2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency

Stefan Kolker MD (Dr. Kolker of the University of Heidelberg, Germany, has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire and Vtesse.)
Originally released July 3, 2005; last updated October 30, 2015; expires October 30, 2018

This article includes discussion of 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, 17beta-hydroxysteroid dehydrogenase type 10 deficiency, and MHBD deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, also denoted 17beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency, is a rare X-linked organic aciduria with a highly unusual “neurodegenerative” disease course involving progressive loss of acquired mental and motor skills, loss of vision, and medically intractable epilepsy in early childhood. There are also patients with a more severe neonatal presentation that may mimic a mitochondrial disease as well as patients without neurologic symptoms despite complete loss of enzyme function. The author reports that HSD10 is identical to the MRPP2 component of the mitochondrial ribonuclease P complex that is required for mitochondrial DNA transcript processing. This mechanism explains why inherited deficiency of HSD10 results in a primary mitochondrial disorder.

Key points

 

• 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is a progressive multisystem disease resembling mitochondrial disorders.

 

• It is caused by mutations in the HSD17B10 gene, which codes for a multifunctional protein; the pathogenesis of the condition is poorly understood.

 

• Inheritance is X-chromosomal, with severe symptoms in males and variable or no symptoms in females.

 

• The predominant clinical features are progressive severe neurologic symptoms and cardiomyopathy; onset is at birth or in the first years of life.

 

• There is no effective treatment.

Historical note and terminology

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency, also denoted 17beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency, is an X-linked organic aciduria first described in 2000 (Zschocke et al 2000).

Meanwhile, some additional patients (mostly males) have been identified (Ensenauer et al 2002; Olpin et al 2002; Sutton et al 2003; García-Villoria et al 2004; Poll-The et al 2004; Sass et al 2004). The disease is caused by mutations in HSD17B10 (previously denoted HADH2), which is located on the X chromosome (Ofman et al 2003). Identification of this gene also opened a new approach to the understanding of the pathogenesis. The protein encoded by the HSD17B10 gene, correctly denoted HSD10, had been reported to be involved in the pathogenesis of Alzheimer disease (Yan et al 1997) and is now known to be identical to MRPP2, an essential component of the mitochondrial ribonuclease P (Holzmann et al 2008).

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