Form Of Charcot-Marie-Tooth Research Articles

The influence of somatosensory and muscular deficits on postural stabilization: Insights from an instrumented analysis of subjects affected by different types of Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (CMT) disease is the most common hereditary neuromuscular disorder. CMT1 is primarily demyelinating, CMT2 is primarily axonal, and CMTX1 is characterized by both axonal and demyelinating abnormalities. We investigated the role of somatosensory and muscular deficits on quiet standing and postural stabilization in patients affected by different forms of CMT, comparing their performances with those of healthy subjects. Seventy-six CMT subjects (CMT1A, CMT2 and CMTX1) and 41 healthy controls were evaluated during a sit-to-stand transition and the subsequent quiet upright posture by means of a dynamometric platform. All CMT patients showed altered balance and postural stabilization compared to controls. Multivariate analysis showed that in CMT patients worsening of postural stabilization was related to vibration sense deficit and to dorsi-flexor's weakness, while quiet standing instability was related to the reduction of pinprick sensibility and to plantar-flexor's weakness. Our results show that specific sensory and muscular deficits play different roles in balance impairment of CMT patients, both during postural stabilization and in static posture. An accurate evaluation of residual sensory and muscular functions is therefore necessary to plan for the appropriate balance rehabilitation treatment for each patient, besides the CMT type.

A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.

Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.

Pain and small fiber function in charcot–marie–tooth disease type 1A

Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively. We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds. Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively. Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy.

Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can envision treatment options for these rare diseases in the near future.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can envision treatment options for these rare diseases in the near future.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can envision treatment options for these rare diseases in the near future.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy.

Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can envision treatment options for these rare diseases in the near future.

Neuropathologic Characterization ofINF2-Related Charcot-Marie-Tooth Disease: Evidence for a Schwann Cell Actinopathy

The association of Charcot-Marie-Tooth (CMT) disease with renal dysfunction is uncommon but has long been recognized in several families. Recently, mutations in the INF2 gene, which encodes inverted formin-2, were identified in patients with focal segmental glomerulosclerosis and a dominant intermediate form of CMT (CMTDIE, OMIM #614455). We describe the pathologic lesions of nerve biopsies from 6 patients with INF2-related CMTDIE. There were 4 females and 2 males; ages were from 12 to 47 years; durations between neuropathy onset and biopsy were from 2 to 37 years. Clinical phenotypes were similar to those seen in other forms of CMT disease, but there was always an associated proteinuria (and later renal failure). Motor median nerve conduction velocities were in the range of intermediate CMT disease. Pathologic lesions suggested chronic demyelination and remyelination associated with progressive axonal loss. By electron microscopy, we observed unusual whorl-like proliferations of flattened Schwann cell cytoplasm and anomalies of unmyelinating Schwann cell cytoplasm with supernumerary elongated extensions similar to those described in CMT4C. We also observed abnormal accumulation of β-actin in the cytoplasm of Schwann cells. Our results suggest that these lesions reflect a global disorder of the actin cytoskeleton in Schwann cells and that CMTDIE is the first peripheral nerve disorder associated with a Schwann cell actinopathy.

The MFN2 V705I Variant Is Not a Disease-Causing Mutation: A Segregation Analysis in a CMT2 Family.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders affecting both motor and sensory neurons in the peripheral nervous system. Mutations in the MFN2 gene cause an axonal form of CMT, CMT2A. The V705I variant in MFN2 has been previously reported as a disease-causing mutation in families with CMT2. We identified an affected index patient from an Australian multigenerational family with the V705I variant. Segregation analysis showed that the V705I variant did not segregate with the disease phenotype and was present in control individuals with an allele frequency of 4.4%. We, therefore, propose that the V705I variant is a polymorphism and not a disease-causing mutation as previously reported.

Clinical and neurophysiological investigation of a large family with dominant Charcot-Marie-Tooth type 2 disease with pyramidal signs

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy of motor and sensory impairment with distal predominance. Atrophy and weakness of lower limbs are the first signs of the disease. It can be classified, with the aid of electromyography and nerve conduction studies, as demyelinating (CMT1) or axonal (CMT2). Clinical and neurophysiological investigation of a large multigenerational family with CMT2 with autosomal dominant mode of transmission. Fifty individuals were evaluated and neurophysiological studies performed in 22 patients. Thirty individuals had clinical signs of motor-sensory neuropathy. Babinski sign was present in 14 individuals. Neurophysiological study showed motor-sensory axonal polyneuropathy. The clinical and neurophysiological characteristics of this family does not differ from those observed with other forms of CMT, except for the high prevalence of Babinski sign.

