Histopathological Findings in Hereditary Motor and Sensory Neuropathy of Axonal Type With Onset in Early Childhood Associated WithMitofusin 2Mutations

Abstract

Neuropathologic abnormalities can be sufficiently characteristic to suggest the genetic basis of some hereditary neuropathies such as those associated with mutations in MPZ, GJB1, GDAP1, MTMR2, SH3TC2, PRX, FGD4, and LMNA. We analyzed the morphologic features of 9 sural nerve biopsies from 6 patients with mutations of mitofusin 2. All patients presented in early childhood with axonal neuropathies designated as mild or severe motor and sensory neuropathy. In all cases, there was a marked decrease in density of myelinated fibers, mainly of large diameter fibers. These changes were more marked in the second biopsies of 3 patients that were performed from 7 to 19 years after the first biopsies. Neurophysiologic findings were most suggestive of axonal degeneration, but some onion bulbs were present in all cases. Axonal mitochondria were smaller than normal, were round, and were abnormally aggregated. These changes may result from abnormal mitochondrial fusion and fission. The results suggest that these clinical and pathological features may be sufficiently characteristic to suggest the diagnosis of mitofusin 2-related neuropathy.

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Type 2 Caused by Mitofusin 2 Mutations

“…In both patients, electron microscopy of the nerve biopsy showed ultrastructural abnormalities similar to those observed in previously reported early-onset cases, 15 with a marked decrease in the density of myelinated fibers and abnormal axonal mitochondria, which appeared round and abnormally aggregated on longitudinal sections of the sural nerve (Figure 2).…”

Role of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A

“…Rather, in two anatomo-clinical reports, mitochondria have been found to accumulate in the distal part of sural nerve axons (Vallat et al, 2008;Verhoeven et al, 2006) (Fig. 2).…”

Bioenergetic defect associated with mK ATP channel opening in a mouse model carrying a mitofusin 2 mutation

“…Mitochondrial transport and distribution patterns are thus particularly crucial for neurons. Abnormal accumulations of mitochondria have been observed in the distal axon of sural nerve biopsies of patients with CMT2A (6,7), and mitochondrial aggregations around the nucleus have also been found in mouse embryonic fibroblasts and dorsal root ganglion neurons expressing some CMT2A disease mutations (8,9). Mitochondrial morphology was not affected in fibroblasts of CMT2A patients carrying a MFN2 mutation (10,11); however, these mitochondria demonstrated a decrease in efficiency of oxidative phosphorylation (OXPHOS) and in membrane potential (⌬⌿ m ; ref.…”