lyase – rare, autosomal recessive, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased serum and urine argininosuccinic acid, increased serum citrulline, glutamine, alanine, and lysine, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is low-protein diet, arginine supplementation and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Arginase – very rare (least common urea cycle defect), autosomal recessive, delayed development, protein intolerance, spasticity, hyperammonemia (sometimes), assay for erythrocyte arginase activity. Treatment is low-protein diet and administration of oral sodium benzoate or sodium phenylbutyrate to reduce ammonia concentration when appropriate.
Branched-Chain Amino Acids leucine α-keto-β-methylvalerateα-ketoisovalerateα-ketoisocaproate valine Aminotransferase isoleucine Branched-chain α-ketoacid dehydrogenase α-methylbutyl CoAisobutyl CoAisovaleryl CoA Aminotransferase propionyl CoA D-methylmalonyl CoA succinyl CoA L-methylmalonyl CoA 3-hydroxy-3-methylglutaryl CoA acetoacetate Propionyl CoA carboxylase Methylmalonyl CoA mutase HMG CoA lyase
Branched-Chain Amino Acid Disorders Branched-chain α-ketoacid dehydrogenase – rare, autosomal recessive, newborn screening, poor feeding, vomiting, lethargy, and developmental delay, sweet odor of affected infants' urine, increased serum leucine and isoleucine concentrations, increased alloisoleucine concentrations by day 6, increased urine alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate concentrations, enzyme assay of lymphocytes or cultured fibroblasts (not necessary for diagnosis). Treatment is dietary restriction of branched-chain amino acids and supplementation of thiamine as appropriate. MSUD Express for juveniles and adults. Propionyl CoA carboxylase – autosomal recessive, failure to thrive due to feeding intolerance and vomiting, ketoacidosis, dehydration, shock, increased serum anion gap and ketones, decreased urine pH, increased urine β-hydroxy propionic acid, lactic acid, and methylcitrate concentrations, enzyme assays of leukocytes. Treatment with restriction of branched-chain amino acids.
Branched-Chain Amino Acid Disorders Methylmalonyl CoA mutase – autosomal recessive, seizure, encephalopathy, stroke, hypotonia, lethargy, failure to thrive, hepatosplenomegaly, increased serum ammonia, glycine, propionic acid, and methylmalonic acid concentrations, increased urine methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxypropionate concentrations. Treatment with protein restriction and carnitine supplementation. 3-Hydroxy-3-methylglutaryl CoA lyase – rare, autosomal recessive, vomiting, diarrhea, dehydration, lethargy, hypotonia, non-ketotic hypoglycemia, metabolic acidosis, increased serum 3-hydroxy isovaleryl-carnitine and 3-methylglutaryl-carnitine concentrations, increased urine 3-hydroxy-isovaleric, 3-methylglutaric, glutaric, 3-methyl-glutaconic, 3- hydroxy-3-methyl-glutaric acids and 3-methyl-crotonyl-glycine concentrations. Treatment with limiting fasting periods, low-leucine diet, and supplementation of carnitine.
Steroid Pathway Disorders Desmolase – very rare (lipoid adrenal hyperplasia), autosomal recessive poor weight gain, vomiting, males are undervirilized, dehydration, hyperpigmentation, increased serum ACTH, hyponatremia, hyperkalemia, metabolic acidosis. Treatment with saline and fludrocortisone, female also with estrogen replacement. 17-Hydroxylase – very rare (congenital adrenal hyperplasia), autosomal recessive, patients with XX or XY karyotypes are phenotypic females or ambiguous genitalia, hypertension, hypokalemia, metabolic alkalosis, increased serum progesterone, corticosterone, and deoxycorticosterone concentrations, decreased 17-hydroxyprogesterone, estrogens, and androgens concentrations. Treatment with glucocorticoid and estrogen replacement, salt restriction, diuretics as appropriate. 3β-Hydroxysteroid dehydrogenase – very rare (congenital adrenal hyperplasia), autosomal recessive, ambiguous genitalia or female genitalia, hyperpigmentation, increased serum 11-deoxycortisol and deoxycorticosterone, increased ratio of 24-hour urine metabolite of 11-deoxycortisol to metabolite of cortisol. Treatment with glucocorticoid and mineralocorticoid therapy as appropriate.
Steroid Pathway Disorders 21-Hydroxylase – very rare (most common congenital adrenal hyperplasia), autosomal recessive, males have failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, shock, accelerated growth and skeletal maturation; in addition, females have ambiguous genitalia at birth, later in childhood with precocious pubic hair, clitoromegaly, increased serum 17-hydroxyprogesterone concentrations, increased urine pregnanetriol concentrations. Treatment with glucocorticoid and mineralocorticoid therapy as appropriate. 11-Hydroxylase – very rare (congenital adrenal hyperplasia), autosomal recessive, androgen excess, masculinization of female newborns and precocious puberty in male children, hypertension, increased serum 11-deoxycortisol and deoxycorticosterone, urine 17- ketosteroids, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione, and testosterone. Treatment with glucocorticoid replacement and antihypertensive therapy. Aromatase – very rare, autosomal recessive, virilization manifests as pseudohermaphroditism in female infants, affected males do not present with obvious defects at birth, tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity, increased serum testosterone concentrations. Treatment with estrogen replacement.
Steroid Pathway Disorders Aldosterone synthase – rare, autosomal dominant, autosomal recessive, severe salt- wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood, increased serum renin activity, decreased serum aldosterone concentrations, increased serum 18-hydroxycorticosterone. Treatment with mineralocorticoid therapy (fludrocortisone) and sodium supplementation. 5α-Reductase – rare, autosomal recessive, ambiguous genitalia, clitoral-like phallus, markedly bifid scrotum, pseudovaginal perineoscrotal hypospadias, rudimentary prostate, uterus and fallopian tubes are absent, testes are intact and usually found in the inguinal canal or scrotum, amniocentesis or chorionic villus sampling show XY karyotype, fluorescent in situ hybridization results positive for sex-determining region, increased serum testosterone-to- dihydrotestosterone ratio, molecular genetics studies. Treatment considerations of gender assignment. 17-Ketoreductase – rare, autosomal recessive, characterized by clitoromegaly, posterior labioscrotal fusion and perineal blind vaginal pouch, testes are inguinal or in the labioscrotal folds, internal urogenital tract (epididymides, vasa deferentia, seminal vesicles, ejaculatory ducts) well developed; prostate and Müllerian structures are absent, baseline and post-human chorionic gonadotropin stimulation hormonal evaluation shows increased androstenedione and decreased testosterone concentrations, with an increased androstenedione-to- testosterone ratio. Treatment considerations of gender assignment.