Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant 2

A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-2 (PEOA2) is caused by heterozygous mutation in the nuclear-encoded ANT1 gene (SLC25A4; 103220) on chromosome 4q35.

Heterozygous mutation in the SLC25A4 gene can also cause autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A; 617184), and homozygous mutation in the SLC25A4 gene causes autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418).

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. 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 mutations in the POLG gene are associated with more complicated phenotypes than those forms caused by mutations in the ANT1 or C10ORF2 genes (Lamantea et al., 2002).

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

Clinical Features

Kaukonen et al. (1996, 1999) reported several Italian adPEO families. All patients had progressive external ophthalmoplegia and ptosis, but no generalized muscle weakness. Age at onset was approximately 35 years. Several affected family members had sensorineural hearing loss. Two subjects had goiter associated with hypo- or hyperthyroidism. Two elderly subjects suffered from dementia manifesting as impairment of cognitive functions, with no affective component. An increased serum lactate level at rest was detected in 1 patient. A typical example of a patient in this family was a 67-year-old woman with ptosis and ophthalmoplegia, bilateral hearing loss, and hyperthyroidism with goiter. Her standard electromyogram was myopathic, and nerve conduction-velocity studies were normal. Multiple mtDNA deletions were detected in an analysis of muscle biopsy from the biceps brachialis. Histologic analysis of her muscle sample showed that 3% of the fibers were ragged red and 5% showed partial COX deficiency (see 220110). No elevation of lactic acid was detected at rest or after standard exercise, and her serum CPK level was within the normal range. Respiratory chain analysis showed slightly reduced activities of complexes III and IV (65 to 70% of the mean of controls), whereas activities of complexes I and II were within the normal range.

Mapping

In an Italian family with adPEO, Kaukonen et al. (1999) mapped the disease locus, formerly designated 'PEO3,' to a 13.5-cM interval between markers D4S2920 and D4S2924 on chromosome 4q34-q35. The results yielded 2-point and multipoint lod scores of 3.51 and 4.7, respectively. In 3 Italian families with autosomal dominant PEO, Kaukonen et al. (1996) found linkage to a locus on chromosome 3p (formerly designated 'PEO2'). However, in a reanalysis of these families, Kaukonen et al. (2000) failed to find significant lod scores to the locus on chromosome 3p (highest new multipoint lod score of 2.85). Further haplotype analysis did not support the existence of an adPEO locus on chromosome 3, and a mutation in the ANT1 gene (103220.0001) on 4q35 was later identified in these families (see Kaukonen et al., 2000).

Molecular Genetics

In affected members of 5 4q-linked Italian families with adPEO reported by Kaukonen et al. (1996, 1999), Kaukonen et al. (2000) identified a heterozygous mutation in the ANT1 gene (103220.0001). The affected families originated from the Romagna County of Italy, suggesting a founder effect. Except for a lack of cardiac symptoms, the features of the patients resembled those in Ant1 knockout mice (Graham et al., 1997).

In 3 members of a Greek family with PEOA2, Napoli et al. (2001) identified a heterozygous mutation in the SLC25A4 gene (103220.0003). The mutation was absent in several unaffected family members and in Italian and Greek controls.

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.