HSD10 disease in a female: A case report and review of literature

Abstract

HSD10 disease is a rare X‐linked mitochondrial disorder caused by pathogenic variants in the HSD17B10 gene. The phenotype results from impaired 17β‐hydroxysteroid dehydrogenase 10 (17β‐HSD10) protein structure and function. HSD10 is a multifunctional protein involved in enzymatic degradation of isoleucine and branched‐chain fatty acids, the metabolism of sex hormones and neurosteroids, as well as in regulating mitochondrial RNA maturation. HSD10 disease is characterised by progressive neurologic impairment. Disease onset is varied and includes neonatal‐onset, infantile‐onset and late‐onset in males. Females can also be affected. Our index case is a 45‐month‐old female, who initially presented at 11 months of age with global developmental delay. She subsequently began to lose previously acquired cognitive and motor skills starting around 29 months of age. Brain MRI showed abnormalities in the basal ganglia indicative of possible mitochondrial disease. Urine organic acid analysis revealed elevations of 2‐methyl‐3‐hydroxybutyric acid and tiglyglycine. HSD17B10 gene sequencing revealed a likely pathogenic variant, NM_001037811.2:c.439C>T (p.Arg147Cys) inherited from her mother, expected to be causative of HSD10 disease. Her X‐chromosome inactivation study is consistent with a skewed X‐inactivation pattern. We report a female patient with HSD10 disease caused by a missense pathogenic variant, Arg147Cys in the HSD17B10 gene. The patient is the fifth severely affected female with this disease. This case adds to the small number of known affected families with this highly variable disease in the literature. These findings support the possibility of X‐inactivation patterns influencing the penetrance of HSD10 disease in females.

A novel c.59C>T variant of the HSD17B10 gene as a possible cause of HSD10 mitochondrial disease with hepatic dysfunction: a case report and review of the literature

“…is the most frequent variant [12] . At present, the reported mutation types in neonatal patients include c.740A > G (p.N247S), c.677G > A (p.R226Q) and c.257A > G (p.D86G).…”

“…Pathogenic variants of the HSD17B10 gene cause HSD10 MD, the clinical features of which are similar to those of severe mitochondrial diseases (progressive neurodegeneration, cardiomyopathy and metabolic disorders). Since it was rst reported in 2000 [2] , relatively few cases worldwide have been reported in the literature [6,[11][12][13] .…”

Novel Mutation in the <i>HSD17B10</i> Gene Accompanied by Dysmorphic Findings in Female Patients

“…Although multisystemic involvement has been reported, central nervous system and cardiac involvement are prominent [7]. HSD10 disease is characterized by metabolic decompensation episodes, lethargy, restlessness, global developmental delay, hypotonia, epilepsy, encephalopathy, progressive psychomotor retardation (frequently after infection or vaccination), microcephaly, movement disorder, gait abnormality, spasticity, visual and hearing impairment, cardiomyopathy (hypertrophic or dilate), speech difficulty, intellectual disability, learning difficulties, autistic features, and behavioral abnormalities [2][3][4][6][7][8][9][10].…”

“…Generally, learning difficulties, intellectual disability, and speech difficulties have been reported in symptomatic females. Only 5 female patients have been reported in the infantile and neonatal form as seen in males [1][2][3][4]. Although dysmorphic findings have been reported in mitochondrial diseases, dysmorphic findings are not prominent and highlighted features for HSD10 disease [5].…”

Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer’s Disease

“…The structure of the HSD17B10 gene was found to be highly conserved across a broad evolutionary distance [65], as its gene product 17β-HSD10 is vital to life [47,52]. Studies on the properties of 17β-HSD10 are critical to the search for potential treatments of HSD17B10 gene-related disorders, including infantile neurodegeneration or HSD10 deficiency due to a missense mutation [52,58,[66][67][68][69][70][71][72][73][74][75][76][77][78] and intellectual disabilities caused by a silent mutation [79,80] as well as a gene duplication [81]. Elevated levels of 17β-HSD10 were reportedly involved in the pathogenesis of Alzheimer's disease [11,[82][83][84][85][86][87].…”