Japanese Male Siblings with 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency (HSD10 Disease) Without Neurological Regression

Abstract

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) is a rare X-linked disorder caused by a mutation in the HSD17B10 gene. Fewer than 30 patients with this disorder have been reported worldwide. The classical infantile form of HSD10 disease is characterized by a progressive neurodegenerative course with retinopathy and cardiomyopathy, although HSD10 disease has broad clinical heterogeneity. However, several male patients have not shown neurological regression. Here, we describe two Japanese siblings with HSD10 disease without neurological regression. A 4-year-old boy presented with unconsciousness due to severe hypoglycemia. Laboratory testing on admission showed mild metabolic acidosis and mild hyperammonemia. Urinary organic acid analysis in the acute phase showed elevated excretion of 2-methyl-3-hydroxybutyric acid, tiglylglycine, and ketones. However, 2-methylacetoacetate was not elevated. HSD10 disease was suspected based on urinary organic acid data. The patient had a novel hemizygous c.470C>T (p.A157V) mutation in the HSD17B10 gene. His mother was a heterozygous carrier of this mutation. The patient’s older brother also had the c.470C>T (p.A157V) mutation. Neurological development was normal at the time of evaluation. The pilot newborn screening results using tandem mass spectrometry of the proband were reevaluated retrospectively and showed a high C5:1 carnitine level of 0.070 nmol/mL (upper cutoff limit, 0.05 nmol/mL) and a normal C5-OH carnitine level of 0.290 nmol/mL (upper cutoff limit, 1.0 nmol/mL). His affected brother and another patient with the atypical form of HSD10 disease having p.A154T also showed elevated C5:1 but not C5-OH in serum acylcarnitine analysis. Thus, these data suggested that some patients with this disorder may be identified using newborn screening.

Appendices

Take-Home Message

Patients of HSD10 disease without neurological regression during childhood may not be as rare as was previously thought.

Conflict of Interest

Shohei Akagawa, Toshiyuki Fukao, Yuko Akagawa, Hideo Sasai, Urara Kohdera, Minoru Kino, Yosuke Shigematsu, Yuka Aoyama, and Kazunari Kaneko declare that they have no conflicts of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the family for inclusion in this report. The molecular study was approved by the Ethical Committee of the Graduate School of Medicine, Gifu University, Gifu, Japan, and carried out with written approval.

Compliance with Ethics guidelines

This article does not contain any studies with animal subjects performed by the any of the authors.

Author Contributions

SA is the attending doctor of the siblings. YA, UK, and MK followed and treated the patients with SA. YS chemically diagnosed these patients by GC-MS. TF, HS, and YA performed molecular analysis and contributed to molecular diagnosis. TF, YS, and KK helped SA to diagnose and treat the patient as advising doctors. SA and TF contributed to the conception and design of this report. YS and KK contributed to drafting of the article. SA, TF, YS, YA, and KK contributed to critical editing of the article. All authors approved the final version of the article.