Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant 3

A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-3 (PEOA3) is caused by heterozygous mutation in the C10ORF2 gene (TWNK; 606075) on chromosome 10q24.

Description

Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

PEO caused by mutations in the POLG gene (174763) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).

Clinical Features

Suomalainen et al. (1992) described a Finnish family with PEO in association with deletions of mitochondrial DNA of different sizes. There were 9 affected individuals spanning 3 generations, with one instance of male-to-male transmission. The proband had a normal childhood. From age 19 years, she had episodes of severe psychomotor retardation and depressive mood, with apathy, mutism, fatigue, insomnia, and loss of initiative. The depression was often accompanied by long periods of amenorrhea. Physical examination at age 52 years showed external ophthalmoplegia, ptosis, generalized muscle weakness, and generalized decreased in muscle bulk. She had increased serum creatine kinase and increased serum lactate. Skeletal muscle biopsy showed a mitochondrial myopathy with ragged-red fibers and numerous mitochondrial DNA deletions. No mtDNA deletions were detected in leukocytes. She died at age 60 from a ventricular fibrillation. One affected brother had cardiac arrhythmias, and 1 affected sister had respiratory insufficiency requiring mechanical ventilation. Postmortem examination of the proband showed mtDNA deletions in brain tissue, heart muscle, liver, and kidney. Suomalainen et al. (1997) provided further clinical information on 7 affected members of this family. Age at onset ranged from the early twenties to 50 years. The most common features were periodic diplopia, ptosis, muscle weakness, and muscle cramps. Three patients had increased serum lactate, and 5 had increased serum creatine kinase. All 7 symptomatic patients and 4 asymptomatic family members had abnormal muscle fibers on skeletal muscle biopsy, including ragged-red fibers, cytochrome C oxidase (COX)-negative fibers, abnormal mitochondria, and mtDNA deletions. There was a high frequency of avoidant personality traits and depression, but these symptoms did not always cosegregate with the mutant mtDNA.

Li et al. (1999) reported a Pakistani family with adPEO spanning 4 generations. One family member reported onset at age 17 years of ptosis and impaired extraocular movements. He also had limb weakness. Muscle biopsy was consistent with a mitochondrial myopathy. Other affected family members had a similar disease course, with onset around 20 years of age, and a relatively mild neuromuscular phenotype.

Hudson et al. (2005) identified a heterozygous mutation in the C10ORF2 gene (K319E; 606075.0010) in 2 sibs with PEO. The mutation was not identified in the parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germline mosaicism. The 45-year-old proband presented at age 40 years with gait disturbances and ptosis. Neurologic examination showed revealed external ophthalmoplegia, moderate proximal weakness of the legs, severe sensory ataxia, and moderate dementia. Cranial MRI showed mild cortical atrophy. Sural nerve potentials were absent, and muscle biopsy showed a mild myopathic pattern with 4% COX-negative fibers and 4% ragged-red fibers. The sister had a long history of ptosis and developed a gait disturbance at age 36. Neurologic examination at age 39 showed bilateral ptosis and ophthalmoplegia, proximal leg weakness, dysarthria, ataxia, and signs of a sensory neuropathy. Cranial MRI showed supratentorial brain atrophy. She subsequently developed dementia, diabetes, and seizures. At age 41 she developed status epilepticus and died. Neuropathologic examination showed generalized cerebral gliosis and loss of neurons. Hudson et al. (2005) emphasized that the findings broadened the phenotype associated with C10ORF2 mutations, and they noted probable autosomal dominant inheritance.

Baloh et al. (2007) reported a 4-generation family in which 5 members had genetically confirmed PEOA3 and 3 deceased members reportedly had PEO. Three of the 5 who were clinically examined also had mild to moderate dopa-responsive parkinsonism, including asymmetric resting tremor, rigidity, and bradykinesia that developed about 10 to 20 years after onset of PEO. One of the patients with PEO and parkinsonism had mild axonal sensory and motor neuropathy, whereas another had episodes of major depression and bipolar disorder. Muscle biopsy of 2 affected family members showed mtDNA deletions and COX-negative muscle fibers. Baloh et al. (2007) suggested that parkinsonism may be a feature of PEOA3, as has been reported in some patients with PEOA1.

