Review

Nature Clinical Practice Neurology (2006) 2, 45-53
doi:10.1038/ncpneuro0071  
Received 21 June 2005 | Accepted 11 October 2005

Mechanisms of Disease: a molecular genetic update on hereditary axonal neuropathies

Stephan Züchner* and Jeffery M Vance  About the authors

Correspondence *Center for Human Genetics, Duke University Medical Center, 595 LaSalle Street, Box 3445 DUMC, Durham, NC 27710, USA

Email szuchner@chg.duhs.duke.edu

Summary

Hereditary axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under the name of Charcot–Marie–Tooth (CMT) disease type 2 (CMT2). Historically, two classes of CMT have been differentiated: demyelinating forms of CMT (CMT1), in which nerve conduction velocities are decreased, and the axonal CMT2 forms, in which nerve conduction velocities are preserved. Recently, a number of genes that are defective in patients with the main forms of CMT2 have been identified. The molecular dissection of cellular functions of the related gene products has only just begun, and detailed pathophysiological models are still lacking. The known CMT2-related genes represent key players in these pathways, however, and are likely to provide powerful tools for identifying targets for future therapeutic intervention.

Review criteria

PubMed was searched for articles published up to June 19th 2005, including electronic release publications. Search terms included "Charcot*", "CMT", "CMT2" and "motor neuropathy". The abstracts of retrieved citations were reviewed and prioritized by relative content. Full articles were obtained and references were checked for additional material when appropriate. We also looked up all diseases in OMIM® to identify relevant additional citations.

Keywords:

axonal neuropathy, Charcot–Marie–Tooth disease, HMSN II, motor neuropathy

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Introduction

Traditionally, the Charcot–Marie–Tooth (CMT) neuropathies—also known as hereditary motor and sensory neuropathies (HMSNs)—fall into two main groups: CMT disease type 1 (CMT1), in which nerve conduction velocities (NCVs) are reduced, and CMT disease type 2 (CMT2), in which NCVs are normal but conduction amplitudes are decreased. The CMT clinical phenotype is one of the most common inherited disorders in humans, with an estimated prevalence of one case per 2,500 individuals.1 The classic clinical hallmarks of CMT are distal weakness of the lower (and, later in the disease course, the upper) limbs, sensory loss, decreased reflexes and foot deformities. Less-frequent symptoms include cranial nerve involvement, scoliosis, vocal cord paresis and glaucoma. In CMT2, the unifying pathological signature of the peripheral nerves is chronic axonal degeneration and regeneration, leading to a steady loss of available nerve fibers.

Beyond the clinical and neuropathological classification, further exploration of the diversification into the various CMT subtypes is possible primarily by genetic analysis. All CMT forms are characterized as Mendelian traits and usually show complete PENETRANCE, although the severity and extent of disease can vary even between affected members of the same family. Autosomal-dominant, autosomal-recessive and X-linked forms have been described. During the past 15 years, more than 30 genes have been shown to be defective in cases of CMT; however, it is only relatively recently that mutations in 10 genes have been described that underlie axonal neuropathies.2 Despite this spectacular development, many CMT genes still await discovery, which will possibly inflate the number of CMT genes to beyond 50 in the near future. Although this situation provides serious challenges for the efficient clinical application of molecular diagnosis in CMT patients, the wealth of information has presented valuable opportunities to decipher the main molecular pathways that underlie CMT2 (Figure 1).

Figure 1 Schematic of a peripheral nerve axon, illustrating the molecular pathways involved in Charcot–Marie–Tooth disease type 2.
Figure 1 : Schematic of a peripheral nerve axon, illustrating the molecular pathways involved in Charcot|[ndash]|Marie|[ndash]|Tooth disease type 2. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Most gene products identified to date are associated with mitochondria and endosomal trafficking. DNM2, dynamin 2; GARS, glycyl-tRNA synthetase; IM, inner mitochondrial membrane; GDAP1, ganglioside-induced differentiation-associated protein-1; HSP, heat shock protein; IMS, intermembrane space; MFN2, mitofusin 2; NEFL, neurofilament light chain; OM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation complex; tRNA, transfer RNA.

