Mental Retardation and Isoleucine Metabolism

17β-Hydroxysteroid dehydrogenase type 10 (HSD10) is encoded by the HSD17B10 gene (formerly HADHII), which maps to Xp11.22. At least ten different mutations have been identified in this gene. Missense mutations of this gene result in 17β-HSD10 Deficiency, an intellectual developmental disability characterized by progressive psychomotor regression and occasionally cardiomyopathy. Patients with this deficiency excrete isoleucine metabolites, e.g. 2-methyl-3-hydroxybutyrate (MHB) and tiglylglycine from urine. Although a blockade of isoleucine degradation is a clinical indicator of this disease, it is the imbalance of neuroactive steroid metabolism that is likely a major cause of the neurological handicap. About 50% of cases are caused by a c.388C>T transition due to a 5-methylcytosine hotspot. This de novo mutation results in the 17β-HSD10(R130C) mutant protein. 17β-HSD10 is a mitochondrial multifunctional enzyme, and is essential for the degradation of isoleucine and the oxidative inactivation of allopregnanolone, a potent, positive allosteric modulator of GABAA receptors. A silent mutation in this gene causes milder mental retardation without the isolucine metabolites accumulation. This disease has been designated as Mental Retardation, X-linked, choreoathetosis, and abnormal behavior (MRXS10). The HSD17B10 gene product had been mischaracterized as the Endoplasmic Reticulum-associated Aβ-Binding protein (ERAB) as well as Aβ-Binding Alcohol Dehydrogenase (ABAD), based upon non-reproducible and erroneous data published in various journals [see Yang, He, Isaacs, Dobkin, Miller et al (2014) J Steroid Biochem Mol Biol. 143, 460-472]. Other inborn metabolic disorders involving the excretion of MHB in urine are also discussed. Understanding the pathophysiological basis of 17β-HSD10 deficiency may lead to treatment of this inherited isoleucine metabolic disease.