Isobutyryl-Coa Dehydrogenase Deficiency

A number sign (#) is used with this entry because isobutyryl-CoA dehydrogenase deficiency (IBDD) is caused by homozygous or compound heterozygous mutation in the ACAD8 gene (604773) on chromosome 11q25.

Clinical Features

The first patient with isobutyryl-CoA dehydrogenase deficiency was described by Roe et al. (1998) and presented at age 12 months with dilated cardiomyopathy, anemia, and carnitine deficiency. An elevated C4-acylcarnitine was noted in a plasma acylcarnitine profile, but a subsequent urine organic acid analysis was normal. Treatment with oral L-carnitine supplementation led to catch-up growth and normalization of the cardiac status. Oglesbee et al. (2007) reported that the patient remained carnitine-dependent at almost 11 years of age.

Eight additional patients with IBD deficiency were reported by Koeberl et al. (2003), Sass et al. (2004), and Pedersen et al. (2006). All were identified by newborn screening when isolated elevation of C4-acylcarnitine prompted further diagnostic investigations. There was clinical information available on 6 of the 9 patients. Two patients remained asymptomatic for more than 1 year without treatment. One patient was noted to have muscle hypotonia and mild developmental delay at 8 months of age. Two patients were treated for speech delay at 5 years and 2 years of age, respectively, but had normal growth and development; and 1 patient was incidentally noted at 1 year of age to have mild branch peripheral pulmonary stenosis, which was detected by echocardiography to rule out a cardiomyopathy.

Oglesbee et al. (2007) reported an additional 13 patients with IBD deficiency who were identified by newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. At the time of their report, 10 of the 13 remained asymptomatic, 2 were lost to follow-up, and 1 had required frequent hospitalizations due to emesis and dehydration during the first 2 years of life but was developing normally at 5 years of age.

Diagnosis

Oglesbee et al. (2007) described an algorithm for the diagnosis of IBD deficiency identified by elevated C4-acylcarnitine on newborn screening. They noted that urine acylcarnitine analysis appeared to be a practical tool for diagnosing IBD deficiency.

Molecular Genetics

Nguyen et al. (2002) found a homozygous mutation in the ACAD8 gene (R302Q; 604773.0005) in the original patient with IBD deficiency described by Roe et al. (1998).

Oglesbee et al. (2007) found 10 different mutations in the ACAD8 gene in 9 individuals with IBD deficiency (see, e.g., 604773.0001-604773.0004). Six infants were compound heterozygotes, and 3 were homozygotes. Three infants of European descent carried the same allele (M130T; 604773.0001). Another allele was common to 3 additional infants (G355S; 604773.0002). In 1 of the infants carrying the G355S allele, no alteration was found on the other ACAD8 allele.