OMIM ID:
External Ophthalmoplegia, C10ORF2 and mtDNA Mutations
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Ptosis and external ophthalmoplegia are found in almost all patients. These have a variable onset with some patients not symptomatic until midlife or later. External ophthalmoplegia may be the only symptom. Onset in late adolescence has also been reported. Cataracts often occur.
Systemic Features
About half (52%) of patients have fatigue and weakness. Ataxia and peripheral neuropathy with paresthesias are sometimes present. Some patients report bulbar symptoms of dysphagia, dysarthria and dysphonia. Skeletal muscle biopsies show typical ragged red fibers and evidence of mitochondrial dysfunction with cytochrome c oxidase (COX) deficiency. Late onset of typical features of parkinsonism including a resting tremor, rigidity, and bradykinesia is seen in some patients. Several individuals have reported major depression and/or bipolar disorder. Myopathy (33%) with muscle wasting and respiratory difficulties can occur. As many as 24% of patients have cardiac abnormalities consisting primarily of conduction defects.
Genetics
Inheritance
This an autosomal dominant disorder secondary to mutations in the C10ORF2 (Twinkle) gene (10q24) in association with mitochondrial DNA depletion. It accounts for approximately 35% of autosomal dominant cases of external ophthalmoplegia.
At least two additional mutations cause similar external ophthalmoplegia syndromes: PEOA1 (157640, 258450), and PEOA2 (609283).
The same gene may have mutations that are responsible for spinocerebellar ataxia, infantile-onset (271245), a more generalized and progressive neurodegenerative disease transmitted in an autosomal recessive pattern.
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission