“Mitochondrial neuropathies”: A survey from the large cohort of the Italian Network

Highlights

• Analyses of 1200 patients with mitochondrial disorders showed that minimum prevalence of peripheral neuropathy is 12.4%.

• Mitochondrial neuropathic patients have an increased prevalence of ataxia, hearing loss, muscle weakness and muscle wasting.

• Mitochondrial DNA single deletions and LHON mutations are rarely associated with neuropathy.

• POLG mutations may cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy.

• TYMP and SURF1 mutations lead to a demyelinating sensory-motor polyneuropathy.

Abstract

Involvement of the peripheral nervous system in mitochondrial disorders has been previously reported. However, the prevalence of peripheral neuropathy in mitochondrial disorders is still unclear. Based on the large database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”, we reviewed the clinical data of 1200 patients, with special regard to peripheral neuropathy (mean age at onset 24.3 ± 20.1 years; age at last evaluation 39.8 ± 22.3 years; females 52.7%; childhood onset [before age 16 years] 43.1%). Peripheral neuropathy was present in 143/1156 patients (12.4%), being one of the ten most common signs and symptoms. POLG mutations cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy; TYMP mutations lead to a demyelinating sensory-motor polyneuropathy; SURF1 mutations are associated with a demyelinating/mixed sensory-motor polyneuropathy. The only mtDNA mutation consistently associated with peripheral neuropathy (although less severely than in the above-considered nuclear genes) was the m.8993T > G (or the rarer T > C) changes, which lead to an axonal, mainly sensory polyneuropathy. In conclusion, peripheral neuropathy is one of the most common features of a mitochondrial disorder, and may negatively impact on the quality of life of these patients. Furthermore, the presence or absence of peripheral neuropathy, as well as its specific forms and the association with neuropathic pain (indicative of a POLG-associated disease) can guide the molecular analysis.

Introduction

The central task of mitochondria is to generate energy in the form of adenosine triphosphate, through the electron transport chain and oxidative phosphorylation (OXPHOS) [1]. This pathway is under control of both nuclear and mitochondrial (mtDNA) genomes. Mitochondrial diseases are a group of disorders caused by OXPHOS impairment. They are one of the commonest inherited neuromuscular diseases, with an estimated prevalence of 1–2 in 10,000. The genetic classification distinguishes the disorders due to defects in mtDNA from those due to defects in nuclear DNA.

Both mtDNA and nuclear mutations affecting OXPHOS usually result in multisystem clinical phenotypes, including peripheral neuropathy [2]. Peripheral neuropathy is a defining feature in some mitochondrial disorders such as SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoplegia), NARP (neuropathy, ataxia and retinitis pigmentosa), or MNGIE (mitochondrial neuro-gastro-intestinal encephalomyopathy) [3], and occasionally is the prevalent disease manifestation [4], [5]. However, the exact prevalence of peripheral neuropathy in mitochondrial disorders is still unknown [6].

The aim of this retrospective study is to evaluate the minimum prevalence of peripheral neuropathy in patients with mitochondrial disorders, taking advantage of the large database built by the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. Specific genotype–phenotype correlations are highlighted.