HSD10 disease

Johannes Zschocke MD PhD

Neurogenetic Disorders

Updated 09.24.2023
Released 04.12.2021
Expires For CME 09.24.2026

HSD10 disease

Author: Johannes Zschocke MD PhD

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Editor: Deepa S Rajan MD

HSD10 disease

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Introduction

Overview

HSD10 disease is a rare X-linked disease with a wide spectrum of clinical and biochemical presentations in males. It is caused by pathogenic variants in the HSD17B10 gene. Dr. Johannes Zschocke, Professor of Human Genetics at the Medical University of Innsbruck, Austria, who first recognized the condition, explains that HSD17B10 encodes a moonlighting protein with at least two distinct functions that may be differentially affected with divergent clinical and biochemical effects. This is essential to understand for correct interpretation of clinical, biochemical, and molecular data.

Key points

	• The X-chromosomal HSD17B10 gene encodes a moonlighting protein with at least two distinct functions, disruptions of which have diverse effects.
	• The classical presentation of HSD10 disease is a progressive mitochondrial multisystem disease in boys thought to be due to deficient mtDNA transcript processing.
	• Deficiency of the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase function of the protein causes typical biochemical abnormalities but may be asymptomatic.
	• There is no effective treatment for HSD10 disease.
	• Heterozygous females with pathogenic HSD17B10 variants are usually, but not always, asymptomatic.

Historical note and terminology

HSD10 disease was first described in 2000 as an atypical organic aciduria denoted 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (22). It is caused by mutations in HSD17B10 (denoted HADH2 at the time) located on chromosome Xp11.22 (13). The protein encoded by this gene is officially named 3-hydroxyacyl-CoA dehydrogenase type-2 but has been described with a range of other names, including 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD), 17-beta-hydroxysteroid dehydrogenase type 10 (HSD10), mitochondrial ribonuclease P protein 2 (MRPP2), and others (19). It is a moonlighting protein with two different and unrelated functions. In the mitochondrial matrix, it serves as a NAD-dependent dehydrogenase with primary relevance in isoleucine breakdown (MHBD function), and the disturbance of this function led to the identification of HSD10 disease (22). Clinically more relevant is the function as a component of the mitochondrial ribonuclease P complex at the mitochondrial membrane. Ribonuclease P consists of a HSD10 tetramer, the methyltransferase protein TRMT10C, and the nuclease protein PRORP (03) and mediates the first step in the processing of the polycistronic mtDNA transcripts, ie, the modification and 3’ cleavage of tRNA sequences (10). Various additional enzyme activities in bile acid and neurosteroid hormone metabolism have been identified in vitro (15; 17), but there is now evidence that they are clinically important. Wohlfarter and colleagues argued that evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro: the combination of an essential structural with a nonessential enzymatic function in the same protein may direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket (19). Thus, activities measured with purified enzyme do not necessarily reflect physiological relevance. HSD17B10 expression appears to be altered in some cancers, and overexpression or knock down was found to be associated with increased or reduced mtDNA levels, respectively (02). This may indicate a role of HSD10 in mtDNA maintenance, but the true role of HSD10 in cancer development remains to be characterized (17).

Clinical manifestations

Presentation and course

	• Only males are affected in most families, although females occasionally have variable cognitive impairment.
	• The classical infantile manifestation resembles a mitochondrial multisystem disorder with a progressive neurodegenerative course, retinopathy, and often fatal cardiomyopathy.
	• There are also neonatal and juvenile manifestations.
	• Development of symptoms is independent from the isoleucine metabolic function of the protein.

Approximately 40 families with functional HSD17B10 variants of diverse clinical relevance have been reported. In the majority of families, only male individuals are affected; some heterozygous females may show symptoms ranging from mild learning difficulties, nonprogressive intellectual disability, and possible hearing impairment to occasionally more severe infantile neurologic manifestations (12; 16). Complete absence of the HSD10 protein appears to be incompatible with life.

