The term "organic acidemia" or "organic aciduria" (OA) applies to a group of disorders characterized by the excretion of non-amino organic acids in urine. Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, usually the result of deficient enzyme activity. The majority of the classic organic acid disorders are caused by abnormal amino acid catabolism of branched-chain amino acids or lysine. They include maple syrup urine disease (MSUD), propionic acidemia, methylmalonic acidemia (MMA), methylmalonic aciduria and homocystinuria, isovaleric acidemia, biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency, ketothiolase deficiency, and glutaricacidemia type I (GA I). A neonate affected with an OA is usually well at birth and for the first few days of life. The usual clinical presentation is that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. Outcome is enhanced by diagnosis and treatment in the first ten days of life. In the older child or adolescent, variant forms of the OAs can present as loss of intellectual function, ataxia or other focal neurologic signs, Reye syndrome, recurrent ketoacidosis, or psychiatric symptoms.
Clinical laboratory findings that suggest an organic acidemia include acidosis, ketosis, hyperammonemia, abnormal liver function tests, hypoglycemia, and neutropenia. First-line diagnosis in the organic acidemias is urine organic acid analysis using gas chromatography with mass spectrometry (GC/MS), utilizing a capillary column. The urinary organic acid profile is nearly always abnormal in the face of acute illness with decompensation; however, in some disorders diagnostic analytes may be present only in small or barely detectable amounts when the affected individual is not acutely ill. Depending on the specific disorder, plasma amino acid analysis using a quantitative method such as column chromatography, high-performance liquid chromatography (HPLC), or GC/MS can also be helpful. A plasma or serum acylcarnitine profile can also provide a rapid clue to the diagnosis. Urine acylcarnitine profiling is more complex and interpretation can be difficult. Confirmatory testing involves assay of the activity of the deficient enzyme in lymphocytes or cultured fibroblasts and/or molecular genetic testing.
The organic acidemias considered in this overview are inherited in an autosomal recessive manner. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known. Prenatal diagnosis for pregnancies at increased risk varies by disorder and may include measurement of analytes in amniotic fluid, measurement of enzyme activity, or molecular genetic testing in cells obtained by CVS or amniocentesis.