Neuropathy, Hereditary Motor And Sensory, Type Via, With Optic Atrophy
A number sign (#) is used with this entry because of evidence that autosomal dominant hereditary motor and sensory neuropathy type VIA with optic atrophy (HMSN6A), also referred to as Charcot-Marie-Tooth disease type 6A (CMT6A), is caused by heterozygous mutation in the mitofusin-2 gene (MFN2; 608507) on chromosome 1p36.
See also CMT2A2 (609260), an allelic disorder with overlapping features.
DescriptionHereditary motor and sensory neuropathy type VI is an autosomal dominant neurologic disorder characterized by peripheral neuropathy and optic atrophy (summary by Voo et al., 2003).
Genetic Heterogeneity of Hereditary Motor and Sensory Neuropathy Type VI
See also HMSN6B (616505), caused by mutation in the SLC25A46 gene (610826) on chromosome 5q22, and HMSN6C (618511), caused by mutation in the PDXK gene (179020) on chromosome 21q22.
For a general phenotypic description and a discussion of genetic heterogeneity of CMT, see CMT1B (118200).
Clinical FeaturesDyck et al. (1993) referred to a report by Vizioli (1889) describing a father and 2 sons with optic atrophy in association with peroneal muscular atrophy. The father became ill at age 59, one son at age 26, and the other at age 6. The older son and the father lost visual acuity and eventually became blind. Deep tendon reflexes were normal or decreased. Dyck et al. (1993) categorized this report and other cases of peroneal muscular atrophy with optic atrophy as hereditary motor and sensory neuropathy VI.
Ballet and Rose (1904) described 2 brothers with a similar phenotype. Schneider and Abeles (1937) described peroneal muscular atrophy and optic atrophy in 2 middle-aged brothers, the product of a first-cousin mating. The report was consistent with autosomal recessive inheritance. Visual deterioration began at age 7 years and progressed through adolescence when gait difficulties began. The affected sibs had 2 healthy sisters and 2 healthy brothers. Milhorat (1943) described 2 brothers, born of first-cousin parents, who developed nystagmus at age 9 years, distal muscular atrophy at age 15, and decreased visual acuity in their 20s. One sister had an illness that resembled multiple sclerosis (MS; 126200) but without peripheral neuropathy. Hoyt (1960) described a 17-year-old boy with muscle weakness beginning at 2 years of age who abruptly developed difficulty with visual acuity in the right eye and a month later in the left eye. The author commented on the similarity to Leber optic atrophy (535000).
Barreira et al. (1990) described an affected 12-year-old boy and his 10-year-old sister born to consanguineous parents. Electromyography demonstrated denervation and a marked decrease in nerve conduction velocity (NCV).
Ippel et al. (1995) reported a family with clear autosomal dominant inheritance of HMSN VIA. A father and 2 children, 1 son and 1 daughter, had both polyneuropathy and optic atrophy. Sural nerve biopsy from the father showed a mixed pattern of axonal and demyelinating neuropathy with small onion bulbs. Ippel et al. (1995) noted that several earlier reports of familial HMSN VI were consistent with autosomal recessive inheritance and proposed that HMSN VI may be genetically heterogeneous.
Chalmers et al. (1996, 1997) reported 2 unrelated HMSN VIA families that showed autosomal dominant and autosomal recessive inheritance, respectively.
Voo et al. (2003) reported a large family in which 58 members were reportedly affected by autosomal dominant HMSN VIA. Twelve affected individuals were examined by a physician and confirmed to have both peripheral neuropathy and optic atrophy; 3 other family members had either neuropathy or optic atrophy. Although there was clinical variability, most had childhood onset of progressive visual loss due to optic atrophy, abnormal gait, distal sensory impairment, and hyporeflexia. Other variable features included hearing loss, tinnitus, cogwheel ocular pursuit, and anosmia. Incomplete penetrance was observed.
Zuchner et al. (2006) reported 10 affected individuals from 6 unrelated families with HMSN VIA. Inheritance in all cases was autosomal dominant. All had a very early onset of axonal peripheral neuropathy, ranging from 1 to 10 years (mean age at onset 2.1 years). The symptoms showed severe progression, with almost all patients becoming wheelchair-bound. Features of the neuropathy included pes cavus, muscle atrophy, and distal sensory impairment for all modalities. Affected individuals in 1 family also had scoliosis and vocal cord paresis. Onset of optic atrophy was later, between 5 and 50 years of age (mean age 19 years). Most individuals experienced subacute deterioration of visual acuity with color vision defects, central scotoma, and pale optic discs. Remarkably, 60% of the patients experienced significant recovery of their visual acuity after several years. Incomplete penetrance was observed in 1 family.
Clinical Variability
Del Bo et al. (2008) reported an Italian father and 2 sons with peripheral neuropathy and a highly variable phenotype. The father had a symmetric axonal predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with CMT2A2, as well as impaired nocturnal vision and sensorineural hearing loss, consistent with HMSN6A. He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. Molecular analysis identified a heterozygous mutation in the MFN2 gene (608507.0014) in all 3 individuals. Del Bo et al. (2008) suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations.
Molecular GeneticsIn affected members of 6 unrelated families with autosomal dominant HMSN VIA, Zuchner et al. (2006) identified 6 different heterozygous mutations in the MFN2 gene (see, e.g., 608507.0009-608507.0012).