Hsd10 Mitochondrial Disease

A number sign (#) is used with this entry because of evidence that HSD10 mitochondrial disease (HSD10MD) is caused by hemizygous or heterozygous mutation in the HSD17B10 gene (300256) on chromosome Xp11.

Description

HSD10 mitochondrial disease most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; review by Zschocke, 2012).

In a review of the disorder, Zschocke (2012) noted that although this disorder was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS below).

Clinical Features

Zschocke et al. (2000) reported a male patient who was born at term and recovered well from an episode of metabolic decompensation and lactic acidosis. Psychomotor development was only moderately delayed at age 1 year, but he subsequently showed a gradual loss of mental and motor skills, which progressed with profound developmental regression, choreoathetosis, near blindness, and epilepsy. Brain MRI showed a slight frontotemporal atrophy. Urinary organic acid analysis revealed marked excretion of tiglylglycine and 2-methyl-3-hydroxybutyrate. Enzyme studies showed a virtually complete absence of MHBD activity. Zschocke (2012) stated that dietary changes in the patient reported by Zschocke et al. (2000) did not prevent progression of the disorder, suggesting that reduction of isoleucine metabolites is of no benefit in HSD10MD.

Ensenauer et al. (2002) reported two 7-year-old patients (one male and one female) with the disorder. The male had progressive neurodegenerative symptoms, and the female had psychomotor retardation without loss of developmental milestones. A short-term biochemical response to an isoleucine-restricted diet was reported in both children.

Olpin et al. (2002) reported a 23-year-old man with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency with a very mild clinical course. He had apparently normal early development and remained relatively well until the age of 6 years, when he contracted measles. Following that illness, his motor skills and school progress deteriorated. At 15 years he had significant dysarthria and generalized rigidity with some dystonic and unusual posturing. He was then treated with a low protein high carbohydrate diet with a good response in terms of balance and gait. At 18 years he was treated with benzhexol, increased slowly from 2 mg to 6 mg daily, which resulted in improvement in tremor and dystonia. At 23 years he could dress himself and worked in sheltered employment but remained severely dysarthric.

Sass et al. (2004) described an affected male who, in contrast to the first published case (Zschocke et al., 2000), did not present with neonatal metabolic decompensation, but rather showed essentially normal development through most of his first year of life. Like patient 2 in the report of Ensenauer et al. (2002), he showed development of cerebral atrophy including symmetric alterations of the basal ganglia beginning after the age of 1 year.

Perez-Cerda et al. (2005) reported 3 patients with MHBD deficiency from 2 unrelated Spanish families. In the first family, a girl presented with psychomotor delay from the first months of life and later showed ataxic gait, speech delay, and sensorineural deafness. She also showed episodes of myoclonus during stress. Cultured fibroblasts showed intermediate MHBD activity at 3.8 nmol/min/mg protein (control value of 7.1). She was started on a low-protein, isoleucine-restricted diet and showed moderate psychomotor retardation at age 10 years. A younger affected brother died during the neonatal period from lactic acidosis. Both patients and their asymptomatic mother carried a mutation in the HSD17B10 gene (300256.0003). In the second family, a boy presented in the neonatal period with hypotonia, dehydration, and horizontal nystagmus. He later developed myoclonus and brain MRI showed frontotemporal atrophy. MHBD activity was severely decreased at 0.8 nmol/min/mg protein. Genetic analysis revealed a mutation in the HSD17B10 gene (300256.0001), which was also found in his mother who had borderline learning difficulties. Despite institution of an isoleucine-restricted diet, the patient died at age 18 months. All 3 patients had increased urinary 2-methyl-3-hydroxybutyryl-CoA. In a review of previously reported patients, Perez-Cerda et al. (2005) noted that the most common clinical symptom was speech delay. Affected males followed a severe neurodegenerative course with psychomotor regression, whereas females showed mild to moderate developmental delay.