Charcot‐Marie‐Tooth disease

Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder affecting at least 1 in 2,500. Over the last two decades, there have been rapid advances in understanding the molecular basis for many forms of CMT with more than 30 causative genes now described. This has made obtaining an accurate genetic diagnosis possible but at times challenging for clinicians. This review aims to provide a simple, pragmatic approach to diagnosing CMT from a clinician's perspective.

Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to Unravel Their Pathogenesis

Charcot-Marie-Tooth (CMT) neuropathies are very heterogeneous disorders from both a clinical and genetic point of view. The CMT genes identified so far encode different proteins that are variably involved in regulating Schwann cells and/or axonal functions. However, the function of most of these proteins still remains to be elucidated. To characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of CMT neuropathy. A cohort of 131 unrelated patients were screened for mutations in 12 genes responsible for CMT neuropathies. Demyelinating, axonal, and intermediate forms of CMT neuropathy were initially distinguished as usual on the basis of electrophysiological criteria and clinical evaluation. A sural nerve biopsy was also performed for selected cases. Accordingly, patients underwent first-level analysis of the genes most frequently mutated in each clinical form of CMT neuropathy. Although our cohort had a particularly high percentage of cases of rare axonal and intermediate CMT neuropathies, we found mutations in 40% of patients. Among identified changes, 7 represented new mutations occurring in the MPZ, GJB1, EGR2, MFN2, NEFL, and HSBP1/HSP27 genes. Histopathological analysis performed in selected cases revealed morphological features, which correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism. Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.

Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot–Marie–Tooth 1X

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been previously shown to be an important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A and 1B. In mice deficient in the gap junction protein connexin 32 (Cx32def), an established model for the X-chromosome-linked dominant form of CMT (CMT1X), we investigated the role of the chemokine in macrophage immigration and neural damage by crossbreeding the Cx32def mice with MCP-1 knockout mutants. In Cx32def mutants typically expressing increased levels of MCP-1, macrophage numbers were strongly elevated, caused by an MCP-1-mediated influx of haematogenous macrophages. Curiously, the complete genetic deletion of MCP-1 did not cause reduced macrophage numbers in the nerves due to compensatory proliferation of resident macrophages. In contrast, and as already seen in other CMT models, heterozygous deletion of MCP-1 led to reduced numbers of phagocytosing macrophages and an alleviation of demyelination. Whereas alleviated demyelination was transient, axonal damage was persistently improved and even robust axonal sprouting was detectable at 12 months. Other axon-related features were alleviated electrophysiological parameters, reduced muscle denervation and atrophy, and increased muscle strength. Similar to models for CMT1A and CMT1B, we identified MEK-ERK signalling as mediating MCP-1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the inhibitor CI-1040 caused reduced MCP-1 expression, attenuation of macrophage increase and amelioration of myelin- and axon-related alterations. Thus, attenuation of MCP-1 upregulation by inhibiting ERK phosphorylation might be a promising approach to treat CMT1X and other so far untreatable inherited peripheral neuropathies in humans.

P2X7-mediated Increased Intracellular Calcium Causes Functional Derangement in Schwann Cells from Rats with CMT1A Neuropathy

Charcot-Marie-Tooth (CMT) is the most frequent inherited neuromuscular disorder, affecting 1 person in 2500. CMT1A, the most common form of CMT, is usually caused by a duplication of chromosome 17p11.2, containing the PMP22 (peripheral myelin protein-22) gene; overexpression of PMP22 in Schwann cells (SC) is believed to cause demyelination, although the underlying pathogenetic mechanisms remain unclear. Here we report an abnormally high basal concentration of intracellular calcium ([Ca(2+)](i)) in SC from CMT1A rats. By the use of specific pharmacological inhibitors and through down-regulation of expression by small interfering RNA, we demonstrate that the high [Ca(2+)](i) is caused by a PMP22-related overexpression of the P2X7 purinoceptor/channel leading to influx of extracellular Ca(2+) into CMT1A SC. Correction of the altered [Ca(2+)](i) in CMT1A SC by small interfering RNA or with pharmacological inhibitors of P2X7 restores functional parameters of SC (migration and release of ciliary neurotrophic factor), which are typically defective in CMT1A SC. More significantly, stable down-regulation of the expression of P2X7 restores myelination in co-cultures of CMT1A SC with dorsal root ganglion sensory neurons. These results establish a pathogenetic link between high [Ca(2+)](i) and impaired SC function in CMT1A and identify overexpression of P2X7 as the molecular mechanism underlying both abnormalities. The development of P2X7 inhibitors is expected to provide a new therapeutic strategy for treatment of CMT1A neuropathy.

