Adult case of 17β-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency due to the p. Arg130Cys mutation of the HSD17B10 gene: case report

Introduction

HSD10 mitochondrial disease (HSD10MD) is caused by pathogenic mutations in the HSD17B10 gene, an X-linked gene that encodes the mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10). This enzyme plays a critical role in brain neural cell development, neuroactive steroid metabolism, and isoleucine degradation. The disease is characterized by a multisystemic presentation, including progressive neurodegenerative symptoms, such as psychomotor regression, intractable seizures, and choreoathetosis, as well as retinopathy leading to visual impairment and cardiomyopathy. While the disease typically manifests in infancy or early childhood, with severe forms often resulting in death at a young age, milder forms can also present in adulthood, as seen in rare cases.

Mild or attenuated phenotypes of HSD10MD have previously been reported in association with specific HSD17B10 variants, such as p.Leu122Val, which appears to be linked to a nonprogressive clinical course (1).

The pathogenic mutations in HSD17B10 lead to the loss of enzyme function, which disrupts mitochondrial function and impairs cellular processes such as tRNA maturation and mitochondrial protein synthesis. This mitochondrial dysfunction underlies the clinical manifestations of the disease. Previous reports have described severe infantile forms of HSD10MD, but adult cases with milder presentations are extremely rare. A genotype-phenotype correlation has been established, with females generally exhibiting milder forms, such as psychomotor delay and moderate intellectual disability (2), and males showing more severe phenotypes, especially when mutations are inherited in a hemizygous state. The c.388C>T mutation in HSD17B10 has been identified in several cases, typically presenting with early-onset neurodegeneration and early death. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-280/rc).

Case presentation

De-identified patient-specific information

• A 49-year-old male of a Caucasian origin;
• Born to non-consanguineous parents;
• No similar neurological or cardiac conditions were reported in first-degree relatives, based on available clinical history.

Primary concerns and symptoms of the patient

• Hypertrophic cardiomyopathy (detected during cardiology consultation for repeated falls);
• Intellectual disability, with a delay in language acquisition and no reading or writing skills;
• Psychomotor delay;
• Stereotypies (stereotypical movements and echolalic communication);
• First epileptic seizure at age 14 years, followed by a 36-hour coma;
• Repeated falls (since 2014), often resulting in facial injuries, but without loss of consciousness or abnormal movements;
• Orthostatic hypotension;
• Behavioral disturbances, especially in times of frustration, though can establish social contact.

Psycho-social history including relevant genetic information

• Psycho-social history: despite intellectual disability, can establish social contact; communicates in a stereotypical and echolalic manner.
• Genetic information:
  • Normal karyotype;
  • Normal comparative genomic hybridization (CGH)-array, reasonably excluding large copy number variations of the X chromosome;
  • Negative fragile X test;
  • Variant in the DMD gene (c.8509G>A, p. Asp2837Asn) (no conclusive findings);
  • Pathogenic missense mutation in the HSD17B10 gene (c.388C>T, p. Arg130Cys) with a variant allele frequency of 55%, suggesting possible somatic mosaicism.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

HSD10MD is a rare neurodegenerative disorder caused by mutations in the HSD17B10 gene, leading to dysfunction of mitochondrial processes. The c.388C>T, p. Arg130Cys mutation in HSD17B10 has been reported in several cases, with most presenting in infancy or early childhood with severe neurodegenerative symptoms, including progressive seizures, choreoathetosis, and early death (3-5). However, our patient presents with a more moderate phenotype, with hypertrophic cardiomyopathy as the leading symptom. The observed somatic mosaicism, indicated by the variant allele frequency of 55%, may explain the milder clinical presentation in this adult patient.

The clinical features of our patient—intellectual disability, psychomotor delay, stereotypies, and epilepsy—are consistent with HSD10MD, but the progression is slower, and the patient did not exhibit the early-onset neurodegenerative features typical of the disease. The presence of cardiomyopathy in our patient suggests that the cardiac manifestations of the disease may be more prominent in some cases (6), potentially leading to earlier diagnosis. The lack of significant neurological regression in adulthood is noteworthy, as most HSD10MD patients exhibit rapid decline in early childhood. This case emphasizes the importance of considering HSD10MD in the differential diagnosis of patients with unexplained cardiomyopathy and neurodevelopmental delay, especially when traditional genetic testing yields no results.

This case also highlights the role of somatic mosaicism in influencing the severity of HSD10MD. Somatic mosaicism was suspected based on the intermediate variant allele frequency (~55%) observed in peripheral blood DNA; however, additional tissue analyses could not be performed due to the patient’s clinical condition and subsequent death.

While somatic mosaicism has been suggested in some reports, it remains an area of ongoing investigation. Further studies are needed to confirm the contribution of mosaicism to the clinical variability observed in HSD10MD.

Family-based segregation analysis could not be performed because no biological samples from relatives were available.

Conclusions

This case highlights, to our knowledge, the first adult presentation associated with the classically severe p.Arg130Cys mutation in the HSD17B10 gene, likely modulated by somatic mosaicism. The milder phenotype, dominated by hypertrophic cardiomyopathy and neurodevelopmental delays, emphasizes the clinical variability of HSD10MD and underscores the importance of considering this diagnosis in adults with unexplained cardiomyopathy and intellectual disability. This report expands the phenotypic spectrum of HSD10MD and suggests a role for somatic mosaicism in modulating disease severity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-280/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-280/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-280/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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