Alternative titles; symbols
SNOMEDCT: 764850002; ORPHA: 99947; DO: 0110155;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Charcot-Marie-Tooth disease, axonal, type 2A2A | 609260 | Autosomal dominant | 3 | MFN2 | 608507 |
A number sign (#) is used with this entry because autosomal dominant Charcot-Marie-Tooth (CMT) disease type 2A2A (CMT2A2A) is caused by heterozygous mutation in the MFN2 gene (608507) on chromosome 1p36.
Homozygous or compound heterozygous mutation in the MFN2 gene causes autosomal recessive CMT2A2B (617087), a more severe disorder with earlier onset.
Another form of CMT2A mapping to chromosome 1p36, CMT2A1 (118210), is caused by mutation in the KIF1B gene (605995).
See also hereditary motor and sensory neuropathy VI (HMSN6; 601152), an allelic disorder with overlapping features.
Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (118200) and CMT1A (118220) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (214400) and CMTX1 (302800) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively.
For a discussion of genetic heterogeneity of axonal CMT type 2, see 118210.
Saito et al. (1997) reported a Japanese family (family 693) in which 11 members spanning 4 generations had CMT2A2A inherited in an autosomal dominant pattern. The proband was a 45-year-old woman who developed a foot deformity, limping gait, and difficulty running at age 8 years. At age 20, she had difficulty climbing stairs. On examination at age 45, she had bilateral pes cavus, hammertoes, and mild muscle weakness of the anterior tibial, peroneal, and posterior tibial muscles without atrophy. She had lower limb hyporeflexia and ankle areflexia, as well as mildly decreased sensation of pain and vibration in her feet. Median nerve motor conduction velocity was normal, but sural nerve sensory action potentials could not be evoked. Nerve biopsy was not performed. Zuchner et al. (2004) identified a heterozygous mutation in the MFN2 gene (608507.0001) in affected members of this family.
Muglia et al. (2001) reported a large pedigree from southern Italy with CMT2A2A. Affected family members had distal muscle weakness and wasting with reduced or absent reflexes and mild distal sensory loss. Nerve biopsies in 2 members confirmed a loss of large myelinated fibers but no myelin abnormalities.
Vucic et al. (2003) and Zhu et al. (2005) reported a family (CMT66) in which 11 members had CMT2A2. Age at onset ranged from 4 to 20 years. In addition to typical signs and symptoms of CMT, most patients also had pyramidal signs, including extensor plantar responses, mild increases in muscle tone, and preserved or increased reflexes. However, there was no spasticity. The phenotype in this family indicated that CMT2A can be associated with pyramidal signs.
Lawson et al. (2005) reported 3 unrelated Utah families with CMT2A2 caused by 3 different mutations, respectively, in the MFN2 gene. The phenotypes were consistent with typical axonal CMT, with distal predominant lower extremity weakness and wasting, sensory loss, and areflexia. In the largest family, 6 mutation carriers had signs and symptoms mild enough that they had not sought medical attention. The findings indicated that in some families with CMT2A2 as many as 25% of individuals with mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait.
Pipis et al. (2020) reported clinical features in 179 individuals from 133 families with CMT2A2A from an international cohort study. One hundred and forty-four of the patients had childhood-onset disease (age 1-20 years). Most patients first noticed symptoms, usually walking or balance difficulties, in the first 2 decades of life. Compared to patients with adult-onset CMT2A2A, fewer childhood-onset patients had hearing loss (6% vs 12%) or scoliosis was (12% vs 13%), but more had optic nerve atrophy (9% vs 0). Childhood-onset of CMT2A2A was the most predictive indicator of significant disease severity but was found to be independent of disease duration. Childhood-onset disease was also associated with higher rates of use of foot-ankle orthoses, full-time use of a wheelchair, dexterity difficulties, and higher CMT Examination (CMTESv2) and Neuropathy (CMTNSv2) scores at initial assessment. Longitudinal data in a subset of these patients showed that the CMTESv2 scores increased significantly over 1 year, and scores on both the CMTESv2 and the Rasch-modified CMTESv2 significantly increased over 2 years.
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 HMSN6. 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.
