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.

Thirty-seven 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 (06; 08; 13; 22). Complete absence of the HSD10 protein appears to be incompatible with life.

Different disease manifestation patterns have been summarized by Zschocke (27). 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 (28; 06; 21; 17; 19). A small number of patients with a more severe neonatal presentation and early death have been reported (08; 18). Other boys have an attenuated juvenile presentation with intellectual disability, seizures, and neurologic abnormalities from the age of 6 onwards (15). 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 (12). 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 (18; 13; 24). These manifestation patterns have been denoted atypical (27).

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 (24).

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 6 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 (26) and is associated with the classical infantile presentation. Another variant, p.L122V (c.364C> G), was identified in 5 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 1 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 2, 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 (28). 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 (12). Similarly, there is no confirmed evidence that reduced activity towards other metabolites, such as bile acids or neurosteroids (10; 23), 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 (18). Similarly, Oerum and colleagues showed complete loss of allopregnanolone oxidation caused by variant p.V176M, which is also associated with normal development (13). 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 (18) demonstrated that HSD10 is essential for structural and functional integrity of mitochondria independent of its dehydrogenase activity. Reduced activity of the mitochondrial respiratory chain complex I was demonstrated in muscle (06). 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 (09). Several studies confirmed that HSD17B10 variants associated with clinical disease interfere with ribonuclease P assembly and cause abnormal mtDNA transcript processing (05; 07). 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 (12). Nevertheless, one study showed evidence that this function may also be affected by the apparently benign variant p.V176M in an in vitro system (13). Further work is required to elucidate the exact molecular pathomechanism of HSD10 disease.

Epidemiology

This is an exceedingly rare X-linked disease, most likely because the majority of HSD17B10 mutations are incompatible with cell survival. The variant p.L122V (c.364C> G) was identified in 5 seemingly unrelated families, mostly from Quebec, Canada. It causes biochemical features of dehydrogenase deficiency but appears to be clinically harmless.

Prevention

The disease cannot be prevented. It may be recognized by prenatal diagnosis when the mutation is known in a family.

Differential diagnosis

Confusing conditions

The clinical presentation resembles a mitochondrial disorder, but biochemical studies, in particular urinary organic acid analyses, easily indicate the correct diagnosis. The pattern of urinary metabolites may resemble mitochondrial acetoacetyl-CoA thiolase deficiency because 2-methylacetoacetate, which is typical for the latter condition, is unstable and may be degraded. Marked differences in the clinical picture between the 2 conditions, particularly in affected boys, usually become obvious in the second year of life.

Diagnostic workup

	• 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.

The most important diagnostic investigation is the analysis of organic acids in a urine sample by gas chromatography-mass spectroscopy. Most patients excrete large amounts of 2-methyl-3-hydroxybutyric acid and tiglylglycine, precursor metabolites in the isoleucine catabolic pathway; 2-methylacetoacetate is not detectable in urine. 2-ethylhydracrylic acid has been reported as a sensitive biochemical marker in heterozygous females (08). Acylcarnitine profiling usually shows normal results, although C5:1 carnitine levels can be elevated (01). The diagnosis is confirmed by molecular analysis in genomic DNA; enzyme analyses are possible in leucocytes or fibroblasts. Prenatal diagnosis is carried out by mutation analysis. It is important to keep in mind that identification of a functional HSD17B10 variant and typical urinary organic acid abnormalities are not necessarily the explanation for clinical symptoms in an individual, particularly when the presentation is atypical.

Management

Management is symptomatic; no curative treatment is known. Dietary restriction of the precursor amino acid isoleucine is not of apparent benefit.

Special considerations

Pregnancy

There is little experience with regard to pregnancy outcome in heterozygous women who have biochemical abnormalities.

Anesthesia

The same precautions as those for individuals with primary mitochondrial disorders should be observed.