Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis.

Objectives: To search for biochemical and molecular markers for the diagnosis of patients and carriers with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency.

Design And Methods: Organic acids in urine, MHBD activity in fibroblasts, immunoblotting and molecular studies were performed in seven patients. Seven carriers were also studied.

Results: Under low protein diet or poor feeding all the patients showed only a slightly altered organic acid profile. Measurement of 2-methyl-3-hydroxybutyric acid and tiglylglycine after an isoleucine loading test, failed to demonstrate the carrier status of one patient. However, measurement of 2-ethylhydracrylic acid (EHA) was positive in all the carriers tested. MHBD activity was clearly deficient in males and in one female patient. We identified four missense mutations, two of them were novel.

Conclusions: Quantification of EHA may be of help for the diagnosis of the heterozygous condition. The carrier females showed the classical biochemical variability of X-linked diseases due to random X-chromosome inactivation.