Full figure and legend (92K)Figures & Tables indexDownload PowerPoint slide (180K)

As information about CMT2 has increased, it has become evident that the distinction between CMT1 and CMT2 is less clear cut than was originally believed. Families previously classified as CMT1 or CMT2 on the basis of NCVs, and even pathology, have been found to carry the same mutated gene and, in some cases, the same mutation. Clearly, new approaches are needed to allow those less familiar with the disease to navigate through the different groups. The currently accepted classification scheme is shown in Table 1. Interestingly, several of these defective gene products share similarities in domain, cellular localization or biological function (Table 1). The emerging pathways for axonal neuropathies will facilitate focused functional and genetic research, and should ultimately enable the identification of targets for therapeutic intervention.

Table 1 Known axonal Charcot–Marie–Tooth disease genes and their products according to the currently accepted classification.
Table 1 - Known axonal Charcot|[ndash]|Marie|[ndash]|Tooth disease genes and their products according to the currently accepted classification.
Full tableFigures & Tables indexDownload PowerPoint slide (250K)

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Emerging pathways for axonopathies

Neuronal tissue is characterized by a high degree of specialization and limited regenerative capacity. This is reflected in the number of mutated genes that are expressed ubiquitously throughout the body, but only present with neurological phenotypes. The unique requirements and emphasis of certain pathways in neuronal tissue seem to provide much of the specificity of inherited neurological disorders, and neuropathies are no exception. Of particular note are the unique areas of axonal transport, the high energy demand of the nerve, and the rapid and highly specific needs of neuronal transmission, particularly in membrane components and their various functions. Therefore, it is not surprising that the axonal genes identified to date that are important in hereditary neuropathies might have important functions relating to these specialized needs (Figure 1).

Mitochondrial proteins

Mitochondrial dysfunction is known to be involved in various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and neuromuscular diseases. Mitochondria have numerous vital functions, ranging from energy supply to the initiation of APOPTOSIS. Several CMT-associated genes have recently been identified that reside in the nuclear genome but encode proteins that function in mitochondria. Therefore, some of the CMT subtypes could be viewed as mitochondrial diseases. It is unclear why these mutations manifest phenotypes primarily in the peripheral nerves, but it seems probable that this characteristic is related to their extraordinary length, and their energy and transport requirements.

Mutations in the mitofusin 2 (MFN2) gene have been shown to cause CMT disease type 2A (CMT2A), which was the first hereditary axonal neuropathy to be linked to a chromosomal locus.3 Just 1 year after we initially reported the MFN2 mutations,4 it was established that mutations in MFN2 account for approx20% of CMT2 cases,5 making this the most prevalent axonal form of CMT, and second in frequency only to peripheral myelin protein 22 (PMP22) gene duplications as the main cause of the CMT phenotype. Clinically, most cases of CMT2 are more consistent with the classic motor CMT phenotype than with the sensory CMT phenotype, and might in fact be the only true 'axonal' NCV phenotype, as all known MFN2-related cases have NCVs greater than 38 m/s, the traditional cutoff originally proposed by Harding and Dyck.6

Diagnosis of CMT2 can be difficult, however, as many authors have noted that this type of CMT appears to have greater variability in its clinical presentation than CMT1. Indeed, Lawson et al. highlighted that, in their CMT2A families, a quarter of individuals with an MFN2 mutation presented with features mild enough not to warrant diagnosis of CMT2 on clinical examination or electrophysiological findings alone.5 This suggests that the presence of any signs of CMT in CMT2 patients, even in the presence of normal findings such as retained reflexes, should raise an index of suspicion for molecular testing.

Recently an Australian CMT2 family with a new MFN2 mutation presented with additional clinical features of spasticity; this disorder was described previously as HMSN V.7 We have also reported a case with a de novo truncation mutation in MFN2, resulting in CMT2 and optic atrophy, also known as HMSN VI.4 Lawson et al. reported that 59% of affected individuals in their largest MFN2 family had sensorineuronal hearing loss.5 As the spectrum of patients with MFN2 mutations increases, it is therefore expected that the number of variations in the expression of the MFN2 mutant phenotype will also continue to expand.

The MFN2 protein is a large DYNAMIN-like GTPase that spans the outer mitochondrial membrane.8 Several studies revealed that MFN2 is an important factor in the fusion of mitochondria, specifically the outer mitochondrial membrane.9 Mitochondria constitute a highly dynamic network that constantly undergoes fusion and fission events.10 The ability of the mitochondria to undergo these events allows mixing of mitochondrial DNA and respiratory complementation, and is central to the replication of these organelles. Mitochondrial membrane fusion and fission are particularly complex processes, as mitochondria have two membranes that must be coordinated during the process.11 Chan and colleagues recently showed that oligomerization of mitofusins allows tethering of mitochondrial membranes to each other.12MFN2 mutations and mitofusin deficiency have been shown to lead to dispersal of mitochondria and reduced mitochondrial mobility.13 This reduced mobility could lead to insufficient axonal transport of mitochondria, presumably in the extended axons of peripheral nerves. Recently, Pich et al. also linked MFN2 function with the regulation of differential expression of oxidative phosphorylation complexes.14 It is therefore possible that different MFN2 mutations could affect different aspects of MFN2 protein function.

Defects in two small heat shock proteins (HSPs), HSP22 and HSP27, have been shown to underlie different forms of axonal CMT and distal hereditary motor neuropathy;15, 16, 17 however, these defects have been reported in only a few families. HSPs operate as MOLECULAR CHAPERONES, preventing misfolding of proteins, especially in oxidative environments such as mitochondria.18 The HSP genes are characterized by a conserved alpha-crystallin domain, and a wide range of endogenous or exogenous factors can induce their expression.19 Small HSPs such as HSP22 and HSP27 have been shown to protect against H2O2-mediated cell death.20 Neuronal cell lines transfected with mutant forms of HSP22 or HSP27 showed reduced viability, and the mutant HSP22 protein promoted the formation of intracellular aggregates.15, 21 HSP27 has been shown to be directly responsible for a stable mitochondrial membrane potential through an increase in and maintenance of the reduced form of the redox modulator glutathione.22

In 2002, Baxter et al. and Cuesta et al. demonstrated that mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene cause autosomal recessive CMT neuropathy type 4A.23, 24 This finding was fascinating, as the two reports differed markedly with respect to the phenotypes of their families. Cuesta et al. described families who had an axonal phenotype24 (Online Mendelian Inheritance in Man [OMIM®, Johns Hopkins University, Baltimore, MD] 607706), whereas Baxter's families showed a demyelinating phenotype25 (OMIM® 214400). This was one of the first examples of a situation in which unique mutations in the same gene cause different NCVs, and, consequently, two apparently distinct classes of neuropathies. Subsequent reports have confirmed the duality of GDAP1 phenotypes, even for the same mutation site.26 Senderek et al. have also reported on two families with intermediate NCV and signs of both axonal and demyelinating pathology in sural nerve biopsies.27 Current evidence indicates that GDAP1 represents an evolutionarily unique class of glutathione transferase,28 and Pedrola et al. have shown that this protein localizes within mitochondria.29

The axonal form of GDAP1-related CMT has been associated with vocal cord and diaphragmatic paralysis, often not appearing until mid-life, but this does not seem to be a feature of the demyelinating forms. Families with GDAP1 mutations and an axonal phenotype therefore need to be considered for possible respiratory involvement,30 even if they are clinically asymptomatic at initial presentation. Although GDAP1-related CMT seems to be one of the most common autosomal recessive forms of CMT, Claramunt et al. recently reported on two families from Spain with autosomal dominant inheritance, with the unique missense mutation R120W (tryptophan [W] substituted for arginine [R] at position 120).31 These families presented with a milder form of symptoms than did the families in the study with autosomal recessive GDAP1 mutations. This finding indicates that GDAP1 should be considered in the screening of autosomal dominant families who have had negative results for the more common genes.

Endosomal trafficking

It is obvious that the trafficking of vesicles, mitochondria and other membrane-encased organelles along MICROTUBULES in the axons of peripheral nerves is crucial for the functioning of neurons. It is to be expected that impairment of trafficking would affect the distal-most segments of axons first, and this is indeed the case in most axonal neuropathies, perhaps explaining why defects in ubiquitously expressed proteins lead exclusively to neuronal damage. Motor neuron death, on the other hand, could be the consequence of disturbed retrograde axonal transport, possibly owing to depletion of the neurotrophic factors that need to be supplied in a constant, target-derived manner to protect against apoptosis signals.32

Intracellular transport in extended axons depends on an intact cytoskeleton, so it was not surprising that neurofilament light chain (NEFL) was the first gene to be associated with the hereditary axonal neuropathies of the peripheral nervous system.33 Mutations in this gene, however, have remained an uncommon cause of the phenotype, with only 11 unique mutations currently reported.2 As with the GDAP1 gene defects, both slow and normal NCVs have been reported in patients, and many, but not all, of the cases have their onset in childhood.34, 35 Neurofilaments are synthesized in the PERIKARYON and are then transported to the axons, where they assemble into filamentous networks. Neurofilaments comprise the most abundant intermediate filament in neurons. In a cell culture system, Pérez-Ollé et al. demonstrated that mutant NEFL had various negative effects on axonal transport in both directions, and specifically on the transport of mitochondria.36

Many intracellular components move along microtubules in a bidirectional manner, mediated by PLUS-END-directed kinesin motor proteins (KIFs) and MINUS-END-directed dynein–dynactin motors. A mutation in the KIF1B gene has previously been reported in a single Japanese family with CMT2A, and mice that are heterozygous for a Kif1b knockout show a neuropathy-like phenotype.37 It has recently been questioned, however, whether KIF1B is associated with the CMT phenotype in humans, as no further instances have been identified where a mutation in this gene has led to the disease, and in all other families with CMT2A (including the other Japanese family reported in the report on the KIF1B mutation37) the phenotype was attributed to mutations in MFN2, which lies very near to KIF1B on chromosome 1p36. It has become clear that KIF1B should not be considered as a significant or even viable candidate for the etiology of CMT2 in future studies, or in unknown CMT2 patients, until confirmation of the KIFIB mutation is found.

RAB7 is a member of the RAB family of RAS-associated GTP-binding proteins, and defects in the gene that encodes this protein underlie CMT disease type 2B (CMT2B).38 CMT2B is clinically characterized by prominent sensory loss, leading to severe ulcerations of the lower legs and feet, which often require amputation, and has been argued to actually fall within the hereditary sensory and autonomic neuropathies.39, 40 Only a few families with this condition have been reported, so it seems to be rare. RAB proteins are important regulators of vesicular transport and are located in specific endosomal compartments.41 RAB7 has been localized to late endosomes, and has been shown to be important in the LATE ENDOCYTIC PATHWAY.42, 43

Recently, we have shown that defects in the dynamin 2 (DNM2) gene underlie an intermediate subtype of CMT, dominant intermediate CMT type 2B (DI-CMTB), that is characterized by both axonal and demyelinating NCV.44 Currently, only three families with this type of CMT have been described. Two of these families, who have the same mutation site, also demonstrated reduced white-blood-cell counts, although this reduction was clinically insignificant. The large GTPase DNM2, a mechanochemical protein, is ubiquitously expressed, and a large body of literature shows its role in modulating several important cellular processes, including receptor-mediated endocytosis, membrane trafficking from the late endosomes and Golgi complex,45 actin assembly,46 and CENTROSOME COHESION.47 In neuronal cell lines, we showed that mutant DNM2 is dislocated from membranes, and the microtubule network is disorganized in cells that express this form of the protein.44