Different disease manifestation patterns have been summarized by Zschocke (21). The classical infantile presentation resembles a mitochondrial multisystem disorder with a progressive neurodegenerative course. Affected boys often show mild, nonspecific developmental delay in the first year of life, and lactic acidosis is frequently found. Between the ages of 6 and 18 months, patients typically start to lose acquired psychomotor skills and develop progressive neurologic anomalies, including retinopathy-associated loss of vision, epilepsy, dystonia, or spasticity. Severe cardiomyopathy is common and is often the cause of death. Brain MRI may reveal progressive, variable changes, including cerebral atrophy and infarctions. Patients often die during infancy but may reach school age or even adulthood. A small number of patients with a more severe neonatal presentation and early death have been reported (14). Other boys have an attenuated juvenile presentation with intellectual disability, seizures, and neurologic abnormalities from the age of 6 onwards. It is important to note that the development of all these symptoms appears to be independent from the dehydrogenase function of the protein. Several male individuals in a family with a HSD178B10 variable splicing variant had nonprogressive intellectual disability and neurologic features without evidence of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase dysfunction (11). In contrast, several male individuals were reported with absence of dehydrogenase activity and typical biochemical features of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, and they had no neurologic symptoms up to adult age (14; 12; 18). These manifestation patterns have been denoted atypical (21).

The available data indicate that the identification of putative functional variants in HSD17B10—even when accompanied by typical biochemical features of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency—do not necessarily explain clinical symptoms in an individual. Indeed, Waters and colleagues reported that clinical presentation in several male patients hemizygous for the functional HSD17B10 variant p.L122V was due to other genetically defined conditions, in line with the notion that this variant may have little or no clinical relevance (18).

Prognosis and complications

The prognosis in boys with classical HSD10 disease is poor, although some have survived into adulthood. No effective treatment is known. Prognosis in affected females is usually good but may be variable depending on the X-inactivation pattern; the outcome cannot be predicted in heterozygous females diagnosed before birth.

Clinical vignette

The index patient reported in 2000 was the first child of an unrelated German couple and was born at term. On the second day of life he developed tachydyspnea and metabolic acidosis with severe hypoglycemia (0.17 mmol/L), elevated lactate (11.6 mmol/L), mild hyperammonemia (210 µmol/L), and ketonuria. Seizure-like movements were observed but stopped without treatment. The child recovered with intravenous glucose infusion; no diagnosis was made at that stage. Subsequent development showed mild psychomotor delay. The boy achieved head control at the age of 4 months and sat with support at 8 months. At the age of 13 months, he moved by rolling from side to side and was able to sit by himself and stand when held by both hands. Expressive and receptive language as well as cognitive development was delayed, though emotional reactions were appropriate for age. After 14 months of age, coinciding with a vaccination, he started to show progressive loss of motor skills. He lost the ability to stand or sit and developed marked restlessness and choreoathetoid movements. Visual contact was lost, and ophthalmologic investigations indicated non-pigmentary retinal degeneration verging on blindness and normal nerve conduction latency. Acoustic evoked potentials were normal. During the next weeks the child developed seizures in the form of repeated head dropping and a modified hypsarrhythmia-pattern on EEG. Treatment with vigabatrin reduced the frequency of seizures but the boy did not become seizure-free. A brain MRI revealed slight frontotemporal atrophy without significant changes in the basal ganglia or white matter. At 2 years of age, the boy had severe intellectual impairment, choreoathetoid movements, absence of directed hand movements, marked hypotonia, and minimal reaction to external stimuli. The subsequent course was characterized by severe epilepsy that was resistant to antiepileptic treatment. The boy died at 3.5 years of age in status epilepticus.

The diagnosis in this child was based on urinary organic acid analysis, which showed high concentrations of 2-methyl-3-hydroxybutyric acid and tiglylglycine in the absence of 2-methylacetoacetate and was confirmed by enzyme studies.

Biological basis

	• Nineteen putative disease-causing variants in HSD17B10 have been reported to date; complete loss of function is not viable.
	• Deficiency of the dehydrogenase function of HSD10 on its own does not usually appear to cause clinical symptoms.
	• Clinical symptoms appear to be due to impaired 5’ cleavage of tRNA sequences in the polycistronic mtDNA transcript.

Etiology and pathogenesis

HSD10 disease is an X-linked disorder caused by mutations in the HSD17B10 gene. This gene stretches over 3.1 kb on chromosome Xp11.2 and contains six exons. Nineteen putative disease-causing variants have been reported. Different variants have different effects on stability as well as structural and functional protein characteristics. No null variants that cause complete loss of the protein have been observed. There is one common missense variant, p.Arg130Cys (c.419C> T) in exon 4 of the HSD17B10 gene, which is found in approximately one third of the reported families. This recurrent variant affects a methylated CpG site (20) and is associated with the classical infantile presentation. Another variant, p.L122V (c.364C> G), was identified in five seemingly unrelated families, mostly from Quebec, Canada; the variant appeared to be identical by descent. Individuals hemizygous for this variant showed biochemical alterations specific for 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency but had atypical clinical features, which in some cases were subsequently shown to be due to other monogenic conditions, or were asymptomatic. This variant is also listed in the Genome Aggregation Database in one male individual aged 75 to 80 years. It is, therefore, doubtful that p.L122V causes clinical disease in the majority of individuals. Other variants were reported in single, or at most two, families. Clinical manifestations in males with the same pathogenic variant are generally similar, indicating relatively stable genotype-phenotype correlations.

