Mitochondrial Dna Depletion Syndrome 7 (Hepatocerebral Type)

A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-7 (MTDPS7) is caused by homozygous or compound heterozygous mutation in the C10ORF2 gene (TWNK; 606075), which encodes the twinkle and twinky proteins, on chromosome 10q24.

Biallelic mutation in the C10ORF2 gene can also cause Perrault syndrome-5 (PRLTS5; 616138), a less severe disorder that shares some features with MTDPS7.

Description

Mitochondrial DNA depletion syndrome-7 is an autosomal recessive severe neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy. Although originally classified as a form of spinocerebellar ataxia (see, e.g., SCA1, 164400) (Koskinen et al., 1994), it has been reclassified as a mitochondrial DNA depletion syndrome (Hakonen et al., 2008) based on the finding of mtDNA depletion in the brain and liver of affected individuals.

For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Clinical Features

Santavuori and Vihavainen (1981) observed 8 patients in 5 families (3 pairs of sibs; brother and sister pairs) with sudden onset of deafness at an age after they had learned to speak, a peculiar ophthalmoplegia with only convergence persisting, and ataxia and athetosis developing later. Intelligence was normal in all but 1, although the inability to speak, strabismus, and tendency to hold the mouth open continually gave an impression of stupidity. Kallio and Jauhiainen (1985) indicated that 11 patients had been observed. They commented particularly on the disorders related to the auditory and vestibular nerves and the communication handicap resulting therefrom. Consanguinity was reported in 1 family. Complete loss of vestibular caloric responses was found. Balance was markedly disturbed at the onset of symptoms, suggesting involvement of the vestibular organ. Ataxia and muscular hypotonia had their onset between 10 and 18 months of age. Athetotic dyskinesia of the face and upper limbs varied in severity. Progressive changes in sensory nerve conduction velocities indicated a polyneuropathy.

Koskinen et al. (1994) reported the clinical findings in 19 Finnish patients, including 6 pairs of sibs, with an early-onset spinocerebellar ataxia. Some of the same patients had been reported by Kallio and Jauhiainen (1985). Slowly progressive clinical symptoms manifested between 1 and 2 years of age in previously healthy infants. The first manifestation was clumsiness and loss of ability to walk. Ataxia, athetosis, and muscle hypotonia with loss of deep tendon reflexes were discovered on clinical examination. By school age, ophthalmoplegia and hearing loss were found, while sensory neuropathy developed by adolescence. An acute crisis with status epilepticus was a late manifestation. Koskinen et al. (1994) demonstrated marked decrease in sensory nerve conduction velocities, progressive loss of myelinated fibers in sural nerve specimens, and abnormal background activity in EEG with advancing age. The main finding in neuroradiologic studies was cerebellar atrophy. The occurrence in sibs with unaffected parents, the occurrence of parental consanguinity in 1 case, and the fact that 14 of the 19 patients, including all the sporadic cases, originated from North Carelia, a county in eastern Finland, suggested that this is yet another recessive Finnish disease.

Hakonen et al. (2007) reported 2 Finnish sibs with a severe form of IOSCA. Both had onset at age 6 months of abnormal eye movements and involuntary movements of the face and limbs. Other features included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, and refractory epilepsy. The older sib died at age 4.5 years of status epilepticus. One patient had mtDNA depletion in liver, and both had elevation of liver transaminases, suggestive of hepatic involvement. Hakonen et al. (2007) noted that the phenotype was reminiscent of Alpers syndrome (MTDPS4A; 203700), which is caused by mutation in the POLG1 gene (174763).

Lonnqvist et al. (2009) reported long-term follow-up of 21 patients with IOSCA who were homozygous for the Y508C (606075.0012) mutation. Age at the time of study ranged from 14 to 48 years. There were 2 patients with compound heterozygosity for C10ORF2 mutations (reported by Hakonen et al., 2007) who showed consistently earlier onset of all features and died at age 4.5 years. By adolescence, all patients had learning difficulties with mild to moderate mental retardation. Females developed hypergonadotrophic hypogonadism. All developed severe migraine-like headaches, with nausea, vomiting, and lethargy. Eighteen of 23 patients developed severe refractory epilepsy, which developed into an epileptic encephalopathy in 15 (65%). The seizures manifested as myoclonic jerks or focal clonic seizures, with later generalization and progression to epilepsia partialis continua or status epilepticus. Eight patients died of severe epilepsy. Psychiatric features, including mood swings, uncontrolled rage attacks, and psychosis, were also observed. Brain MRI and neuropathologic studies showed edematous areas and necrosis in various brain regions. Valproate treatment was initiated in 2 patients, but had to be discontinued because of a severe elevation of liver enzymes. Lonnqvist et al. (2009) concluded that the phenotype of IOSCA progresses after childhood to involve a severe epileptic encephalopathy.