RNA processing

One of the more-unexpected genes to have been associated with axonal CMT is glycyl-tRNA synthetase (GARS), mutations in which cause CMT disease type 2D (CMT2D) and distal spinal muscular atrophy type V/distal hereditary motor neuropathy type V.48 The GARS protein charges transfer RNAs (tRNAs) with glycine, and therefore has an essential role in all cells. For proper protein translation in eukaryotic cells, tRNA molecules must be charged in both the cytoplasm and mitochondria. GARS is thought to aminoacylate tRNAGly molecules in both locations.49 The GARS gene is ubiquitously expressed, and it was surprising to find that such a fundamental RNA process would have an important role in CMT. The underlying mechanism leading to disease is currently unclear.

Families with mutations in the GARS gene illustrate perfectly the difficulties of categorizing CMT disorders. CMT2D and distal spinal muscular atrophy type V are very similar in clinical appearance, except for the presence of sensory symptoms and signs in patients with CMT2D. Interestingly, the isolated presence of both phenotypes was observed in different individuals of the same family.48 One associated symptom, which is not 'classic' for CMT, is the occurrence of hand weakness before foot weakness, which occurred with high frequency in the five known CMT2D families.

Other genes

Given the clinical and neurophysiological overlaps discussed above, it is not surprising that a number of genes that are primarily associated with demyelinating CMT1 disease have also been implicated in axonal neuropathies. Myelin protein zero (MPZ or CMT1B) and gap junction protein beta 1 or connexin 32 (GJB1 or CMTX1) are both expressed in Schwann cells, but in some cases the axonal degeneration precedes the demyelinating and remyelinating process that usually leads to a decrease in NCV.50, 51 Of particular interest is the T124M mutation (methionine [M] substituted for threonine [T] at position 124) in MPZ. This specific variation is one of the few in CMT with clear genotype–phenotype correlation. Deafness and autonomic nervous system abnormalities—usually manifested via pupil changes—are found to be highly associated with this mutation, as are normal NCVs. The molecular reasons for these varying phenotypes and the highly specific T124M phenotypes are not fully understood. A mutation in lipopolysaccharide-induced TNF factor (LITAF/SIMPLE or CMT1C) has been reported in one case with axonal neuropathy.52, 53

Mutations in the lamin A/C (LMNA) gene cause a form of autosomal recessive axonal neuropathy.54, 55 Lamins constitute a class of intermediate filaments that are structural protein components of the inner nuclear membrane, determining the shape and size of the nucleus.56 Ultrastructural exploration of sciatic nerves of LMNA null mice revealed a profound reduction in axon density, enlargement of axons, and presence of nonmyelinated axons.54 The mechanism that leads to axonal neuropathy as a consequence of LMNA mutations is not well understood. It is interesting to note that specific mutations in LMNA cause a number of unique phenotypes, including Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, lipodystrophy disorders and Hutchinson–Gilford progeria syndrome.57

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Discussion

Until recently, the majority of known CMT-related genes have been associated with the CMT1 phenotype, perhaps in part because the slow NCVs of CMT1-affected individuals provide a clear diagnosis for investigators. This allows the gene to be easily tracked in families, so that recombinations defining the candidate region can be clearly determined. In CMT2, normal NCV makes the diagnosis entirely clinical for most family studies, thereby increasing diagnostic error and reducing the ability to narrow down the DNA region that contains the disease gene. With the completion of the Human Genome Project, however, the inaccuracy of positional cloning is no longer a serious barrier in CMT2, and we have recently seen an explosion in the identification of fascinating genes that contribute to this form of CMT. Although axonal CMT still appears to be less common than CMT1, it seems highly likely that we will find that CMT2 accounts for more CMT cases than the current estimate of one-third. Indeed, most 'idiopathic' neuropathies that present to the average neurology clinic are primarily axonal in nature.

