The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation

Abstract

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (2M3HBD) deficiency (HSD10 disease) is a rare inborn error of metabolism, and <30 cases have been reported worldwide. This disorder is typically characterized by progressive neurodegenerative disease from 6 to 18 months of age. Here, we report the first patient with this disorder in Asia, with atypical clinical presentation. A 6-year-old boy, who had been well, presented with severe ketoacidosis following a 5-day history of gastroenteritis. Urinary organic acid analysis showed elevated excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. He was tentatively diagnosed with β-ketothiolase (T2) deficiency. However, repeated enzyme assays using lymphocytes showed normal T2 activity and no T2 mutation was found. Instead, a hemizygous c.460G>A (p.A154T) mutation was identified in the HSD17B10 gene. This mutation was not found in 258 alleles from Japanese subjects (controls). A normal level of the HSD17B10 protein was found by immunoblot analysis but no 2M3HBD enzyme activity was detected in enzyme assays using the patient's fibroblasts. These data confirmed that this patient was affected with HSD10 disease. He has had no neurological regression until now. His fibroblasts showed punctate and fragmented mitochondrial organization by MitoTracker staining and had relatively low respiratory chain complex IV activity to those of other complexes.

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

“…13 Yet, their overlapping biochemical signature has led to clinical misdiagnosis. 14 HSD10 disease has been reported only in a small number of families world-wide, mostly occurring in males, consistent with HSD17B10 being located on the X-chromosome. 7 DNA sequencing analyses to date have identified 10 missense mutations in HSD17B10.…”

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

“…Moreover, his male cousin, who had the same mutation, achieved normal neurodevelopment until his current age of 8 years (Rauschenberger et al 2010). We recently reported another patient with the c.460G>A (p.A154T) mutation who showed no neurological regression until his current age of 6.5 years (Fukao et al 2014). Thus, in this report, we described an additional two patients with c.470C>T (p.A157V) mutations, leading to the atypical presentation of HSD10 disease.…”

“…Additionally, immunoblot analysis showed that fibroblasts from patients with p. A157V or p.A154T mutations had similar levels of HSD17B10 protein as control fibroblasts ( Fig. 1) (Fukao et al 2014). These mutations may affect catalytic activity but not stability.…”

“…These mutations may affect catalytic activity but not stability. Our proband and the patient with the p.A154T mutation developed ketotic hypoglycemic episodes several times, leading to further urinary organic acid analyses and thereby facilitating the final diagnosis (Fukao et al 2014). However, it is not clear whether patients with HSD10 disease may tend to develop ketotic hypoglycemia owing to the lack of sufficient cases; further studies are needed to determine the associations between ketotic hypoglycemia and HSD10 disease.…”

“…Classical infantile form of HSD10 disease is characterized by a progressive neurodegenerative course with retinopathy and cardiomyopathy, leading to death at the age of 2-4 years or later (Zschocke 2012); however, this disorder has wide clinical heterogeneity. Only three patients in two families have been reported to have the atypical presentation of the disease, without neurological regression (Rauschenberger et al 2010;Fukao et al 2014). Moreover, one patient without neurological regression during childhood was reported to develop Parkinsonism in adulthood, as an abstract form (Lorea et al 2015).…”