Autosomaldominantrecessive PEO with multiple mtDNA deletions

Autosomal-dominant/-recessive progressive external ophthalmoplegia (ad/ar PEO) usually refers to an adult-onset condition with PEO plus various additional clinical manifestations and multiple mtDNA deletions in muscle (Suomalainen and Kaukonen, 2001; Van Goethem et al., 2003b). A special entity, which usually is included in this group of disorders, is the mitochondrial neurogas-trointestinal encephalomyopathy (MNGIE) syndrome (Hirano et al., 1994; Nishino et al., 2001; Hirano et al., 2004).

In ad/ar PEO, muscle weakness and exercise intolerance are the most common symptoms. Additional manifestations, which sometimes may be the presenting symptoms, include peripheral neuropathy, ataxia, tremor, parkinsonism, mental depression, cataracts, pigmentary retinopathy, dysphagia, hypoacusia, episodic rhabdomy-olysis and hypogonadism (Zeviani et al., 1990; Servidei et al., 1991; Kaukonen et al., 1996; Melberg et al., 1996a; 1996b; Suomalainen et al., 1997; Melberg et al., 1998; Kaukonen et al., 1999). The MNGIE syndrome includes gastrointestinal manifestations, cachexia, leuko-encephalopathy, peripheral neuropathy and mitochondrial myopathy (Nishino et al., 2001).

Fig. 6.9. Magnetic resonance scan of the brain of a nine-year-old girl with a multisystem disorder with a single large-scale deletion of mtDNA showing hyperintensive signals in the (A) the globus pallidus and thalamus and (B) subcornical white matter on T2-weighted images. Illustration courtesy of Lars-Martin Wiklund.

Nuclear gene mutations associated with adPEO include the muscle-heart specific mitochondrial adenine nucleotide translocator 1 (ANT1 ; Kaukonen et al., 2000), C10orf2, encoding a mitochondrial protein similar to phage T7 primase/helicase (gp4) called Twinkle (Spelbrink et al., 2001) and mtDNA polymerase g (POLG1), which is the only mtDNA polymerase in mitochondria (Van Goethem et al., 2001). arPEO and sporadic cases of PEO have been associated with mutations in POLG1 (Van Goethem et al., 2002; Di Fonzo et al., 2003). The sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) syndrome has also been associated with recessive POLG1 mutations (Van Goethem et al., 2003a). MNGIE, which is a recessively inherited disease, is associated with mutations in the thymidine phosphorylase (TP) gene (ECGF1 ; Nishino et al., 1999; 2000).

Most patients with ad/arPEO and MNGIE show mitochondrial myopathy with COX-deficient, and occasionally COX-positive, ragged red fibers. Biochemical analysis typically shows reduction in the partially mtDNA-encoded respiratory chain complexes I, III and IV (Suomalainen et al., 1992a). However, mitochondrial myopathy and multiple mtDNA deletions in muscle are not a consistent finding (Van Goethem et al., 2003a), and the clinical manifestations evolve gradually probably as a consequence of the gradual accumulation of somatic mtDNA mutations.

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