Van Hove et al. (2009) reported a 71-year-old woman who developed PEOA3 at age 51, She also had cataracts, adult-onset diabetes mellitus, distal paresthesias, sensorineural hearing loss, mild sensory ataxia, and chronic progressive limb-girdle muscle weakness. She also reported cognitive processing difficulties, short-term memory problems, and depression. Brain MRI showed scattered white matter changes in the subcortical and periventricular regions. Skeletal muscle biopsy showed a few ragged-red fibers and multiple mtDNA deletions. Family history was significant for a brother with ptosis, diabetes, who had died of coronary disease, and another brother had learning disabilities, short stature, and cataract, but no eye movement problems or ptosis. Genetic analysis identified a heterozygous mutation in the C10ORF2 gene (R303Q; 606075.0013).

Echaniz-Laguna et al. (2010) reported 2 unrelated French families with PEOA3 caused by the same mutation in the C10ORF2 gene (R374W; 606075.0014). In all, there were 5 affected living members and 4 affected deceased members. All living members developed progressive eyelid drooping in their forties, followed by progressive hearing loss and external ophthalmoplegia in their fifties and sixties. Two patients in their sixties had mild proximal limb weakness with areflexia and no obvious cognitive impairment. Two living individuals in their early seventies developed gait difficulty, dysphagia, dysphonia, and progressive severe cognitive impairment. All 4 deceased affected family members reportedly had severe cognitive impairment in addition to ptosis, hearing loss, and gait abnormalities. Serum creatine kinase and lactate at rest were within normal values in all 5 living patients. Other features included mild cerebral atrophy on brain imaging, axonal sensory peripheral neuropathy, and multiple mtDNA deletions on skeletal muscle biopsy. Echaniz-Laguna et al. (2010) emphasized the severe features in these families, particularly dementia.

Fratter et al. (2010) reported the clinical feature of 33 patients from 26 families with genetically confirmed PEOA3. The mean age at onset was 42 years, with a range of 8 to 65 years. The most common features were ptosis (97%) and ophthalmoparesis (94%), followed by fatigue (52%) and proximal myopathy (33%). Mild cardiac involvement, including left ventricular hypertrophy and arrhythmias, were present in 24%. Less common features, each present in 12% of patients, included muscle pain, dysphagia, visual impairment, and endocrine dysfunction (i.e., hypothyroidism). Three patients each had cataract, migraine, hearing loss, and gastrointestinal problems. Skeletal muscle biopsies showed showed remarkable variability regarding mitochondrial changes and secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Sixteen different heterozygous mutations, including 7 novel mutations, were found in the C10ORF2 gene: all were missense mutations, except for 1 in-frame duplication, and all occurred in exons 1 and 2. There were no apparent genotype/phenotype correlations. A review of 70 patients reported in the literature revealed similar features, with the addition of rare reports of bulbar symptoms, muscle wasting, and respiratory insufficiency. Fratter et al. (2010) emphasized that mild multiorgan involvement can occur in this disorder and that mtDNA depletion in muscle biopsies may be mild.

Mapping

In the affected family reported by Suomalainen et al. (1992), Suomalainen et al. (1995) found linkage to a 27-cM region on chromosome 10q23.3-q24.3 (maximum lod score of 4.52 at marker D10S597). Linkage analysis of 2 additional Italian PEO families excluded 10q, indicating genetic heterogeneity.

In a large Pakistani kindred with adPEO, Li et al. (1999) demonstrated linkage to a 7-cM interval on 10q23.31-q25.1 between markers D10S198 and D10S1795 (maximum lod score of 5.72 at D10S1267).

Molecular Genetics

In 12 different pedigrees of various ethnic origin, including those reported by Suomalainen et al. (1995) and Li et al. (1999), Spelbrink et al. (2001) identified 11 different coding region mutations in the C10ORF2 gene (see, e.g., 606075.0001606075.0007) cosegregating with adPEO.

Hirano and DiMauro (2001) reviewed the molecular genetics of progressive external ophthalmoplegia and classified the specific disease type according to mutation in the autosomal SLC25A4, C10ORF2, and POLG genes, as well as in multiple mitochondrial genes.

Lamantea et al. (2002) stated that mutations in the ANT1 and C10ORF2 gene account for approximately 4% and 35% of familial adPEO cases, respectively. Mutations in the POLG gene are the most frequent cause of all forms of familial PEO, accounting for approximately 45% of cases.

Animal Model

Tyynismaa et al. (2005) generated transgenic mice overexpressing mouse Twinkle due to mutations corresponding to the PEO-associated mutations ala359 to thr (A359T; 606075.0003) and duplication of amino acids 352 to 364 (606075.0001) in humans. Multiple mtDNA deletions accumulated in the tissues of mutant mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of mutant mice faithfully replicated features of PEO patients. These mice had progressive COX deficiency in distinct neuronal populations, but they did not display premature aging.