2-methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive disease characterized by an impairment in the degradation of isoleucine. Most people with this rare enzymatic deficiency are asymptomatic and are identified by elevated plasma levels of C5-carnitine found on routine newborn screening. Urine organic acid analysis, measurement of enzymatic activity, and genetic testing are employed for confirmation.
2-methylbutyryl-CoA dehydrogenase deficiency, also referred to as short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, is a rare genetic disease in which insufficient levels of this enzyme result in impaired metabolism of L-isoleucine   . This autosomal recessive disorder is attributed to mutations in the SBCAD gene  . Overall, it is more predominant in the Hmong community in China , in whom there is a recurrence of a known SBCAD mutation . The prevalence of the disease is 1:250 to 1:500 in the Hmong population.
Affected individuals are diagnosed either due to increased C5-carnitine levels discovered during newborn screening   , or secondary to clinical features and 2-methylbutyrylglycinuria   . The majority of cases, whether of Hmong descent or not, remain asymptomatic  . However, those with manifestations present as neonates or young children with an onset characterized by poor feeding, lethargy, irritability, and emesis. Moreover, newborns may exhibit acute metabolic acidosis accompanied by seizures, weak muscle tone, vomiting, as well as delays in development and motor skills   .
2-methylbutyryl-CoA dehydrogenase deficiency does not confer the same impact on all patients. Most are asymptomatic, hence, complications are very rare.
Hypotonia  , inadequate growth, psychomotor difficulties, and possibly respiratory trouble are remarkable signs observed on the physical exam.
All babies and children suspected to have 2-methylbutyryl-CoA dehydrogenase deficiency, whether due to abnormal newborn screening or clinical manifestations, warrant a personal and family history, physical exam, and follow-up studies. In addition to plasma and urine tests, fibroblast cultures and genetic testing are also used to confirm the diagnosis.
2-methylbutyryl-CoA dehydrogenase deficiency is one of the disorders tested for in routine newborn screening  , which is how most patients are identified. Specifically, this disease is associated with elevated plasma levels of C5-carnitine , which can be demonstrated through blood spot tandem mass spectrometry . Note that C5-carnitine may be normal in affected individuals. Another marker, 2-ethylhydracrylic acid, is sensitive for this disease .
In patients with abnormal C5-carnitine levels, a further assessment with urine organic acid analysis and urine acylglycine detection is required  . Consequently, a urine organic acid profile may reveal increased amounts of 2-methylbutyrylglycine and possibly 2-methylbutyrylcarnitine  .
Finally, fibroblast assays should reflect a profound reduction in 2-methylbutyryl-CoA activity in these patients  .
Molecular analysis for mutations in SBCAD genes is performed for diagnostic confirmation . Moreover, genetic counseling should be offered to parents with personal or family history.
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