Mapping

Nikali et al. (1995) found that the Finnish form of infantile-onset spinocerebellar ataxia does not share a gene locus with any of the previously identified hereditary ataxias. Based on the assumption of 1 founder mutation, the authors performed a primary screening of the genome using DNA samples from 4 affected individuals in 2 consanguineous pedigrees. The identification of a shared chromosomal region in these 4 patients ('homozygosity mapping') provided evidence that the IOSCA locus is on 10q23.3-q24.1. This localization was confirmed by conventional linkage analysis in the complete family material. Strong linkage disequilibrium was used to define accurately the critical chromosomal region. The locus was designated SCA8.

Nikali et al. (1997) used haplotype analysis combined with genealogic data to provide evidence that all the IOSCA cases in Finland originated from a single 30- to 40-generation-old founder mutation. By analyzing extended disease haplotypes observed presently, the IOSCA locus could be restricted to a region between 2 adjacent microsatellites, D10S192 and D10S1265, with no genetic intermarker distance. Nikali et al. (1997) constructed a detailed physical map of this 270-kb IOSCA region and localized it cytogenetically to 10q24. They also assigned 2 previously known genes, PAX2 (167409) and CYP17 (609300), more precisely into this region, but the sequence analysis of coding regions of these 2 genes revealed no mutations in an IOSCA patient. The order of the genes and markers was cen--D10S192--PAX2--D10S278--D10S1265--CYP17--tel.

By sequence and expression analysis in 2 patients and a control, Nikali et al. (2002) excluded C10ORF6 (610348), which is in close vicinity to D10S1265, as a candidate gene for IOSCA.

Molecular Genetics

In Finnish patients with infantile-onset spinocerebellar ataxia, Nikali et al. (2005) identified a founder mutation in the C10ORF2 gene: Y508C (606075.0012). One Finnish patient was compound heterozygous for the Y508C mutation inherited from his mother and a silent mutation in C10ORF2 (1472C-T) inherited from his father that affected allelic expression. The authors suggested that the severe neurologic phenotype observed in IOSCA indicated that the twinkle and twinky proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations.

In 2 Finnish sibs with a severe form of IOSCA with onset at age 6 months and rapid progression to epileptic encephalopathy, Hakonen et al. (2007) identified compound heterozygosity for 2 mutations in the C10ORF2 gene: Y508C and A318T (606075.0015). The phenotype was more severe than that observed in patients homozygous for the Y508C mutation.

Sarzi et al. (2007) identified a homozygous mutation in the C10ORF2 gene (606075.0011) in 3 affected members of a consanguineous Algerian family with mtDNA depletion syndrome and hepatic involvement.

Pathogenesis

Nikali et al. (2005) found no evidence of mitochondrial DNA instability in skeletal muscle derived from patients with IOSCA due to the Y508C mutation (606075.0012).

By quantitative PCR analysis of tissue samples from 4 patients with C10ORF2-associated IOSCA, Hakonen et al. (2008) observed mitochondrial DNA (mtDNA) depletion in the brain and the liver, but not in skeletal muscle. Postmortem examination showed mtDNA depletion at 5 to 20% of controls in the cerebrum and cerebellum, as determined by PCR and Southern blot analysis. In the liver, mtDNA was decreased to 10 to 30% of controls, as determined by PCR, and to 10 to 70% of controls as determined by Southern blot analysis. No mtDNA depletion was observed in skeletal muscle. Immunohistochemical analysis showed large neurons in the frontal cortex and cerebellum with deficiency of respiratory chain complexes I and IV, which was confirmed by Western blot and SDS-PAGE analysis. However, in vitro functional expression assays showed that Y508C-mutant C10ORF2 had increased helicase activity, but normal hexamerization and nucleoid structure. These results suggested that twinkle-Y508C dysfunction affects mtDNA maintenance in a highly context and cell-type specific manner, particularly affecting the central nervous systems. Hakonen et al. (2008) concluded that IOSCA can be considered a a member of the mitochondrial DNA depletion syndromes.

Population Genetics

Nikali et al. (2005) stated that IOSCA is a typical representative of the Finnish disease heritage, having been described in 21 Finnish patients in 15 nuclear families and not found elsewhere in the world. IOSCA is the second most common inherited ataxia in Finland, with a carrier frequency of more than 1 in 230 individuals.