The pathogenesis of HSD10 disease appears to be due to dysfunction of mitochondrial transcript processing and possibly mtDNA maintenance. The condition was originally reported as an atypical organic aciduria with pathogenesis linked to the disturbance of isoleucine metabolism (22). However, the deficiency of the last reaction of isoleucine breakdown, 2-methylacetoacetyl-CoA thiolase, causes similar metabolic anomalies but has a completely different clinical presentation. There is no correlation between the degrees of dehydrogenase dysfunction. Some boys with substantial residual enzyme activity present as neonates whereas several males with complete loss of dehydrogenase function are asymptomatic. The pathogenic variant c.574C>A (p.R192R) does not alter the protein structure but causes reduced splicing efficiency and a reduced amount of the normal protein. Males with this variant are symptomatic, although there is no substantial reduction of the dehydrogenase function (11). Similarly, there is no confirmed evidence that reduced activity towards other metabolites, such as bile acids or neurosteroids (09; 17), is the cause of clinical features in HSD10 disease. Variant p.Q165H, which is located at the active center of the protein and destroys cofactor binding required for all known substrates, is associated with normal neurologic development (14). Similarly, Oerum and colleagues showed complete loss of allopregnanolone oxidation caused by variant p.V176M, which is also associated with normal development (12). Thus, the pathogenesis of HSD10 disease appears to be unrelated to its enzymatic dehydrogenase function.

The clinical features of HSD10 disease resemble primary disorders of energy metabolism. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10-/- knockout mice (14) demonstrated that HSD10 is essential for structural and functional integrity of mitochondria independent of its dehydrogenase activity. Multiple oxidative phosphorylation deficiency (complexes 1, 3, 4, and 5) was demonstrated in heart and liver tissue (04). In line with these observations, the pathogenesis of HSD10 disease is thought to be due to impaired ribonuclease P function, causing mitochondrial energy failure predominantly affecting brain, heart, retina, and other organ systems. Loss-of-function variants in the ELAC2 gene, which encodes ribonuclease Z, the protein that mediates 3’ cleavage of tRNA sequences in the polycistronic mtDNA transcripts, causes a very similar clinical presentation (08). Several studies confirmed that HSD17B10 variants associated with clinical disease interfere with ribonuclease P assembly and cause abnormal mtDNA transcript processing (05; 06). Reduced HSD10 (MRPP2) concentrations in patient fibroblast and HSD10-deficient mice also cause a reduction of MRPP1 protein, indicating that alterations of HSD10 (MRPP1) concentrations may regulate ribonuclease P function (05). This phenomenon could also explain why relatively minor alterations of the structurally normal protein due to the splicing variant c.574C>A still cause disease (11). Nevertheless, one study showed evidence that this function may also be affected by the apparently benign variant p.V176M in an in vitro system (12). Further work is required to elucidate the exact molecular pathomechanism of HSD10 disease.