Boaretto et al. (2010) reported 2 sisters and a brother with a severe form of adult-onset axonal CMT associated with a fatal subacute encephalopathy characterized by vomiting, nystagmus, chorea, clouded consciousness, and dysautonomia. At age 50, after colectomy, 1 sister developed encephalopathy. Postmortem examination of this patient showed vasculonecrotic lesions in the upper brainstem and periaqueductal gray matter. Their father had a similar course and died at age 61. Genetic analysis identified a heterozygous splice site mutation in the MFN2 gene (608507.0016), which was not found in 200 control chromosomes. An unaffected 64-year-old sister also carried the mutation, indicating incomplete penetrance. Boaretto et al. (2010) noted the unusual encephalopathy present in this family, and suggested that the nature of the mutation may have put sensitive areas of the brain in a precarious energetic equilibrium. However, unknown genetic, epigenetic factors, or environmental factors likely played a role in the phenotype.
The transmission pattern of CMT2A2A in the families studied by Zuchner et al. (2004) was consistent with autosomal dominant inheritance.
In studies of 2 CMT2 pedigrees, Hentati et al. (1992) excluded the CMT2 locus from the region of chromosome 17 and the region of chromosome 1 where CMT1A and CMT1B are located, respectively. This was evidence of a fundamental distinction between the hypertrophic demyelinating and neuronal forms of Charcot-Marie-Tooth disease.
In linkage studies of 6 large autosomal dominant CMT2 families, Ben Othmane et al. (1993) demonstrated linkage to a series of microsatellite markers in the distal region of the short arm of chromosome 1. Using admixture analysis and 2-point lod scores, they were able, however, to demonstrate heterogeneity. Multipoint analysis examining the 'linked' families showed that the most favored location of the CMT2 gene is within the interval flanked by D1S244 and D1S228 in the region 1p36-p35.
Muglia et al. (2001) refined the localization of the CMT2A2 locus to chromosome 1p36-p35 between markers D1S503 and D1S228.
Zuchner et al. (2004) identified heterozygous mutations in the MFN2 gene (608507.0001-608507.0006) in affected members of several families with CMT2A2A, including 1 family reported by Bissar-Tadmouri et al. (2004), 1 reported by Muglia et al. (2001), and 1 (family 693) reported by Saito et al. (1997).
In 11 affected members of the family reported by Vucic et al. (2003), Zhu et al. (2005) identified a heterozygous mutation in the MFN2 gene (608507.0008).
Chung et al. (2006) identified 10 pathogenic MFN2 mutations (see, e.g., 608507.0004; 608507.0009; 608507.0011) in 26 patients from 15 (24.2%) of 62 Korean families with CMT2A2 or HMSN VI. There were 2 main groups of patients, including those with early onset before 10 years and those with late onset after age 10 years. Those with early onset had a severe disorder, often with scoliosis and contractures, whereas those with later onset had a milder disorder and a higher frequency of unusual findings such as tremor, pain, and hearing loss. The severity of the disorder tended to be the same within families, suggesting a genotype/phenotype correlation.
Cho et al. (2007) identified mutations in the MFN2 gene in 4 (33%) of 12 unrelated Korean patients with CMT type 2. Two of the 4 patients had a family history of the disorder.
Calvo et al. (2009) identified 20 different missense mutations, including 10 novel mutations, in the MFN2 gene in 20 of 150 probands with CMT and a nerve conduction velocity (NCV) of 25 m/s or greater. Eighteen of the patients had been previously reported. The mutation frequency was 17.8% (19 of 107 patients) in CMT2 and 2.3% (1 of 43) with CMT1 (NCV less than 38 m/s). Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance; the remaining 5 patients were sporadic cases with heterozygous mutations. The phenotypes varied from mild forms to early-onset severe forms, and additional features, such as pyramidal signs or vasomotor dysfunction, were encountered in 8 patients (32%). The study indicated that MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. Calvo et al. (2009) suggested that testing for mutations in MFN2 showed be a first-line analysis in axonal CMT regardless of the mode of inheritance or the severity of the peripheral neuropathy.
