Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review of the literature

Abstract

Forty-three cases of peripheral neuropathy (PN) have been reported in the literature with a proven mitochondria (mt) DNA mutation, and 21 had a peripheral nerve biopsy (PNB). We studied 8 patients, 1 of whom had severe sensory PN, 3 mild PN, and 4 subclinical PN. Nerve biopsy was performed in every case; all patients showed axonal degeneration and 4 showed features of primary myelin damage. In addition, there were 2 crystalline-like inclusions in the Schwann cell cytoplasm of a patient with MERRF, and 1 in a patient with multiple deletions on the mtDNA. There are 11 cases of PNB in the literature with axonal lesions, 5 with demyelination, and 4 with mixed lesions. One PNB was not modified. A few crystalline-like inclusions were seen in 1 case of MERRF. Such inclusions were first reported in the Schwann cell cytoplasm of unmyelinated fibers in a patient with Refsum disease and were considered to be modified mitochondria. However, their mitochondrial origin remains debatable.

Combined muscle and nerve biopsy

“…Additional muscle specimens can be important in the diagnosis of neuropathies related to mitochondrial cytopathies [14][15][16] (cf. Chapter 17).…”

“…Progressive external ophtalmoplegia (PEO) is present is some cases, and may be associated with a sensory ataxic polyneuropathy. Ultrastructural examination of nerve specimens can show intraaxonal mitochondria with distorted cristae, but enlarged mitochondria with abnormal cristae within the Schwann cell cytoplasm of a few myelinated fibers are more characteristic [15,16].…”

Peripheral neuropathies in mitochondrial disorders

“…Mitochondrial DNA point mutations are maternally inherited and the level of heteroplasmy (percentage of mutated mtDNA in a given tissue/cell type) is a determinant of the resulting phenotype. In most cases of PNP associated with mtDNA point mutations, clinical examination, and electroneuromyography (ENMG) disclose a sensory or sensorimotor axonal neuropathy [1,2]. Sural nerve biopsy, when performed, showed a decrease density of myelinated fibers with clusters of regenerating myelinated fibers (indicating chronic axonal degeneration).…”

“…Sural nerve biopsy, when performed, showed a decrease density of myelinated fibers with clusters of regenerating myelinated fibers (indicating chronic axonal degeneration). These alterations were sometimes associated with minimal changes in myelin (disproportionately thin myelin sheaths, few onion bulbs) and subtle mitochondrial alterations in axons and in the Schwann cell cytoplasm [2]. More interestingly, several patients with a Charcot-Marie-Tooth type 2 (CMT2) phenotype were recently found to harbor the m.9185T > C mutation in the MT-ATP6 gene (representing ~1% of undefined CMT2 cases in a series of 442 patients) [3].…”

“…In a patient with another nearby mutation of the MT-ATP6 gene, m.9176T > C, nerve biopsy showed features suggestive of a chronic demyelinating neuropathy, with multiple multilayered onion bulbs. In a few other patients with mtDNA point mutations, moderately reduced nerve conduction velocities at ENMG and demyelinating features at nerve biopsy have been reported [2].…”