Seaver et al. (2011) reported a 10-year-old boy of mixed ancestry, including East Asian descent, with HSD10MD. The patient had normal early development, but showed developmental regression around age 2 to 3 years. Gait became unsteady around age 3 to 4 years, and he developed a hyperkinetic involuntary movement disorder. Around this time, he also developed severe refractory seizures, which varied in type. He had poor overall growth, moderate cognitive impairment, and mild impairment in social interactions; he attended school in a self-contained special education setting. Brain imaging was normal. He had no episodes of metabolic decompensation or metabolic acidosis. Mitochondrial electron transport chain enzyme activities in fibroblasts were normal.

Falk et al. (2016) reported a 14-year-old Caucasian boy with onset of intractable epilepsy around 2.5 years of age, followed by developmental regression, loss of ability to walk or sit unassisted, choreoathetotic movements, progressive spastic tetraparesis, and static encephalopathy. Additional features included optic nerve atrophy with visual loss, nystagmus, lack of speech, gastrointestinal dysmotility necessitating tube feeding, urinary dysfunction, drooling, dysphagia, and chronic lactic acidemia, all suggestive of a multisystem mitochondrial disorder. Brain imaging showed diffuse cerebral atrophy. Muscle biopsy was suggestive of a mitochondrial myopathy with increased lipid content, abnormal mitochondrial histology, and mitochondrial proliferation. Mitochondrial respiratory chain enzyme activities were decreased compared to controls. Family history revealed 2 maternal half-uncles with suspected mitochondrial disease and seizures resulting in death in early childhood; no tissue or DNA was available from the uncles.

Clinical Variability

Reyniers et al. (1999) described a 'new' neurologic syndrome in 5 male patients from a 4-generation Luxembourg family. The features were mild mental retardation with choreoathetosis and abnormal behavior. Choreoathetosis, the most distinguishing feature in these 5 patients, was characterized by involuntary, irregular, purposeless, nonrhythmic, abrupt, rapid movements flowing from one part of the body to another (chorea) that blend with slow, writhing, continuous movements (athetosis). Behavioral abnormalities in these patients involved aggressiveness and agitation in the proband and hallucinations and automutilation in 3 of the proband's great-uncles, as well as speech impairment. In relation to the proband it was stated that 'except for arachnodactily (sic), he did not show any dysmorphic features.' In relation to 1 or more of the great-uncles, it was stated that 'dysmorphic features were restricted to arachnodactily (sic).' The pedigree pattern strongly suggested X-linked recessive inheritance.

Rauschenberger et al. (2010) reported a boy with HSD10MD who presented with pre- and postnatal failure to thrive, but normal cognitive and motor development. Neurologic examination in this boy and 2 affected relatives was normal up to age 8 years. Molecular studies identified a hemizygous Q165H mutation in the HSD17B10 gene that was located in the active center of the enzyme, and patient fibroblasts had no measurable HSD17B10 dehydrogenase activity and no binding to the NADH or NAD cofactor. The findings expanded the phenotype associated with HSD17B10 mutations and demonstrated a lack of correlation between disease severity and residual enzyme activity in these patients.

Mapping

Reyniers et al. (1999) mapped the mental retardation and choreoathetosis syndrome in the 4-generation family described by them to chromosome Xp11 by linkage analysis, confirming X-linked inheritance. The authors pointed out that the candidate region contains a number of genes possibly involved in neuronal signaling. In the same 4-generation Luxembourgian family reported by Reyniers et al. (1999), Lenski et al. (2007) refined the candidate region to a 13.4-Mb interval on Xp11.

Clinical Management

In a review of HSD10 mitochondrial disease, Zschocke (2012) noted that there is no effective therapy. An isoleucine-restricted diet may result in amelioration of abnormal urinary organic acids on laboratory studies, but does not prevent progression of the disease. As the disorder is related to mitochondrial dysfunction, Zschocke (2012) suggesting that avoidance of catabolic states and drugs known to interfere with mitochondrial energy metabolism should be avoided in affected individuals.

