Mutations in the mitofusin 2 gene are the most common cause of Charcot-Marie-Tooth type 2 disease

In contrast to Charcot-Marie-Tooth type 1 disease (CMT1), which is most commonly caused by 17p11.2-p12 duplication (in 70% of CMT1 cases), the axonal form of hereditary motor and sensory neuropathy (CMT2) seemed to be a genetically heterogeneous disease group, with no single gene playing a major pathogenetic role. In 2004, 10 mutations were identified in CMT2A families in the MFN2 gene coding for the mitochondrial protein mitofusin-2, previously mapped to the 1p35-36 locus. In the last two years, MFN2 gene mutations were shown to be the most common cause of autosomal dominant hereditary axonopathy. In addition, MFN2 gene mutations were also identified in CMT type 6 (axonal neuropathy with optic nerve atrophy). Recent reports indicate that some MFN2 gene mutations may by inherited as autosomal recessive traits. As MFN2 gene mutations are the most common cause of autosomal dominant CMT2 disease (33% of cases), MFN2 gene testing may be considered a diagnostic test for CMT2.     

Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy.

The association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy.     

Ethambutol toxicity exacerbating the phenotype of CMT2A2

Introduction: CMT2A2 is associated with mutations in the mitofusin 2 gene, which encodes a protein involved in mitochondrial fusion. Ethambutol is an antimycobacterial agent associated with toxic optic neuropathies. Ethambutol‐induced optic neuropathy occurs in patients with mutations in a related fusion gene, OPA1, which is responsible for autosomal dominant optic atrophy. Methods: We describe a patient with CMT2A2 (MFN2 mutation: T669G, F223L) who developed accelerated weakness, vocal cord paralysis, and optic atrophy after receiving ethambutol. Results: Deterioration began within months of initiating ethambutol therapy. After discontinuation of ethambutol, neurologic deterioration stabilized with subsequent improvement in visual fields. Conclusions: CMT2A2 is part of a group of genetic disorders which share an association with the process of mitochondrial fusion. This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely susceptible to ethambutol‐induced neurotoxicity. This has implications regarding the underlying pathophysiology of mitochondrial fusion defects. Muscle Nerve, 2013     

A novel type of hereditary motor and sensory neuropathy characterized by a mild phenotype.

BACKGROUND: Three loci for autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1) have been identified on chromosomes 17p11.2 (CMT1A), 1q21-q23 (CMT1B), and 10q21.1-q22.1 (designated here as CMT1D). The genes involved are peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and the early growth response element 2 (EGR2), respectively. Probably a fourth locus (CMT1C) exists since some autosomal dominant HMSN I families have been excluded for linkage with the CMT1A and CMT1B loci. Four loci for autosomal dominant hereditary motor and sensory neuropathy type II (HMSN II) or Charcot-Marie-Tooth disease type 2 (CMT2) have been localized on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), 7p14 (CMT2D), and 3p (HMSN-P). OBJECTIVE: To describe the clinical, electrophysiologic, and neuropathological features of a novel type of Charcot-Marie-Tooth disease. PATIENTS AND METHODS: We performed linkage studies with anonymous DNA markers flanking the known CMT1 and CMT2 loci. Patients and their relatives underwent clinical neurologic examination and electrophysiologic testing. In the proband, a sural nerve biopsy specimen was examined. RESULTS: Linkage studies excluded all known CMT1 and CMT2 loci. The clinical phenotype is mild and almost all affected individuals remain asymptomatic. Electrophysiologic and histopathological studies showed signs of a demyelinating neuropathy, but the phenotype is unusual for either autosomal dominant HMSN I or HMSN II. CONCLUSION: Our findings indicate that the HMSN in this family represents a novel clinical and genetic entity.     

Autosomal recessive inheritance of hereditary motor and sensory neuropathy with optic atrophy.

Three siblings are reported with childhood onset hereditary motor and sensory neuropathy (HMSN) and adult onset optic atrophy. Electrophysiological studies showed an axonal neuropathy and dysfunction of the retinal ganglion cells or optic nerve. The presumed mode of inheritance is autosomal recessive. This is the second family in which autosomal recessive inheritance of HMSN and optic atrophy (HMSN type VI) has been described, and the first in which electrophysiological studies have been reported.     

