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. Additional symptoms are variable, and may include ... 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. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (Filosto et al., 2003; Luoma et al., 2004). PEO caused by mutation in the POLG gene is associated with more complicated phenotypes than those forms caused by mutation in the ANT1 or C10ORF2 genes (Lamantea et al., 2002). - Genetic Heterogeneity of Autosomal Dominant Progressive External Ophthalmoplegia with DNA Deletions See also PEOA2 (609283), caused by mutation in the ANT1 gene (SLC25A4; 103220) on chromosome 4q34; PEOA3 (609286), caused by mutation in the twinkle gene (C10ORF2; 606075) on chromosome 10q24; PEOA4 (610131), caused by mutation in the POLG2 gene (604983) on chromosome 17q; PEOA5 (613077), caused by mutation in the RRM2B gene (604712) on chromosome 8q23; and PEOA6 (615156), caused by mutation in the DNA2 gene (601810) on chromosome 10q.
Lundberg (1962, 1966, 1974) described a large Swedish kindred in which progressive external ophthalmoplegia was associated with hypogonadism. Melberg et al. (1996) provided follow-up. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ... Lundberg (1962, 1966, 1974) described a large Swedish kindred in which progressive external ophthalmoplegia was associated with hypogonadism. Melberg et al. (1996) provided follow-up. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples from advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mitochondrial DNA (mtDNA) deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Melberg et al. (1996) hypothesized that the nuclear gene causing PEO with hypogonadism may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA. In additional studies of 16 members of this family, Melberg et al. (1996) showed that the muscular involvement commenced cranially and descended in relation to increasing disease duration. In addition to PEO, patients had dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyelogram (EMG) was myopathic in facial and proximal limb muscles. Melberg et al. (1998) reported the case of a 57-year-old man, a member of the kindred originally reported by Lundberg (1962), who had PEO and multiple mtDNA deletions and who developed acute rhabdomyolysis provoked by alcohol. A repeated alcohol intake resulted in a 57-fold increase in serum myoglobin. Luoma et al. (2004) found that affected patients in the family reported by Lundberg (1962) developed parkinsonism later in the disease course with rigidity, bradykinesia, tremor, and favorable response to levodopa. A family reported by Pepin et al. (1980) had adPEO with cataracts as a prominent feature. A grandmother, mother, and son had early-onset cataracts, and documented mitochondrial myopathy was present in the 2 older family members. The grandmother, aged 62 years, had severe progressive ophthalmoplegia associated with facial, pharyngeal, and limb muscle involvement, as well as premature ovarian failure. Bilateral cataracts, present from at least age 20 years, were removed at age 40. Muscle biopsy showed ragged-red fibers with abnormal mitochondria. Bilateral cataracts were removed in the daughter at age 32. She had mild facial weakness. Despite the absence of ophthalmoplegia, mitochondrial abnormalities were demonstrated in the inferior oblique muscle. The son, clinically healthy at age 10, had had bilateral cataract extraction at age 3 years. The authors cited another family with mitochondrial myopathy involving type I muscle fibers associated with cataract inherited in an apparently autosomal dominant pattern. They also referred to a family with congenital cataract and myocardial and skeletal myopathy of mitochondrial type, also known as Senger syndrome (212350); in that instance, inheritance was thought to be autosomal recessive. All 3 affected persons in the family of Pepin et al. (1980) had the HLA A2-B21 haplotype. Zeviani et al. (1989) and Servidei et al. (1991) reported an Italian family in which 9 persons in 4 sibships spanning 3 generations were affected by an adult-onset mitochondrial myopathy with multiple mtDNA deletions. Inheritance was autosomal dominant with instances of male-to-male transmission. The main clinical features included progressive external ophthalmoplegia, dysphagia, lactic acidosis, exercise intolerance, and cataracts. Age at onset ranged from 24 to 30 years. Muscle biopsies showed ragged-red fibers and decreased activity of cytochrome c oxidase. Southern blot analysis and PCR showed multiple mtDNA deletions in skeletal muscle of all affected family members, but not in lymphocytes or fibroblasts. The mtDNA deletions appeared to increase with time and correlated with disease severity. Zeviani et al. (1990) reported 2 additional affected families with mtDNA deletions. Clinical features included adult-onset PEO, proximal muscle weakness and wasting, sensorineural hypoacusia, and cataracts in older patients. Affected members of 1 pedigree also showed tremor, ataxia, and chronic axonal sensorimotor peripheral neuropathy. Muscle biopsy showed ragged-red fibers and decreased cytochrome c oxidase activity. The same portion of mtDNA was involved in all patients. Sequence analysis, performed after mtDNA amplification by PCR, showed that all the deletions started within a 12-nucleotide stretch at the 5-prime end of the D-loop region, a site of active communication between the nucleus and the mtDNA. The authors suggested that a mutation in a nuclear-encoded protein could destroy the integrity of the mitochondrial genome in a specific, heritable way, and that there may be other examples of 'human pathology of...factors