Pathogenesis

Rauschenberger et al. (2010) found that development and severity of symptoms in HSD10 disease are unrelated to residual enzymatic activity. They reported a male infant with a severe form of the disorder who had absent neurologic development and died of progressive hypertrophic cardiomyopathy at age 7 months. Genetic analysis identified a hemizygous mutation in the HSD17B10 gene (D86G; 300256.0006); patient fibroblasts showed about 30% residual enzymatic activity. Another boy with a hemizygous HSD17B10 variant (Q165H) had failure to thrive in infancy but had normal cognitive and motor development up to age 8 years, despite his fibroblasts having no detectable MHBD activity. The findings indicated that the clinical effects of this disorder cannot be attributed to the accumulation of toxic metabolites in the isoleucine pathway or other metabolic effects, suggesting that an isoleucine-restricted diet is unlikely to provide therapeutic benefit. Fibroblasts from the individual with the Q165H variant had mostly normal-appearing mitochondria, but 27% showed depletion of cristae. In contrast, fibroblasts from the patient with the D86G or R130C (300256.0001) mutations showed abnormal morphology in 65 to 85% of mitochondria. These findings indicated that HSD10 is required for normal mitochondrial integrity, and that this function is not correlated with residual enzyme activity. Conditional knockout of the Hsd17b10 gene in mouse noradrenergic neurons resulted in a significant number of abnormal mitochondria, and knockdown of the gene in Xenopus caused increased apoptosis in cells. Rauschenberger et al. (2010) concluded that HSD10 disease is not a classic organic aciduria, and that the clinical manifestations result from defects in mitochondrial function.

Deutschmann et al. (2014) provided further experimental evidence that the HSD17B10 gene is necessary for proper mitochondrial function via its role in the RNase P complex, which is essential for mitochondrial tRNA processing.

Molecular Genetics

In 3 male patients with 2-methyl-3-hydroxybutyryl-CoA disease, Ofman et al. (2003) identified hemizygosity for a mutation in the HSD17B10 gene (300256.0001). A female patient also carried the mutation in the heterozygous state. The patients had previously been reported by Zschocke et al. (2000), Ensenauer et al. (2002), and Poll-The et al. (2001).

In a male patient previously reported by Sass and Sperl (2001) with 2-methyl-3-hydroxybutyryl-CoA disease and psychomotor retardation, but no progressive loss of mental and motor skills, Ofman et al. (2003) identified hemizygosity for a mutation in the HSD17B10 gene (300256.0002).

Yang et al. (2009) identified different mutations in the HSD17B10 gene (300256.0001 and 300256.0005) in 2 unrelated male patients with HSD10 disease. After in vitro functional expression studies, Yang et al. (2009) postulated that the neurologic phenotype was due to an imbalance in neurosteroid metabolism, particularly the oxidation of allopregnanolone. The patients had previously been reported by Sutton et al. (2003) and Olpin et al. (2002), respectively.

In all patients and carrier females in the family described by Reyniers et al. (1999), Lenski et al. (2007) identified a splice site mutation in the HSD17B10 gene (574C-A; 300256.0004). Western blot analysis showed that the mutation reduced the amount of protein by 60 to 70% in the proband.

In a 10-year-old boy of mixed ancestry, including East Asian descent, with HSD10MD, Seaver et al. (2011) identified a hemizygous missense mutation in the HSD17B10 gene (V65A; 300256.0007). The patient's unaffected mother was heterozygous for the mutation. Functional studies of the variant were not performed, but patient cells showed decreased HSD17B10 activity and the patient had persistently increased levels of urinary 2-methyl-3-hydroxybutyric acid and tiglylglycine, which prompted sequencing of the HSD17B10 gene.

In a Caucasian boy with HSD10MD, Falk et al. (2016) identified a hemizygous missense mutation in the HSD17B10 gene (K212E; 300256.0008). No parental DNA or DNA from reportedly affected maternal uncles was available for study. In vitro functional expression assays showed that the mutation resulted in decreased dehydrogenase activity. However, more significantly, the mutation disrupted TRMT10C (615423)-associated methyltransferase activity and destabilized the RNase P holoenzyme, resulting in impaired mitochondrial tRNA processing and maturation and impaired mitochondrial protein synthesis. The findings suggested that the major pathogenic mechanism resulting from HSD17B10 mutations is the adverse effect on mitochondrial function.