Polyneuropathy as a multisystemic plus symptom in chronic progressive external ophthalmoplegia: Phenotypic differences in between singular deletions and multiple deletions of mitochondrial DNA

Chronic progressive external ophthalmoplegia (CPEO) is one of the most common manifestations in mitochondrial disorders. Besides manifestation with weakness of extraocular muscles and limb muscles other organs can be affected (CPEO plus) including peripheral nerve system. On molecular levels deletions of mitochondrial DNA (mtDNA) are frequently identified in CPEO.

One can distinguish in between CPEO with multiple deletions that are caused by nuclear defects in several genes (so called defects of intergenomic communication) and singular deletions of mtDNA that occur mainly sporadically.

In mitochondrial disorders genotype-phenotype-correlation is often rare. However, some cases and reports showed that multiple deletions are associated with sensory neuropathy and sensory ataxia quite often.

The purpose of this study was to examine on the presence of neuropathic symptoms in a cohort of patients with CPEO with singular or multiple deletions of mtDNA.

Methods: 33 patients were examined clinically and on electrophysiological examinations (motoric and sensory nerve conduction studies, somatosensory evoked potentials of tibialis nerve and electromyography).

18 patients revealed singular deletions of mtDNA. Multiple deletions were detected in 15 patients. In 6/15 patients with multiple deletion nuclear gene defects were known. Additionally to clinical examination we made use of the „Modified Total Neuropathy Score (mTNS)“ and the „Modified International Ataxia Rating Scale (mICARS)“.

Results: Neuropathy was most common in patients with multiple deletions than in singular deletions. A distal symmetrical polyneuropathy was found in 10/15 (67%) patients with multiple deletions in contrast to 2/18 (11%) patients with singular deletions. Neuropathy was mainly sensory. In contrast to patients with singular deletions patients with multiple deletions presented significantly higher scores (p<0.05) in the ataxia score (mICARS) as well as in the neuropathy score (mTNS). In none of the patients initial symptoms were due to neuropathy.

At the beginning of clinical manifestation there was predominantly weakness of extraocular muscles, presented as ptosis and not at any time neuropathy. Mean of age at the onset of ptosis was 27 years in the group of patients with singular deletions and 42 years in the group of patients with multiple deletions. This is a significant result (p<0.05).

In conclusion 2/3 of CPEO-patients with multiple deletions showed distal-symmetrical axonal neuropathy with sensory focus in contrast to singular deletions that are rarely associated from neuropathy (11%). Examining patients with CPEO and neuropathy as a multisystemic plus symptome defects of intergenomic communication have to be considered primary.