Peripheral neuropathy in patients with CPEO associated with single and multiple mtDNA deletions

摘要

Objective: To characterize peripheral nerve involvement in patients with chronic progressive external ophthalmoplegia (CPEO) with single and multiple mitochondrial DNA (mtDNA) deletions, based on clinical scores and detailed nerve conduction studies. Methods: Peripheral nerve involvement was prospectively investigated in 33 participants with CPEO (single deletions n = 18 and multiple deletions n = 15). Clinically, a modified Total Neuropathy Score (mTNS) and a modified International Cooperative Ataxia Rating Scale (mICARS) were used. Nerve conduction studies included Nn. suralis, superficialis radialis, tibialis, and peroneus mot. Early somatosensory evoked potentials were obtained by N. tibialis stimulation. Results: Participants with multiple deletions had higher mTNS and mICARS scores than those with single deletions. Electrophysiologically in both sensory nerves (N. suralis and N. radialis superficialis), compound action potential (CAP) amplitudes and nerve conduction velocities were lower and mostly abnormal in multiple deletions than those in single deletions. Early somatosensory evoked potentials of N. tibialis revealed increased P40 latencies and decreased N35-P40 amplitudes in multiple deletions. Both sensory nerves had higher areas under the receiver operating characteristic curves for the decreased CAP amplitudes than the 2 motor nerves. The N. suralis had the best Youden index, indicating a sensitivity of 93.3% and a specificity of 72.2% to detect multiple deletions. Conclusions: Peripheral nerve involvement in participants with multiple mtDNA deletions is an axonal type of predominant sensory neuropathy. This is clinically consistent with higher mTNS and mICARS scores. Sensory nerve involvement in participants with multiple deletions was not correlated with age at onset and duration of disease. Chronic progressive external ophthalmoplegia (CPEO) is the main clinical symptom associated with single, large scale, and multiple deletions of mitochondrial DNA (mtDNA). Peripheral neuropathy is a typical but variably expressed additional symptom. 1 , – 3 However, reports about peripheral neuropathy in patients with single deletions are rare. 4 , – 6 Electrophysiologic studies in mitochondrial diseases usually revealed a predominantly axonal type of nerve fiber damage. 7 , – 15 However, a predominantly demyelinating pattern or a mixed axonal and demyelinating type of peripheral nerve involvement has also been found. 4 , 11 , 16 Sural nerve biopsies revealed axonal degeneration 12 , 13 or demyelination. 11 It has already been shown that patients with multiple deletions (clinically SANDO [sensory ataxic neuropathy with dysarthria and ophthalmoparesis] syndrome) had reduced compound action potential (CAP) amplitudes in predominantly sensory nerves. Clinically, they might often present as SANO or SANDO syndrome. 17 There is only one previous study systematically comparing peripheral nerve involvement in patients with CPEO with single and multiple mtDNA deletions. 18 In that study, it has been postulated that peripheral neuropathy is a rare finding in patients with CPEO with single deletions compared with that in patients with CPEO with mtDNA point mutations, multiple mtDNA deletions, and nuclear defects. However, in that study, only one patient with single mtDNA deletion and peripheral nerve involvement has been investigated. Four other patients had the typical mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode mtDNA point mutation. Nine other patients had the nuclear POLG mutation, but multiple deletions have not been analyzed in 3/9 patients. In 2 patients with multiple deletions, the nuclear defect has not been identified. In all these patients, no detailed clinical and neurophysiologic data were presented, and no quantitative electrophysiologic data were provided. 18 In the present study, peripheral nerve involvement was prospectively investigated in 33 participants who had CPEO (single deletions n = 18 and multiple deletions of nuclear defects n = 15). Based on clinical scores and detailed nerve conduction studies, it could be shown that there was a more severe predominant sensory neuropathy in participants with multiple than with single deletions.