Isovaleric acidemia, isovaleryl-CoA dehydrogenase deficiency | Clinical continuum mild to severe: vomiting, acidosis, ketosis, mild hyperammonemia, hypocalcemia, transient bone marrow suppression, lethargy, and coma. 50% of positive newborn screens are asymptomatic | Urine: Isovalerylglycine, during episodes 3-hydroxyisovalerate, isovalerylglucuronide, 4-hydroxyisovalerate. Plasma/blood: Isovaleric acid, isovalerylcarnitine | "Sweaty feet odor" during episodes. Usually normal development with leucine restriction and treatment with carnitine and/or glycine |
3-Methylcrotonyl-CoA carboxylase deficiency | Most patients identified through newborn screening are asymptomatic. Acute episodes can include vomiting, acidosis, hypoglycemia, hypotonia, and coma | Urine: 3-Hydroxyisovalerate, 3-methylcrotonylglycine, 3-hydroxyisovalerylcarnitine Plasma/blood: 3-Hydroxyisovalerylcarnitine but very low free carnitine | Distinct from multiple Carboxylase deficiency; does not respond to biotin. Normal development with protein restriction and carnitine |
3-Methylglutaconic aciduria type I: 3-Methylglutaconyl-CoA hydratase deficiency | Speech retardation, acidosis with intercurrent infection, hypotonia, and hepatomegaly | Urine: 3-Methylglutaconate, 3-hydroxyisovalerate | Diagnosis requires hydratase assay |
3-Methylglutaconic aciduria type II: Barth syndrome | X-linked dilated cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation | Urine: 3-Methylglutaconate, 3-methylglutarate, 3-hydroxyisovalerate not elevated | Normal hydratase. Abnormal G4.5 protein, function unknown |
3-Methylglutaconic aciduria type III: Costeff optic atrophy syndrome | Infantile bilateral optic atrophy, choreiform movements, cerebellar ataxia, and mild spasticity | Urine: 3-Methylglutaconate, 3-methylglutarate, 3-hydroxyisovalerate not elevated | Normal hydratase. Found in Iraqi Jewish patients |
3-Methylglutaconic aciduria type IV: "unclassified" | Variable; psychomotor retardation, neurodegeneration with hypotonia, seizures, optic atrophy, deafness, hepatic dysfunction, cardiomyopathy, and failure to thrive, usually without acidosis | Urine: 3-Methylglutaconate, 3-methylglutarate; 3-hydroxyisovalerate not elevated | Normal hydratase. Some have abnormal mitochondrial electron transport chain, Pearson syndrome. Likely a heterogenous group of underlying diagnoses |
3-Methylglutaconic aciduria type V (DNAJC19 mutations) | Similar to Barth syndrome but with ataxia, growth failure, testicular dysgenesis in males | Urine: 3-Methylglutaconate, 3-methylglutarate. Others not reported | Normal hydratase activity. Limited to Canadian Dariusleut Hutterites thus far. |
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency | Neonatal, infantile, or childhood presentation; vomiting, hypotonia, lethargy, coma, acidosis, and hyperammonemia, hypoglycemia without ketosis | Urine: 3-Hydroxy-3-methylglutarate, 3-methylglutaconate, 3-hydroxyisovalerate, 3-mehtylcrotonylglycine. Plasma/blood: 3-Methylglutarylcarnitine | Often presents like Reye syndrome. Deficient ketogenesis. Covered in detail in Primary Hyperoxaluria. |
Mevalonic aciduria, mevalonate kinase deficiency | Variable; may include dysmorphic features, failure to thrive, gastroenteropathy, hepatosplenomegaly, ... |