2-Methylbutyryl-Coa Dehydrogenase Deficiency

A number sign (#) is used with this entry because short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is caused by homozygous or compound heterozygous mutation in the gene encoding short/branched-chain acyl-CoA dehydrogenase (ACADSB; 600301).

Description

2-Methylbutyryl-CoA dehydrogenase (MBD) deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al.., 2008).

Clinical Features

Andresen et al. (2000) reported a 3-year-old boy, born of consanguineous Pakistani parents, who showed increasing hypotonia and delayed motor development in the second year of life. He also had generalized muscle atrophy and strabismus. Urinary organic acid analysis detected isolated 2-methylbutyryl glycinuria suggestive of a defect in isoleucine catabolism. Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as substrate, confirmed the defect. Although both parents and 2 sibs were asymptomatic, the mother was shown also to excrete 2-methylbutyryl glycine.

Gibson et al. (2000) reported an American boy of northern European and Eritrean descent with SBCADD. Although pregnancy and birth were normal, the infant was readmitted at age 3 days for poor feeding, lethargy, hypothermia, hypoglycemia, and episodes of apnea. Brain MRI showed bilateral areas of subacute ischemia involving the occipital and parietal lobes, consistent with global hypoxia. A female fetus in a subsequent pregnancy was found to be affected.

Madsen et al. (2006) provided follow-up on the patients reported by Gibson et al. (2000). At age 6 years, the boy showed severe developmental delay and epilepsy. He also had microcephaly and left eye exotropia. By contrast, his younger sister showed no clinical symptoms and normal development at age 4 years. The mother took supplemental carnitine during the second pregnancy, and the girl had been treated with carnitine and a low-protein diet since birth.

Madsen et al. (2006) reported an affected child from Somalia. He had 2 episodes of apnea at age 6 weeks and seizures at age 6 months. At age 12 months, he had global developmental delay, hypotonia, and poor eye contact.

Sass et al. (2008) reported 6 patients, including 2 sets of sibs, with SBCADD confirmed by genetic analysis (T148I; 600301.0004 and E387K; 600301.0005). The patients were of Turkish or Lebanese Arab origin. None of the patients had clinical symptoms, and the 3 probands were all ascertained by newborn screening. For the 3 probands, development was normal at age 3, 6, and 6 years, respectively, even without treatment. In vitro studies of patient fibroblasts confirmed an impairment in isoleucine degradation. Sass et al. (2008) stated that most individuals with this trait have been asymptomatic, and that the few reported with clinical symptoms (Gibson et al., 2000; Madsen et al., 2006) may have reflected ascertainment bias. However, Sass et al. (2008) noted that special attention may be needed in situations that could stimulate metabolic decompensation.

Diagnosis

Madsen et al. (2006) stated that routine tandem mass spectrometry-based newborn screening may not be sensitive enough to diagnose SBCAD deficiency, as some patients may show normal or high-normal levels of C5-acylcarnitine.

Molecular Genetics

In a patient with 2-methylbutyryl glycinuria, Andresen et al. (2000) identified a homozygous mutation in the ACADSB gene (600301.0001).

Gibson et al. (2000) described heterozygosity for a mutation in ACADSB cDNA (600301.0002) in a patient with 2-methylbutyryl glycinuria.

In a boy with 2-methylbutyryl glycinuria, whose parents were from Somalia, Madsen et al. (2006) identified a homozygous splice site mutation in the ACADSB gene (600301.0003). Madsen et al. (2006) also identified the splice site mutation in 2 affected sibs previously reported by Gibson et al. (2000).