3-hydroxy-isobutyryl-CoA hydrolase deficiency causing deficiency of multiple mitochondrial respiratory chain enzymes and of the pyruvate dehydrogenase complex

Posted by & filed under Part 09: ORGANIC ACIDS, Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, _.

Ferdinandusse S et al. HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis. 2013 Dec 4;8:188.


Ferdinandusse et al describe two new patients (for a total of four patients described on the literature) with 3-hydroxy-isobutyryl-CoA hydrolase deficiency, a disorder of valine catabolism, presenting as a neurodegenerative disorder in early infancy with basal ganglia abnormalities and leukoencephalopathy. Biochemically, the crucial diagnostic finding was persistent elevation of hydroxy-C4-carnitine (corresponding to 3-hydroxy-isobutytyl-carnitine). Unfortunately, urine organic acid findings (if any) were not described.

Interestingly, the patients were shown to have variable deficiency of multiple respiratory chain enzymes as well as of the pyruvate dehydrogenase complex. The authors hypothesize that accumulation of methacrylyl-CoA, upstream of the enzymatic block, causes toxic damage to multiple mitochondrial enzymes by reacting with exposed thiol groups.

As well as presenting an unusual pathophysiological mechanism of secondary mitochondrial dysfunction, this study illustrates the usefulness of performing a plasma acylcarnitine profile in the differential diagnosis of mitochondrial disease.

Posted by: Alina Levtova, MD


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