Harding and others58 have predicted that CMT2 will turn out to have greater genetic heterogeneity than CMT1, and current findings support this prediction. Although useful for providing windows of opportunity to study the biology of axonal neuropathies, this heterogeneity presents a rising degree of difficulty for neurologists deciding which molecular test to request for their patients. Despite considerable phenotypic overlap, however, some specific phenotypes that are associated with specific CMT2 neuropathies are beginning to emerge. CMT2A (MFN2 mutation) seems to represent the classic axonal CMT form—motor symptoms are more prominent than sensory symptoms), and the 'classic' axonal NCV is observed. CMT2B is associated with severe sensory loss (as the leading symptom of patient complaints), leading to foot ulceration and mutilation. CMT2D patients may show predominant initial distal upper-extremity involvement (before the traditional foot weakness), and CMT disease type 2E (CMT2E) patients often show NCVs in the intermediate range. Patients presenting with axonal neuropathy and pupillary abnormalities should be considered for MPZ mutations, specifically T124M. It seems likely that as more families are examined for these known genes, the clinical spectrum of these genes will increase.

On the basis of mutation frequency alone, axonal cases that have not been further characterized should first be tested for mutations in MFN2 (approximately 20% of CMT2 cases), followed by NEFL (2% of cases). Mutations in all other genes seem to be much rarer. For CMT cases in general, mutations in MFN2 now represent the second-most-common known cause of CMT, after PMP22 mutations in CMT1A individuals.

The main underlying pathways that we have identified in this review relate to mitochondrial function, endosomal trafficking and RNA processing. Some of the causative proteins have been the subject of many molecular biology studies, but not necessarily in relation to the nervous system. Other genes have only recently been defined. The results of future studies promise to be highly relevant to the whole field of neurodegenerative diseases, and also to the common non-hereditary axonal neuropathies. As the identification of genes continues, it seems likely that the added knowledge will continue to substantiate the idea that significant genetic–phenotypic overlap exists between traditionally separate disease entities and classifications. The current classification schemes are not designed to handle this overlap, although a new classification that would allow the needed flexibility was recently proposed.59  Table 1 reflects this confusion, as many types currently designated by OMIM® are only phenotypic variants or single reports of known gene defects.

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Conclusion

Currently, only supportive therapies are available for CMT2, and before targeted therapies can be developed for axonal neuropathies we will require further insights into key questions. For example, why do ubiquitously expressed genes exclusively cause neurological and motor neuron diseases? Is this because of the highly specialized needs of axonal transport in longer axons? Is the high requirement of energy in the nervous system reflected in the preponderance of mitochondria-related defects, leading to specific neuronal involvement? The rapid growth in our understanding of the mutations that cause inherited axonal neuropathies will provide a window of opportunity to answer these essential questions.

Key points

  • Traditionally, the Charcot–Marie–Tooth (CMT) neuropathies fall into two main groups: demyelinating forms (CMT1), in which nerve conduction velocities are reduced, and axonal forms (CMT2), in which nerve conduction velocities are preserved
  • Until recently, most of the known CMT-related genes were associated with the CMT1 phenotype, but several genes have now been identified that are defective in patients with CMT2
  • The CMT2-associated genes encode proteins that are involved in vital cellular processes, including mitochondrial function, endosomal trafficking and RNA processing
  • Despite considerable phenotypic overlap, symptoms that are associated with specific CMT2 neuropathies are beginning to emerge; for example, CMT2B is characterized by severe sensory loss, whereas motor symptoms are more prominent in CMT2A

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Competing interests

The authors have licensed the testing of the MFN2 gene in CMT2 to Athena Neuroscience.

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Subject areas under which this article appears: Peripheral neuropathies | Genetics