mitochondrial deletions

External Ophthalmoplegia, ANT1 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and progressive external ophthalmoplegia are the outstanding features of this form of external ophthalmoplegia.  These symptoms may appear in early adulthood.  A few patients have had thyroid disease as well.  Muscle biopsies from limb muscles show the characteristic ragged red appearance of myopathy in a minority of fibers.  Multiple deletions occur in the mitochondria of skeletal muscles.  EMG studies show myopathy while nerve conduction studies are normal.  Respiratory chain analysis often shows evidence of mitochondrial dysfunction.

Systemic Features: 

Adult patients with SLC25A4 (4q35.1) and mtDNA (ANT1) mutations have exercise intolerance and sometimes skeletal muscle weakness.  They are less likely to have symptoms of parkinsonism or peripheral neuropathy than those with mutations in POLG.  Hearing loss is minimal.

Genetics

This autosomal dominant disorder results from the combination of a mutation in the ANT1 (SLC25A4) gene (4q35) (encoding the adenine nucleotide translocator-1) and mitochondrial DNA deletions.  About 11% of autosomal dominant cases with progressive external ophthalmoplegia have mutations in this gene.  Most reported families have been from Italy.

External ophthalmoplegia may also result from mutations in POLG (most common), and in C10ORF2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

External Ophthalmoplegia, POLG and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia of these types is often associated with widespread neurological and muscle manifestations.  The ophthalmoplegia is adult in onset and frequently combined with exercise intolerance.  Significant lens opacities may be seen in early childhood but may not cause vision problems until early adulthood. Progressive ptosis is often an early and disabling sign.

Systemic Features: 

Facial muscles can be weak, generally in older individuals.  Some patients complain of dysphagia.  Sensoirneural hearing loss, dysarthria, and dysphonia are often associated.  Neurological symptoms include ataxia, sensory neuropathy, tremors, depression and symptoms of parkinsonism but these are variable.   Some patients experience rhabdomyolysis following alcohol consumption.  Dilated cardiomyopathy can be a part of the autosomal recessive form of this disease.

A possible subcategory of this disease is associated with hypogonadism evidenced by delayed sexual maturation, primary amenorrhea, early menopause and testicular atrophy.  Other features as described above may be associated.  Muscle biopsy shows ragged-red fibers with multiple mitochondrial deletions.

Genetics

Progressive external ophthalmoplegia of the type described here is the result of mutations in the autosomal gene POLG combined with deletions in mitochondrial DNA.  POLG mutations account for 13-45% of patients with progressive external ophthalmoplegia who also have mitochondrial deletions.  The inheritance pattern in some families resembles the classical autosomal dominant pattern (PEOA1, 157640) whereas in others the pattern suggests autosomal recessive transmission (PEOB, 258450).  The autosomal defect is in the POLG gene at locus 15q25 which codes for the nuclear-encoded DNA polymerase-gamma gene.  The phenotype in the recessive disease tends to be more severe than in autosomal dominant cases. 

Other autosomal mutations with a less complex clinical picture associated with ophthalmoplegia are located in genes ANT1 (SLC25A4) (609283) at 4q35, and C10ORF2 (606075) at 10q24.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for the general disorder but consideration should be given to ptosis repair.

References
Article Title: 
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