Mutational mechanisms in MFN2‐related neuropathy: compound heterozygosity for recessive and semidominant mutations

Mitofusin‐2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot‐Marie‐Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. We describe a 49‐year‐old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late‐onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semidominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.     

Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults

Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 (MFN2) have recently been identified as the cause of approximately one‐third of dominantly inherited cases of the axonal degenerative forms of Charcot–Marie–Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early‐onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2.     

Two Spanish families with Charcot-Marie-Tooth type 2A: clinical, electrophysiological and molecular findings

Mutations in the Mitofusin 2 (MFN2) gene have been related to the axonal type of Charcot-Marie-Tooth type 2 (CMT 2A). We report the first two Spanish families with CMT 2 and mutations in MFN2 gene. Molecular studies of one family with late onset revealed the novel mutation Arg364Gln. The affected family members presented mild clinical and electrophysiological worsening after 14 years of follow-up. The other family presented an early onset and optic atrophy. Molecular studies revealed the Arg94Gln mutation. This is the first report of a family in which this mutation is related to optic atrophy. Molecular analysis aimed at detecting mutations of MFN2 could be extremely useful in mild axonal neuropathies with slow evolution and indispensable in cases of dominant inheritance or optic atrophy. Population studies of mutations in MFN2 should be undertaken to discover the real frequencies in the Mediterranean area.     

Autosomal recessive Charcot‐Marie‐Tooth disease: from genes to phenotypes

The prevalence of Charcot‐Marie‐Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR‐CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino‐varus, claw‐like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR‐CMT.     

Hereditary motor-sensory neuropathies. Charcot-Marie-Tooth syndrome

The Charcot-Marie-Tooth (CMT) syndrome is also referred to as hereditary motor-sensory neuropathy (HMSN). It is not a single disease but has a multitude of genetic causes. The typical clinical characteristics are distal muscle weakness and atrophy, depressed tendon reflexes, often slow motor NCV, and the frequent finding of other similarly affected relatives. The most common variant of this syndrome is HMSN-I showing autosomal dominant inheritance, markedly slow motor NCV and nerve hypertrophy. One form of HMSN-I is linked to the Duffy locus on chromosome 1. There are numerous other varieties of HMSN including other autosomal dominant conditions such as HMSN-II (with nearly normal motor NCV) and several types of familial amyloid neuropathy (with specific amino acid substitutions in transthyretin); autosomal recessive conditions such as HMSN-III (Déjérine-Sottas hypertrophic neuropathy of childhood) and Refsum's disease (defect of phytanic acid metabolism); and conditions produced by mutations on the X chromosome such as X-linked HMSN, Fabry trihexoside storage disease, and adrenomyeloneuropathy. The known biochemical abnormalities, chromosomal locations, clinical findings and genetic counseling of these disorders are reviewed.     

Linkage of autosomal dominant type I hereditary motor and sensory neuropathy to the Duffy locus on chromosome 1.

Data from English families confirms the probable linkage of the loci for autosomal dominant type I hereditary motor and sensory neuropathy (HMSN) and the Duffy blood group. The locus for autosomal dominant type I HMSN is in chromosome 1 near the centromere, about 15 centimorgans from the Duffy locus. The linkage between type I HMSN and the Duffy locus and the two recombinants found between Duffy and type II HMSN support the hypothesis that there are at least two genetic variants of autosomal dominant HMSN.     

Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.     

Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group.

Hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT 1) is an autosomal dominant disorder of the peripheral nervous system characterized by progressive weakness and atrophy of distal limb muscles. In the majority of HMSN I families, linkage studies localized the gene (CMT 1a) to the pericentromeric region of chromosome 17. We have detected with probe pVAW409R3 (D17S122) localized in 17p11.2 a duplication, co-segregating with the disease in 12 HMSN I families. In these families the duplication was present in all 128 patients but absent in the 84 unaffected and 44 married-in individuals (lod score of 58.44 at zero recombination). Further, on one HMSN I family the disease newly appeared simultaneously with a de novo duplication originating from an unequal crossing-over event at meiosis. Since different allelic combinations were found segregating with the duplication in different families linkage disequilibrium was not a significant factor. These findings led us to propose that the duplication in 17p11.2 itself is the disease causing mutation in all the HMSN I families analyzed.     

