A number sign (#) is used with this entry because of evidence that autosomal recessive axonal Charcot-Marie-Tooth disease type 2A2B (CMT2A2B) is caused by homozygous or compound heterozygous mutation in the MFN2 gene (608507) on chromosome 1p36.

Heterozygous mutation in the MFN2 gene causes autosomal dominant CMT2A2A (609260), a less severe disorder with later onset.

Biallelic mutation in the MFN2 gene also causes multiple symmetric lipomatosis (MSL; 151800) with or without axonal peripheral neuropathy.

Autosomal recessive axonal CMT2A2B is a neurologic disorder characterized by onset of peripheral neuropathy in the first years of life. Patients have difficulty walking due to distal muscle weakness; upper limbs may also be affected. Sensory impairment is more variable. Patients often have optic atrophy (summary by Polke et al., 2011).

Nicholson et al. (2008) reported 2 unrelated adult patients (CMT742 and CMT231) with severe early-onset axonal neuropathy associated with compound heterozygous missense mutations in the MFN2 gene (see, e.g., 608507.0019 and 608507.0021). The patients presented at age 3 years with foot deformities or increased falls. They had muscle weakness and wasting of the upper and lower limbs, distal sensory loss, and normal or mildly decreased nerve conduction velocity. One patient (CMT742) was slightly deaf and had scoliosis. CMT742 became wheelchair-bound at age 10, whereas CMT231 became wheelchair-bound at age 32. Both had a high-pitched voice. All parents were heterozygous for the mutations and were either asymptomatic or mildly symptomatic with some signs of peripheral neuropathy. Nicholson et al. (2008) concluded that inheritance in these families was semidominant and that the parents showed reduced penetrance, although the disorder in the offspring presented as apparently autosomal recessive. The findings indicated that biallelic MFN2 mutations can result in a more severe phenotype and that heterozygous MFN2 mutations may show incomplete penetrance.

Polke et al. (2011) reported 5 patients from 3 unrelated families with autosomal recessive axonal CMT2A2. Two families were of British origin and 1 was of Italian origin. The patients had severe CMT with early onset between ages 12 months to 3 years. All presented with foot drop or walking difficulty associated with muscle weakness of the upper and lower limbs. Distal sensory impairment was only noted in 3 patients. Other variable features included scoliosis/kyphoscoliosis in 3 and pes cavus in 2. Four patients had optic atrophy or pale optic discs, but only 2 older sibs, aged 39 and 42 years, had visual loss. These older patients also had severe facial weakness and respiratory muscle weakness; 1 had hearing loss and vocal cord palsy. Four of the 5 patients were wheelchair-bound.

Carr et al. (2015) reported 3 additional British patients with severe early-onset CMT2A, and reviewed 2 British sibs reported by Polke et al. (2011). The patients ranged in age from 10 to 44 years. All presented between 18 and 24 months of age with difficulty walking due to foot drop. There was weakness of the upper and lower limbs, but sensory impairment was minimal. Four patients had optic atrophy. Four patients became wheelchair-dependent in the second or third decades; one remained ambulatory at age 44. Electrophysiologic studies were consistent with a length-dependent, predominantly motor, axonal neuropathy.

Tan et al. (2016) reported a 20-month-old girl, born of unrelated parents, with recessive CMT2A2B due to compound heterozygous mutations in the MFN2 gene. She reportedly had poor head control and right foot pronation at 2 months of age, and presented at age 7 months with hypotonia and distal weakness. Additional features included foot and wrist drop and areflexia. Electrophysiologic studies showed a severe sensorimotor neuropathy with a prominent motor component. At age 8 months, she developed rapidly progressive diaphragmatic paresis, necessitating mechanical ventilation; she also had poor weight gain necessitating gastrostomy tube. Ophthalmologic examination was normal with no signs of optic atrophy, and brain imaging showed no signs of white matter abnormalities. Both parents, each of whom carried one of the mutations, had normal neurologic examinations. Functional studies of the variants and studies of patient cells were not performed.

Tan et al. (2016) performed a literature review of 24 patients with biallelic mutations in the MFN2 gene resulting in autosomal recessive CMT2A2B. Most had onset in early childhood of a moderate to severe neuropathy and moderate to severe distal muscle weakness. Most also had proximal weakness affecting the upper and lower limbs. Skeletal deformities such as kyphosis, scoliosis, and pes cavus were common, but visual abnormalities were infrequent. Heterozygous carrier parents showed no or minimal symptoms.

Pipis et al. (2020) evaluated clinical features in 17 patients from 13 families with CMT2A2B identified in a large multicenter cohort study. The average age of symptom onset was 8.06 years, with an average disease duration of 25.35 years. Of 15 patients for whom clinical information was available, 8 had foot deformities, 14 had ankle-foot orthoses, 7 had walking aids, 3 were wheelchair dependent, 8 had a history of foot surgery, and 3 had optic atrophy. Of 14 patients for whom clinical information was available, 4 had scoliosis, 1 had hearing loss and 11 had dexterity difficulties.

The transmission pattern of CMT2A2B in the families reported by Polke et al. (2011) was consistent with autosomal recessive inheritance.

In a 32-year-old woman (CMT742) with autosomal recessive early-onset severe axonal neuropathy CMT2A2B, Nicholson et al. (2008) identified compound heterozygous missense mutations in the MFN2 gene (A164V, 608507.0021 and T362M, 608507.0019). Each parent was heterozygous for one of the mutations and showed mild features of the disorder. Nicholson et al. (2008) suggested that the apparent autosomal recessive inheritance of the disorder in this family was actually semidominant and that the parents showed incomplete penetrance. The homozygous mutation in the daughter resulted from the combined effect of 2 mutations and a more severe phenotype with earlier onset.

In 5 patients from 3 unrelated families with autosomal recessive axonal CMT2A2B, Polke et al. (2011) identified compound heterozygous MFN2 mutations (see, e.g., 608507.0017-608507.0020). The parents, who were heterozygous for the respective mutations, were all unaffected or reportedly unaffected. Analysis of the mutations suggested that haploinsufficiency for MFN2 does not result in a phenotype unless coinherited with another pathogenic mutation. Furthermore, inheritance of 2 mutations appears to cause a more severe disease with earlier onset.

Carr et al. (2015) reported 3 additional patients of UK ancestry with autosomal recessive early-onset axonal CMT2A2B due to compound heterozygous mutations in the MFN2 gene. All patients carried the exon 7/8 deletion on 1 allele (608507.0018), and haplotype analysis of these patients and the sibs reported by Polke et al. (2011) indicated a founder effect in this population. The other 3 patients carried a missense mutation on the other allele: 2 carried T362M (608507.0019), and 1 with a milder phenotype carried R707W.