ClinVar

In 2 brothers, born of a consanguineous Arab couple from Lebanon, with 2-methylbutyryl-CoA dehydrogenase deficiency (610006), Sass et al. (2008) identified compound heterozygosity for mutations in the ACADSB gene: a 443C-T transition in exon 4, resulting in a thr148-to-ile (T148I) substitution, and a 1159G-A transition in exon 10, resulting in a glu387-to-lys (E387K; 600301.0005) substitution. One brother was diagnosed by newborn screening, and the other was diagnosed at age 3 years after his brother's diagnosis. Neither patient showed any clinical abnormalities, and both had normal development, but were lost to follow-up when the proband was 10 months old. The authors also identified homozygosity for the T148I mutation in 2 sibs from a consanguineous Turkish family. Both boys had normal development at age 6 and 7 years, respectively. In vitro studies of patient fibroblasts confirmed an impairment in isoleucine degradation.

In a child of European ancestry who was identified by newborn screening to have 2-methybutyryl-CoA dehydrogenase deficiency, Alfardan et al. (2010) identified compound heterozygosity for the T148I and E387K mutations. Alfardan et al. (2010) introduced the T148I mutation into an SBCAD expression vector and expressed it in E. coli. SBCAD protein was not detectable by Western blot analysis, and SBCAD enzyme activity was absent. Molecular modeling showed that the T148 residue resides in a hydrophilic pocket, where an Ile substitution might be disruptive.