线粒体融合蛋白2基因新突变导致的遗传性运动感觉性神经病6型一家系

目的 报道1个遗传性运动感觉性神经病6型家系的临床表现、病理改变以及基因突变特点。方法 先证者男性,15岁。患者5岁出现双下肢无力,症状进行性加重,伴随出现双足跟腱挛缩;11岁开始出现慢性进行性视力下降;12岁出现双手肌肉萎缩,无肢体麻木。周围神经传导速度检查显示诱发电位未能引出或波幅显著下降,感觉神经较运动神经改变更明显。视诱发电位提示双眼P100潜伏期均延长,波幅正常。眼底照相提示视神经萎缩,视网膜电图正常。患者母亲7岁时开始出现走路费力,10岁出现视力下降。对先证者进行腓肠神经活体组织检查。对先证者及其母亲进行线粒体融合蛋白2( MFN2)基因测序,100名健康人作为正常对照。结果 腓肠神经病理改变主要为有髓神经纤维显著减少,电镜检查发现个别有髓神经纤维出现洋葱球样结构和再生簇结构,个别神经纤维的轴索内可见线粒体聚集和空泡化。先证者和母亲的MFN2基因第19号外显子存在c.2218T＞C杂合突变,导致MFN2第740位的色氨酸由精氨酸替代(W740R)。100名健康对照没有发现该突变。结论 MFN2基因c.2218T＞C突变导致了遗传性运动感觉性神经病6型,其视力下降多出现在脊神经损害之后,周围神经可以存在髓鞘损害。     

Revue de la littérature récente sur les neuropathies héréditaires

The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of “mitochondrial CMT” for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease.     

Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.     

Mutation analysis of the small heat shock protein 27 gene in chinese patients with Charcot-Marie-Tooth disease

BACKGROUND: Charcot-Marie-Tooth (CMT) disease, the most common hereditary peripheral neuropathy, is highly clinically and genetically heterogeneous, and mutations in at least 18 genes have been identified. Recently, mutations in small heat shock protein 27 (Hsp27) were reported to cause CMT disease type 2F and distal hereditary motor neuropathy. OBJECTIVE: To investigate the frequency and phenotypic features of an Hsp27 mutation in Chinese patients with CMT disease. DESIGN: DNA samples from 114 unrelated patients with CMT disease were screened for mutations in Hsp27 by polymerase chain reaction and direct sequencing. A cosegregated study was performed using the MbiI restriction endonuclease, and 50 healthy control subjects were analyzed. Haplotype analysis was performed using 5 short tandem repeat markers to analyze whether the families with the same mutation probably had a common ancestor. RESULTS: One missense mutation, C379T, was detected in 4 autosomal dominant families with CMT disease type 2, and haplotype analysis indicated that the 4 families probably had a common founder. The frequency of the Hsp27 mutation is 0.9% (1/111) in Chinese patients with CMT disease in our study, and the phenotypes were characterized by later onset (age, 35-60 years) and mild sensory impairments. Electrophysiological findings showed moderately to severely slowed nerve conduction velocities in lower limb nerves but normal or mildly reduced velocities in upper limb nerves. CONCLUSIONS: To our knowledge, this is the first report of an Hsp27 mutation in the People's Republic of China. The C379T mutation in Hsp27 also causes CMT disease type 2, except for distal hereditary motor neuropathy, and the phenotypes are distinct from the family with CMT disease type 2F described previously. A mutation of Hsp27 may be uncommon in Chinese patients with CMT disease.     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.     

Mitochondrial dysfunction affecting visual pathways

Mitochondrial dysfunction leads to cellular energetic impairment, which may affect the visual pathways, from the retina to retrochiasmal structures. The most common mitochondrial optic neuropathies include Leber's hereditary optic neuropathy and autosomal dominant optic atrophy, but the optic nerve can be affected in other syndromic conditions, such as Wolfram syndrome and Friedreich's ataxia. These disorders may result from mutations in either the mitochondrial DNA or in the nuclear genes encoding mitochondrial proteins. Despite the inconstant genotype-phenotype correlations, a clinical classification of mitochondrial disorders may be made on the basis of distinct neuro-ophthalmic presentations such as optic neuropathy, pigmentary retinopathy and retrochiasmal visual loss. Although no curative treatments are available at present, recent advances throw new light on the pathophysiology of mitochondrial disorders. Current research raises hopes for novel treatment of hereditary optic neuropathies, particularly through the use of new drugs and mitochondrial gene therapy.