Clinical phenotype of autosomal dominant progressive external ophthalmoplegia in a family with a novel mutation in the C10orf2 gene

Abstract

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder caused by mutations in nuclear genes. Here we report the clinical and genetic features of adPEO in a Chinese family. All patients had gradual onset of ptosis, with or without ophthalmoplegia, around age 30. Thirteen patients had limb weakness around age 40. Eight patients developed dysphagia around age 50. Four patients died of cardiac abnormalities around age 60. Muscle biopsy of the proband indicated mitochondrial myopathy characterized by ragged-red fibers, cytochrome c oxidase-negative fibers, and multiple deletions of mitochondrial DNA. A heterozygous missense mutation of c.1342A>G in the C10orf2 gene resulting in the p.448N>D mutation in the protein was found in the proband and four other affected family members. In summary, we identified an adPEO family with a novel C10orf2 gene mutation that manifested an age-dependent phenotype. It suggests that greater attention must be paid to cardiac abnormalities in the late stages of this disease.

TWINKLE gene mutation: report of a French family with an autosomal dominant progressive external ophthalmoplegia and literature review

“…Muscle involvement was the only feature associated with PEO in seven patients [8–11,17,19]. Muscle weakness was generalized in three patients [23,25] and predominated distally in our cases III2 and IV1. Muscle biopsy was performed in almost every case and there were several RRF and cox‐negative fibers, except in one case [21].…”

“…A few cases [23] and our case IV3, not included in Table 1, presented RRF and cox‐negative fibers but had neither clinical features of limb myopathy nor neurological features. In the same way, ptosis and PEO were isolated in relatives of patients with neurological features [17,18,25] and in all members of a German family [27]. Peripheral neuropathy was observed in 12 cases listed in Table 1 and have previously been studied in cases with primary mtDNA mutations [28–30].…”

“…Poor balance was observed in a 40‐year‐old man without any features of peripheral neuropathy [10]. Brain stem symptoms of dysarthria and/or dysphagia were present in six cases without any associated neuropathy [8,14,19,25]. Hearing loss was noticed in seven cases [12,20,22,24].…”

“…Conversely, obesity was observed at first examination of a 35‐year‐old woman and later on in her two daughters [23]. Two patients had palpitations [10,25] and heart failure was observed in two cases [23], as well as in three relatives of the proband in a large Chinese family [25]. Depression was present in three patients [16,19,23], seizures in one [13], migraine in one [19], hypothyroidism in two [19,23], and cataracts in another one but without any clear relationship with the Twinkle mutation [20].…”

“…A few families with recessive transmission of mutated Twinkle have been reported [7] but are not considered in the present paper. Thirty‐three adult cases have been reported with mainly myopathic symptoms albeit central and peripheral nervous system could be affected [8–25]. These reports included 31 cases from 20 unrelated families with an autosomal dominant inheritance and two sporadic cases [11,19].…”