Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Recessive 1
A number sign (#) is used with this entry because autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-1 (PEOB1) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded DNA polymerase-gamma gene (POLG; 174763) on chromosome 15q26.
Homozygous or compound heterozygous mutation in the POLG gene can also cause sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), which shows overlapping features.
Heterozygous mutation in the POLG gene can cause autosomal dominant PEO (PEOA1; 157640).
DescriptionProgressive external ophthalmoplegia (PEO) is characterized by multiple mitochondrial DNA (mtDNA) 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. Less common features include mitral valve prolapse, cardiomyopathy, and gastrointestinal dysmotility. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (Filosto et al., 2003; Luoma et al., 2004).
Drachman (1975) gave a classification of disorders associated with progressive external ophthalmoplegia, which he termed 'ophthalmoplegia plus' (Drachman, 1968).
Genetic Heterogeneity of Autosomal Recessive External Ophthalmoplegia with Mitochondrial DNA Deletions
See also PEOB2 (616479), caused by mutation in the RNASEH1 gene (604123) on chromosome 2p25; PEOB3 (617069), caused by mutation in the TK2 gene (188250) on chromosome 16q21; PEOB4 (617070), caused by mutation in the DGUOK gene (601465) on chromosome 2p13; and PEOB5 (618098), caused by mutation in the TOP3A gene (601243) on chromosome 17p11.
Clinical FeaturesBohlega et al. (1996) reported 6 patients in 2 unrelated families with autosomal recessive ophthalmoplegia and cardiomyopathy. The families derived from the eastern Arabian peninsula and the patients presented with childhood-onset progressive external ophthalmoplegia, mild facial and proximal limb weakness, and severe cardiomyopathy requiring cardiac transplantation. Muscle biopsies showed ragged-red and cytochrome-c oxidase-negative fibers. The activities of several complexes in the electron-transport chain were decreased, and Southern blot analysis showed multiple mitochondrial DNA deletions. The authors thought that the apparent autosomal recessive inheritance and the association with cardiomyopathy distinguished this disorder from autosomal dominant PEO with multiple mtDNA deletions, and suggested a defect of communication between the nuclear and mitochondrial genomes.
Suomalainen et al. (1992) described a mother and son who died of idiopathic dilated cardiomyopathy at ages 37 and 22 years, respectively. The son's cardiac and skeletal muscle showed a high proportion of mitochondrial DNA with multiple large deletions by Southern blot hybridization and PCR analyses. Amplification of the mother's cardiac mtDNA from 20-year-old paraffin-embedded sections showed that she also had deletions of mtDNA. Severe muscle fatigue and weakness became evident, but no ptosis or ophthalmoplegia was detected. The deletions were multiple and the possibility was raised that this represented the effect of a nuclear gene mutation similar to the situation reported by Zeviani et al. (1989).
Van Goethem et al. (1997) reported 2 Belgian families in which 5 individuals had arPEO. Age at onset ranged from 28 to 61 years. The most prominent features were ptosis, ophthalmoplegia, generalized muscle weakness, including the neck and facial muscles, increased serum creatine kinase, and areflexia. Other variable features included distal sensory loss, abnormal nerve conduction studies, and psychiatric symptoms. All 3 affected members of 1 family had mitral valve prolapse. Two patients presented with ocular findings, 1 with muscular symptoms, 2 with neuropathy, and 2 with psychiatric manifestations, illustrating the variable clinical features. All patients had ragged-red fibers and multiple mtDNA deletions on muscle biopsy. Two patients had sudden unexplained death in their late thirties.
Davidzon et al. (2006) reported 2 sisters who presented at ages 26 and 20 years, respectively, with parkinsonism and axonal predominantly sensory peripheral neuropathy. Progressive ophthalmoplegia was not a feature in either patient. Clinical features included dystonic toe curling, action or postural tremor, facial masking, stiffness, bradykinesia, and rigidity. MRI of 1 sister showed moderate generalized cerebral and cerebellar atrophy. Both sisters displayed anxiety, and 1 had depression. Skeletal muscle biopsy showed 1 to 3% ragged-red fibers, decreased cytochrome c oxidase, and decreased mtDNA-encoded proteins. PCR assays in 1 sister showed multiple mtDNA deletions.
