Human 17β-hydroxysteroid dehydrogenase type 10 (HSD10) is a rare X-linked mitochondrial disorder caused by mutations in the HSD17B10 gene. It is typically associated with neurodegeneration and cardiomyopathy in severe cases. The neonatal form often has a poor prognosis; however, its clinical spectrum remains unclear. Herein, we present a neonatal-onset case of HSD10 disease with a previously unreported HSD17B10 variant presenting with early-onset cardiomyopathy triggered by a viral infection. A male infant presented with lactic acidosis and hypoglycemia on the first day of life. Initial treatment improved metabolic status. He was diagnosed with HSD10 disease using a targeted panel of nuclear and mitochondrial genes, which identified a novel hemizygous variant, NM_004493.3: c.34G>A p.(Val12Met). Cardiac function was normal at five months, but neurodevelopmental regression occurred at six months following vaccination. At seven months, viral myocarditis was diagnosed following rhinovirus/enterovirus infection. Echocardiography revealed a reduced left ventricular ejection fraction and ventricular dilation. Despite supportive therapy, cardiac function deteriorated, leading to death at nine months. A patient with a novel HSD17B10 variant showed early-onset cardiomyopathy in a neonatal case of HSD10 disease and rapid and fatal deterioration of cardiac function. This report highlights the importance of clarifying genotype-phenotype correlations to guide the diagnosis and management of rare mitochondrial diseases.

Hydroxysteroid 17-beta dehydrogenase type 10 (HSD10) protein is a mitochondrial enzyme. Multisystemic involvement occurs in HSD10 deficiency as in other mitochondrial diseases. HSD10 deficiency (disease) is rare. Less than 40 index cases have been reported so far. A female patient is even rarer because of X-linked transmission. Five index female cases have been reported. We report a three-year-old female patient who was investigated due to microcephaly and global developmental delay. She had significant dysmorphic findings. The tiglylglycine peak was detected in urinary organic acid analysis. Other metabolic investigations and laboratory tests were unremarkable. Mild cerebral atrophy, mild ventricular dilation, thin corpus callosum, and an increase in T2 signal in the globus pallidus were revealed at brain magnetic resonance imaging. Heterozygous novel mutation in the HSD17B10 gene was found by whole-exome sequencing (WES) analysis. We started isoleucine-restricted diet and a "cocktail" of the mitochondrial vitamin. We will see HSD10 disease patients more frequently with the increasing use of WES and genetic panels. Thus, different findings and phenotypes of the HSD10 disease will be revealed.

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17β-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here.

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.