Casasnovas et al. (2010) identified 9 different heterozygous MFN2 mutations, including 4 novel mutations, in 24 patients from 14 different Spanish families with CMT2A2. Six (42.8%) of 14 families carried the same mutation (R468H; 608507.0015). Overall, MFN2 mutations were identified in 16% of the total cohort of 85 Spanish families with axonal CMT, and Casasnovas et al. (2010) concluded that MFN2 is the most frequent cause of axonal CMT in this population.
Pipis et al. (2020) reviewed molecular findings in 179 individuals from 133 families with dominant mutations in MFN2. The majority of mutations occurred in the dynamin-GTPase domain. Genetic variants at certain amino acid positions, including arg94, arg104, ser249, and trp740, were always pathogenic, with no evidence of reduced penetrance or variable expressivity.
Pipis et al. (2020) evaluated 179 individuals from 133 families with CMT2A2A and compared clinical features of patients with mutations located in (amino acids 93-342) or outside of the dynamin-GTPase domain. There were no significant differences in the age of onset of symptoms or in mean baseline scores on the CMT Neuropathy Score Version 2, the CMT examination Score version 2 (CMTESv2), the Rasch-modified CMTESv2, or the CMT Pediatric Scale. Both groups had similar disease duration periods. A slightly higher proportion of patients with mutations located in the dynamin-GTPase domain used ankle-foot orthoses, had dexterity difficulties, or developed scoliosis. Optic atrophy was most frequently seen in patients with mutations at arg104, followed by an arg364-to-trp (608507.0011) mutation, and mutations at leu248.
In fibroblasts derived from CMT2A2 patients with MFN2 mutations (see, e.g., R94Q, 608507.0001), Guillet et al. (2010) found an uncoupling of mitochondrial oxygen consumption and decreased efficiency of oxygen utilization, but normal ATP production. Normal ATP production was maintained by an increased respiration rate, mainly involving complex II proteins. Mutant fibroblasts also showed overexpression and increased activity of ANT3 (SLC25A6; 300151), which was believed to result in reduced efficiency of oxidative phosphorylation. The findings suggested that MFN2 plays a role in controlling ATP/ADP exchange in mitochondria.
Larrea et al. (2019) evaluated mitochondrial bioenergetics and mitochondrial-associated ER membrane (MAM) function in fibroblasts from 3 individuals with CMT2A2B and mutations in MFN2. The first individual (P1) was a 32-year-old woman with an R364W mutation (608507.0011) and a severe presentation, including onset of mobility and balance issues at age 2 years and 7 months. The second individual (P2) was a 62-year-old man with an M376V mutation who had mild clinical features and presented with weakness at age 11 years. The third individual (P3) was a 34-year-old woman with a W740S mutation (608507.0002) with a mild clinical presentation. Mitochondrial morphology studies showed no difference between control and mutant mitochondrial perimeter or surface area, but patient cells showed a lower degree of physical association between the mitochondria and ER. An assessment of several measures of MAM function showed that, compared to controls, P3 fibroblasts had reduced serine incorporation in phosphatidylserine and phosphatidylethanolamine; P1 and P2 fibroblasts had increased cholesteryl ester synthesis; and P1 fibroblasts had significantly increased lipid droplets.
In 14 (11%) of 127 Japanese patients with axonal CMT, Abe et al. (2011) found mutations in the MFN2 gene, which represented the most common molecular cause. A molecular basis for the disease could not be found in 100 Japanese patients with axonal CMT.
Lin et al. (2011) identified MFN2 mutations in 5 (13.9%) of 36 Taiwanese families of Han Chinese descent with CMT2.
Detmer et al. (2008) generated transgenic mice expressing a pathogenic Mfn2 T105M mutation in peripheral motor neurons. Mutant mice developed key clinical features of CMT2A in a dose-dependent manner. Homozygous mice had a severe gait defect from birth due to an inability to dorsiflex the hindpaws, and they consequently dragged their hindpaws while walking and supported themselves on the hind knuckles, rather than the soles. Anterior calf muscles showed severe atrophy. There was decreased penetrance of the defects as well as lack of progression. Histologic studies showed reduced numbers of motor axons in the motor roots and improper mitochondrial distribution with tight clusters of mitochondria within axons. Homozygous mice had drastically short tails that were deformed, whereas heterozygous mice had shorter tails with mild to moderate bony kinks or thickening.
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