A Novel Mutation in the HSD17B10 Gene of a 10-Year-Old Boy with Refractory Epilepsy, Choreoathetosis and Learning Disability

Abstract

Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal β-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.

Mitochondrial epilepsy in pediatric and adult patients

“…Mutations in components of mitochondrial pathways other than the respiratory chain are increasingly recognized and may also go along with epilepsy . Affected compounds in these patients include, for example, the hydroxysteroid (17beta) dehydrogenase 10 , the lipoic acid synthetase , or the aconitase, a Krebs cycle enzyme, the latter resulting in infancy‐onset hypotonia, athetosis, and ophthalmologic disease in addition to epilepsy . Epilepsy may be also a part of the phenotype in beta‐oxidation disorders, such as in short‐chain acyl‐CoA dehydrogenase deficiency, of which the most common presentation is coma due to hypoglycemia after fasting starting in early infancy .…”

Hydroxysteroid 17-Beta Dehydrogenase Type 10 Disease in Siblings

“…Whereas approximately 50% of these cases are associated with one common missense mutation, c.388C>T (p.R130C), other mutations have been reported as well. Less fulminant courses have been described, associated with the E249Q, L122V, Q165H, A145T, and V65A mutations (Olpin et al 2002;Poll-The et al 2004;Rauschenberger et al 2010;Fukao et al 2014;Seaver et al 2011). In particular, the V65A mutation was reported by Seaver in 2011 in a case of a 10-year-old male with refractory epilepsy, choreoathetosis, ataxia, visual loss, and developmental regression with onset at approximately 2-3 years of life (Seaver et al 2011).…”

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

“…7 DNA sequencing analyses to date have identified 10 missense mutations in HSD17B10. 7,14,15 , and a splice variant that reduces the protein expression level. 16,17 Among the different HSD17B10 missense mutations, the clinical manifestations are diverse, 7 including a neonatal-onset form (associated with mutations p.D86G, p.R226Q, and p.N247S), an infantile-onset form (associated with mutations p.L122V, p.R130C, and p. P210S), a milder atypical form (associated with mutation p.Q165H), and a later-onset form (associated with mutation p. E249Q).…”