Deschauer et al. (2007) reported a 23-year-old man who presented with acute occipital neurologic signs, seizures, and a 2-year history of worsening coordination and concentration. Over the next 5 years, he had no further stroke-like episodes or seizures, but showed a sensory axonal neuropathy, ataxia, increased CSF protein, and multiple mtDNA deletions on skeletal muscle biopsy. Although he fulfilled the diagnostic criteria for MELAS syndrome (540000), he was found to be compound heterozygous for 2 mutations in the POLG gene. A left-sided homonymous hemianopia remained; ophthalmoparesis was not present. Deschauer et al. (2007) noted that this case further broadened the phenotypic spectrum associated with POLG mutations. Tzoulis and Bindoff (2008) objected to the use of MELAS by Deschauer et al. (2007) to describe the phenotype in their patient with POLG mutations. Tzoulis and Bindoff (2008) noted that the phenotype was consistent with PEO and stated that use of the term MELAS, which refers to a genetically distinct disorder, only leads to confusion. In a reply, Deschauer et al. (2008) stated that some patients with the MELAS phenotype do not have mutations in mitochondrial genes, and that clinicians should be aware that a similar phenotype can be associated with POLG mutations.
Clinical Variability
Echaniz-Laguna et al. (2010) reported 2 unrelated patients with recessive mutations in the POLG who each presented in adulthood with clinical features consistent with multiple sclerosis (MS; 126200), including optic neuritis, periventricular white matter abnormalities, and oligoclonal bands in the cerebrospinal fluid. The patients presented at age 37 and 30 years, respectively. Visual evoked-response studies showed increased P100 latency, consistent with optic neuritis. During the next several decades, both patients developed classic neurologic signs, including external ophthalmoplegia, ataxia, hearing impairment, ataxia, myopathy, cardiomyopathy, depression, and even cognitive impairment in 1. Skeletal muscle biopsies showed ragged-red fibers and multiple mtDNA deletions. Echaniz-Laguna et al. (2010) emphasized the atypical presentation of these patients.
Giordano et al. (2010) reported a 27-year-old man who presented with a 3-year-history of progressive weakness of the upper limbs in the absence of sensory disturbances. Physical examination showed reduced muscle strength of the distal upper limbs and normal strength in the lower limbs. There was no external ophthalmoplegia. Deltoid muscle biopsy showed mild variation in fiber size, COX-deficient muscle fibers, and marked mtDNA depletion (up to 93% decrease compared to controls). Genetic analysis identified compound heterozygous mutations in the POLG gene. The report expanded the phenotypic spectrum associated with recessive POLG mutations.
Milone et al. (2011) reported 2 unrelated men with recessive POLG mutations resulting in adult-onset exercise intolerance, generalized progressive proximal muscle weakness, ptosis, and external ophthalmoplegia. One patient, who had poor vision since childhood, was found to have optic atrophy with loss of thickness of the retinal nerve fiber and dyschromatopsia. Other features included dysphagia and mild distal superficial sensory loss. He was initially thought to have an OPA1 (605290)-related disorder, but testing of that gene was negative. The second patient did not have optic atrophy, but developed levodopa-responsive parkinsonism and had mildly increased serum creatine kinase. Both patients had cataracts. Muscle biopsies in both patients showed ragged-red fibers and multiple c oxidase-negative fibers; 1 had multiple mtDNA deletions. Milone et al. (2011) emphasized the occurrence of optic atrophy in 1 of their patients, further expanding the phenotype associated with POLG mutations.
Molecular GeneticsIn affected members of 2 unrelated Belgian families with arPEO reported by Van Goethem et al. (1997), Van Goethem et al. (2001) identified compound heterozygous mutations in the POLG gene (174763.0002-174763.0004).
Lamantea et al. (2002) identified POLG mutations in 3 cases of arPEO (see, e.g., 174763.0006; 174763.0007).
Davidzon et al. (2006) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0018 and 174763.0019).
HistoryIn the family described by Franceschetti et al. (1945), 4 of 5 sibs had cerebellar ataxia (which was considered to be of the Pierre Marie type) combined with ophthalmoplegia. The parents were normal and not related.