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Prevalence is unknown. So far, fewer than 40 cases have been reported worldwide.

HSD10 disease is heterogeneous, including several clinical subtypes, and manifests by severe manifestations in males only; females are either asymptomatic or show non-progressive cognitive impairment ranging from learning difficulties to intellectual disability, as well as variable neurological abnormalities. HSD10 disease, infantile form is the classical presentation. Affected boys may show lethargy, poor feeding and evidence of mitochondrial dysfunction in the newborn period, with subsequent mild developmental delay and abnormal muscle tone. Hallmark of the disease is progressive neurodegeneration and cardiomyopathy, which usually manifests between ages 6 months and 2 years with loss of cognitive and motor skills, epilepsy, progressive visual impairment leading to blindness, and/or hearing loss. As neurodegeneration advances, patients develop progressive ataxia, choreoathetosis, and restlessness. The disease is generally fatal with death usually occurring between 2-4 years of age. Laboratory findings include lactic acidosis, hypoglycemia, hyperammonemia, and increased urinary excretion of specific organic acids. HSD10 disease, neonatal form is the most severe subtype. It is characterized by severe metabolic/lactic acidosis in the neonatal period, scarce neurological development, severe progressive cardiomyopathy and death within the first months of life. Other variants of HSD10 disease are less well defined and usually reflect attenuated forms. Affected individuals may have variable neurological and behavioral symptoms, intellectual disability which may be non-progressive, variable metabolic/non-neurological manifestations, or may be asymptomatic.

HSD10 disease is mostly due to missense mutations in the HSD17B10 gene (Xp11.22), coding for 3-hydroxyacyl-CoA dehydrogenase type 2. This mitochondrial protein has at least dual function: (a) it is one of three proteins that constitute mitochondrial ribonuclease (RNase) P which is responsible for the cleavage of the mtDNA polycistronic transcript between mRNA and tRNA sequences; (b) the enzyme's dehydrogenase function is required for the breakdown of 2-methyl-3-hydroxybutyrate in isoleucine metabolism (MHBD) and may be active on other metabolites such as neuroactive steroids. Null mutations in the HSD17B10 gene are incompatible with life. The clinical manifestations of HSD10 disease are thought to be due to defective RNase P leading to mitochondrial dysfunction, whereas some metabolic abnormalities including the typical urinary organic acids findings are caused by impaired dehydrogenase function.

Diagnosis is based on urinary organic acid analysis, as well as molecular studies. Elevated levels of isoleucine metabolites (in particular 3-hydroxy-2-methylbutyrate and tiglylglycine in conjunction with normal methylacetoacetate) are hallmark findings of the disease, although they reflect dehydrogenase and not RNase P dysfunction. Some individuals with HSD10 disease may show no biochemical abnormalities, whereas others with isolated dehydrogenase dysfunction may have little or no symptoms. Frequently there is biochemical or histological evidence of mitochondrial dysfunction such as rounded mitochondria with depleted cristae observed by microscopy. Diagnosis is confirmed by genetic analysis identifying a hypomorphic disease-causing mutation.

Biochemical abnormalities may resemble beta-ketothiolase deficiency. Clinical abnormalities are similar in other disorders affecting mtDNA transcript processing, in particular ELAC2-associated disease (combined oxidative phosphorylation defect type 17).

Prenatal diagnosis is possible by molecular analysis.

HSD10 disease follows an X-linked inheritance with variable manifestation in females. Genetic counseling should be proposed to at-risk families.

At present, there is no effective treatment for the disease. A low-protein, high-energy dietary regimen with carnitine supplementation reduces the accumulation of isoleucine metabolites in blood and urine, but does not improve psychomotor deterioration. Due to its ability to interfere with mitochondrial energy metabolism, valproic acid should be avoided.

The prognosis is poor, especially for the neonatal and infantile forms of the disease. The prognosis for the attenuated or asymptomatic variants of the disease is currently unknown.