References

01: Akagawa S, Fukao T, Akagawa Y, et al. Japanese male siblings with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) without neurological regression. JIMD Rep 2017;32:81-5. PMID 27306202
02: Amberger A, Deutschmann AJ, Traunfellner P, et al. 17β-Hydroxysteroid dehydrogenase type 10 predicts survival of patients with colorectal cancer and affects mitochondrial DNA content. Cancer Lett 2016;374(1):149-55. PMID 26884257
03: Bhatta A, Dienemann C, Cramer P, Hillen HS. Structural basis of RNA processing by human mitochondrial RNase P. Nat Struct Mol Biol 2021;28(9):713-23. PMID 34489609
04: Chatfield KC, Coughlin CR 2nd, Friederich MW, et al. Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing. Mitochondrion 2015;21:1-10.** PMID 25575635
05: Deutschmann AJ, Amberger A, Zavadil C, et al. Mutation or knock-down of 17β-hydroxsteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts. Hum Mol Genet 2014;23(13):3618-28.** PMID 24549042
06: Falk MJ, Gai X, Shigematsu M, et al. A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression. RNA Biol 2016;13(5):477-85. PMID 26950678
07: Garcia-Villoria J, Navarro-Sastre A, Fons C, et al. Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis. Clin Biochem 2009;42:27-33. PMID 18996107
08: Haack TB, Kopajtich R, Freisinger P, et al. ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am J Hum Genet 2013;93(2):211-23. PMID 23849775
09: He XY, Dobkin C, Yang SY. 17β-Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system. Mol Cell Endocrinol 2019;489:92-7. PMID 30321584
10: Holzmann J, Frank P, Löffler E, Bennett KL, Gerner C, Rossmanith W. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 2008;135(3):462-74.** PMID 18984158
11: Lenski C, Kooy RF, Reyniers E, et al. The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior. Am J Hum Genet 2007;80(2):372-7. PMID 17236142
12: Oerum S, Roovers M, Leichsenring M, et al. Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein. Biochim Biophys Acta Mol Basis Dis 2017;1863(12):3294-302. PMID 28888424
13: Ofman R, Ruiter JP, Feenstra M, et al. 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. Am J Hum Genet 2003;72(5):1300-7. PMID 12696021
14: Rauschenberger K, Schöler K, Sass JO, et al. A non-enzymatic function of 17b-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol Med 2010;2(2):51-62. PMID 20077426
15: Shafqat N, Marschall HU, Filling C, et al. Expanded substrate screenings of human and Drosophila type 10 17beta-hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile acid and steroid hormone metabolism: characterization of multifunctional 3alpha/7alpha/7beta/17beta/20beta/21-HSD. Biochem J 2003;376(Pt 1):49-60. PMID 12917011
16: Upadia J, Walano N, Noh GS, et al. HSD10 disease in a female: a case report and review of literature. JIMD Rep 2021;62(1):35-43. PMID 34765396
17: Vinklarova L, Schmidt M, Benek O, Kuca K, Gunn-Moore F, Musilek K. Friend or enemy? Review of 17β-HSD10 and its role in human health or disease. J Neurochem 2020;155(3):231-49. PMID 32306391
18: Waters PJ, Lace B, Buhas D, et al. HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French-Canadian patients from Quebec. Mol Genet Genomic Med 2019;7(12):e1000. PMID 31654490
19: Wohlfarter Y, Eidelpes R, Yu RD, et al. Lost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism. Cell Mol Life Sci 2022;79(11):562. PMID 36271951
20: Yang SY, Dobkin C, He XY, Philipp M, Brown WT. A 5-methylcytosine hotspot responsible for the prevalent HSD17B10 mutation. Gene 2013;515(2):380-4. PMID 23266819
21: Zschocke J. HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis 2012;35(1):81-9.** PMID 22127393
22: Zschocke J, Ruiter JP, Brand J, et al. Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res 2000;48(6):852-5. PMID 11102558

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Johannes Zschocke MD PhD

Dr. Zschocke of the Medical University of Innsbruck has no relevant financial relationships to disclose.
See Profile

Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
See Profile

Former Authors

Jennifer Friedman MD
Johannes Zschocke MD PhD and Stefan Kolker MD

Patient Profile

Age range of presentation: Neonatal presentation: 0 to 1 month

Infantile presentation: 01 to 23 months

Late infantile presentation: 2 to 5 years

Juvenile presentation: 6 to 10 years
Sex preponderance: male>female, >10:1
Heredity: X-chromosomal inheritance; females are normally unaffected or show milder symptoms
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Disturbances of branched-chain amino-acid metabolism: 270.3
ICD-10: Other disorders of amino-acid metabolism: E71.1
OMIM: HSD10 mitochondrial disease: #300438

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HSD10 disease

Associated Disorders

intellectual and developmental disability
epilepsy
blindness
deafness
cardiomyopathy

Differential Diagnosis

mitochondrial acetoacetyl-CoA thiolase deficiency
primary mitochondrial disorders

Also Relevant

Epilepsy
Intellectual disability
Isolated dystonia
Spasticity

Clinical Categories

Neurogenetic Disorders

HSD10 disease

HSD10 disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

	• The main functional diagnostic test is urinary organic acid analysis, but specific abnormalities cannot be regarded as diagnostic in patients with atypical clinical presentations.
	• Variants causing HSD10 disease are recognized by massive parallel sequencing, but reliable interpretation may be difficult.

HSD10 disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

This is an article preview.
Start a Free Account
to access the full version.