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Branched Chain Amino Acids in Clinical Nutrition pp 157–169Cite as

Mental Retardation and Isoleucine Metabolism

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Part of the book series: Nutrition and Health ((NH))

Abstract

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.

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Notes

  1. 1.

    Please also refer to a previous chapter specifically devoted to this disease.

  2. 2.

    Luo MJ, Mao LF, Schulz H. Short-chain 3-hydroxy-2-methylacyl-CoA dehydrogenase from rat liver: purification and characterization of a novel enzyme of isoleucine metabolism. Arch Biochem Biophys. 1995;321:214–20.

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Acknowledgment

This work was supported by the New York State Office of People with Developmental Disabilities. We thank Dr. David Miller for helpful discussions.

Conflicts of Interest

Authors declare no conflicts of interest.

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Authors and Affiliations

  1. New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA

    Song-Yu Yang M.D., Ph.D., Xue-Ying He Ph.D., Carl Dobkin Ph.D., Charles Isaacs Ph.D. & W. Ted Brown M.D., Ph.D.

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  1. Song-Yu Yang M.D., Ph.D.
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  2. Xue-Ying He Ph.D.
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  3. Carl Dobkin Ph.D.
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  4. Charles Isaacs Ph.D.
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  5. W. Ted Brown M.D., Ph.D.
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Corresponding author

Correspondence to Song-Yu Yang M.D., Ph.D. .

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Editors and Affiliations

  1. Intensive Care, Barnet and Chase Farm Hospitals, Royal Free London NHS Foundation Trust, London, United Kingdom

    Rajkumar Rajendram

  2. Diabetes and Nutritional Sciences, Kings College London, London, United Kingdom

    Victor R. Preedy

  3. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

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Yang, SY., He, XY., Dobkin, C., Isaacs, C., Brown, W.T. (2015). Mental Retardation and Isoleucine Metabolism. In: Rajendram, R., Preedy, V., Patel, V. (eds) Branched Chain Amino Acids in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1923-9_13

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  • DOI: https://doi.org/10.1007/978-1-4939-1923-9_13

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