Homozygous p.R707W MFN2 mutation is associated with neuropathy, lipomatosis, peripheral lipoatrophy and metabolic alterations

Mutations in mitofusin 2 (MFN2), a nuclear encoded mitochondrial GTPase, classically induce autosomal-dominant axonal Charcot-Marie-Tooth (CMT2A) neuropathy, and more rarely recessive demyelinating or axonal forms. A homozygous p.R707W MFN2 mutation was reported in two families with lipomatosis and neuropathy. We studied, in three patients carrying the p.R707W homozygous MFN2 mutations, the characteristics of the peripheral neuropathy and the adipose tissue and metabolic alterations. The first patient, a woman of 52 years old, presented with pes cavus as a child, multiple lipomas affecting cranial, cervicothoracic and abdominal regions since the age of 25, absent ankle reflexes and quadriceps muscle weakness. Lipoatrophy was observed in lower limbs with decreased fat mass (19% of total body mass). Electroneuromyography (ENMG) showed an axonal sensory-motor neuropathy. She also displayed hypertriglyceridemia (2.7 mmol/l), insulin resistant diabetes and liver steatosis. A second 71-year-old patient complained of walking disorder and pes cavus since childhood. She progressively developed distal contractures and muscle weakness of upper and lower limbs, loss of sensitivity in the feet, and exercise intolerance. Lipoatrophy was present in the four limbs, with shoulder and neck lipomas. ENMG revealed anaxonal polyneuropathy. She had hypertriglyceridemia (3.7 mmol/l). A third 55-year-old patient presented with progressive four-limbs lipoatrophy, lipomatosis and abolished reflexes since she was a child. Ankle contractures appeared at 45, walking disorder at 55. Clinical examination showed pes cavus, distal weakness, and proprioceptive disturbance. A sensorimotor demyelinating neuropathy was found on the ENMG. She had hypertriglyceridemia (8.9 mmol/l) and diabetes since age 24. Unlike MT-TK gene mutations (MERRF: myoclonic epilepsy with ragged red fibers), the MFN2 p.R707W homozygous mutation associates not only lipomatosis and CMT but also lipoatrophy and metabolic alterations, and this work emphasize the fact that the MFN2 gene should be screened in cases presenting as such.