involved in the 'cross-talk' between the nuclear and the mitochondrial genomes.' The existence of a nuclear-encoded factor responsible for mitochondrial deletions or a failure of repair was suggested also by Cormier et al. (1991) for the findings in a family with various mtDNA deletions. The proband had ataxia and episodic ketoacidotic coma. Muscle biopsy showed a mitochondrial myopathy with ragged-red fibers. Various mtDNA deletions were detected not only in the proband but also in his healthy mother and maternal aunt, but not in the other progeny of the mother. All of the deletions were located between the Cox II and cytochrome b genes. Van Goethem et al. (1997) identified 3 Belgian families with PEO and multiple mitochondrial deletions. The diagnosis was based on clinical symptoms of PEO and muscle weakness, the presence of ragged-red fibers, and multiple mitochondrial deletions in muscle biopsies. Electron microscopy showed subsarcolemmal accumulation of abnormally structured mitochondria with paracrystalline inclusions. The inheritance pattern in 1 family was autosomal dominant, whereas the other 2 families likely had autosomal recessive inheritance. Chalmers et al. (1996) reported 2 British families with adPEO with additional unusual features, including parkinsonism and pigmentary retinopathy. The parkinsonism was levodopa-responsive. Luoma et al. (2004) reported 7 unrelated families with PEO caused by mutation in the POLG gene; 1 of the families had been reported by Chalmers et al. (1996) and another had been reported by Lundberg (1962). Four families showed definitive autosomal dominant inheritance, 1 showed possible autosomal recessive inheritance, and 2 were undetermined. In 5 families, including the 1 with possible autosomal recessive inheritance, affected members had parkinsonism, with resting tremor, rigidity, bradykinesia, and favorable response to levodopa. Parkinsonism occurred after onset of PEO. Additional features in these families included cataracts, sensory axonal neuropathy, depression, and hypogonadism. Mancuso et al. (2004) reported 2 sibs with early-onset parkinsonism and a heterozygous mutation in the POLG gene (174763.0015). The proband was a 49-year-old woman with PEO, exercise intolerance, sensory neuropathy, parkinsonism, and gonadal dysgenesis. Skeletal muscle biopsy showed multiple mtDNA deletions. Her brother developed parkinsonism in his early forties. Several other family members reportedly had PEO and exercise intolerance. Mancuso et al. (2004) concluded that parkinsonism may be a prominent feature in patients with POLG mutations, and suggested that mitochondrial dysfunction may play a role in the development of parkinsonism.
Lamantea et al. (2002) identified POLG mutations in 10 adPEO families and noted that the clinical features of these patients were often more severe and complex than those associated with ANT1 or C10ORF2 mutations. In particular, patients with ... Lamantea et al. (2002) identified POLG mutations in 10 adPEO families and noted that the clinical features of these patients were often more severe and complex than those associated with ANT1 or C10ORF2 mutations. In particular, patients with POLG mutations also had profound muscle weakness and wasting, severe dysphagia, dysphonia, facial diplegia, ataxia due to distal neurogenic weakness, and severe depression. Lamantea et al. (2002) suggested that the mutant nuclear factor in adPEO may cause a pathologic amplification of the otherwise normal phenomenon of accumulation of mtDNA deletions associated with aging. Luoma et al. (2004) noted that dominant POLG mutations tend to cluster in the polymerase 'pol' domain of the protein, whereas recessive POLG mutations tend to affect the proofreading exonuclease 'exo' domain. The authors noted the cosegregation of parkinsonism and mutations in the pol domain of the protein, and suggested that mtDNA deletions may play a role in the development of parkinsonism by fostering the accumulation of mtDNA mutations. Mitochondrial DNA deletions may lead to reduced ATP production or oxidative stress, resulting in neurodegeneration.
Hirano and DiMauro (2001) reviewed the molecular genetics of progressive external ophthalmoplegia and classified the specific disease type according to mutation in the autosomal ANT1, C10ORF2, and POLG genes as well as in multiple mitochondrial genes.
... Hirano and DiMauro (2001) reviewed the molecular genetics of progressive external ophthalmoplegia and classified the specific disease type according to mutation in the autosomal ANT1, 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. In affected members of a Belgian pedigree with adPEO, Van Goethem et al. (2001) identified a heterozygous mutation in the POLG gene (Y955C; 174763.0001). In affected members of 5 families with adPEO, Lamantea et al. (2002) identified the heterozygous Y955C mutation. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). In affected members of 5 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C POLG mutation. Affected members of 3 of the families also showed parkinsonism. Schulte et al. (2009) identified heterozygous POLG mutations in 2 of 26 patients from 23 families with cerebellar ataxia plus external ophthalmoplegia and/or sensory neuropathy. Nine additional patients from this cohort had homozygous or compound heterozygous POLG mutations, consistent with SANDO. Noting that the molecular diagnosis of cerebellar ataxia can be difficult, Schulte et al. (2009) found that for POLG-associated ataxia, the additional presence of ophthalmoplegia had a predictive value of 80%, whereas the presence of neuropathy had a predictive value of 45%.