Neuropathies périphériques héréditaires

Currently more than 30 genes are known to be responsible for genetically determined neuropathies. Charcot-Marie-Tooth (CMT) disease is the most frequent of these hereditary neuropathies, with a prevalence of 4.7 to 36 per 100 000. In its demyelinating forms (CMT1), approximately 70% of cases are associated with a duplication of the PMP22gene. In its axonal forms (CMT2), 10-20% of the cases may be associated with a mutation of the MFN2gene. For North African patients with recessive transmission, a mutation of the LMNA gene must be sought. It is essential to stress the great variability of the phenotype--clinical, electrophysiological, and histologic--between and within families. A detailed analysis of these criteria, together with consideration of ethnic origin, may guide the search for the causal mutation. Whether the case involves certainly hereditary transmission or a sporadic form, it is desirable to be able to examine the maximum number of the patient's kin, both clinically and electrophysiologically. The forms with recessive transmission usually have a very early onset and are more serious than the dominant forms. The early- and very early-onset forms of CMT are increasingly better distinguished: congenital hypomyelination neuropathy (mutations of PMP22, MPZ or EGR2), or more axonal forms, including SMARD1 (Spinal muscle atrophy with respiratory distress; mutations of IGHMBP2) and EOHMSN (Early-onset hereditary motor and sensory neuropathy; mutations of MFN2). The prevention of cutaneous (ulcerations), bone, and amputation complications is very important in patients with hereditary sensory and autonomic neuropathies, because of the severity of the sensory disorders.

La maladie de Charcot-Marie-Tooth

Charcot-Marie-Tooth (CMT) disease, also known as peroneal muscular atrophy or hereditary motor and sensory neuropathy, is among the most frequent hereditary disorders of the nervous system. The relatively homogeneous clinical phenotype involves mainly progressive weakness and wasting of distal muscles; it starts and predominates in the peroneal muscles. Electrophysiological and pathology data distinguish two principal forms of CMT: demyelinating and axonal. More than 20 distinct genetic subtypes have been identified to date and other new loci and genes remain to be discovered, thus demonstrating wide genetic heterogeneity and a number of different pathophysiological mechanisms. The classification of these different forms is based on both the mode of inheritance--autosomal dominant, recessive or X-linked--and the neuropathy type--demyelinating or axonal or "intermediate". The principal dominant forms are CMT1A, due to a duplication or point mutation in the PMP22 gene, and CMTX, due to mutations in the connexin 32 gene. Autosomal recessive forms are more frequent in North Africa. The most common involve mutations of GDAP1 or lamin A/C and generally lead to more severe phenotypes than the dominant forms. The great genetic heterogeneity necessitates a strategy for genetic diagnosis. It is based in part on the classification of the different genetic forms and in part on the phenotypic particularities and the frequency of the responsible genes in the population under study.

Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2

Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are associated with the autosomal recessive disease subtypes CMT4B1 or CMT4B2. Both forms of CMT share similar features including a demyelinating neuropathy associated with reduced nerve conduction velocity (NCV) and focally folded myelin. Consistent with a common disease mechanism, the homodimeric MTMR2 acts as a phosphoinositide D3-phosphatase with phosphatidylinositol (PtdIns) 3-phosphate and PtdIns 3,5-bisphosphate as substrates while MTMR13/SBF2 is catalytically inactive but can form a tetrameric complex with MTMR2, resulting in a strong increase of the enzymatic activity of complexed MTMR2. To prove that MTMR13/SBF2 is the disease-causing gene in CMT4B2 and to provide a suitable animal model, we have generated Mtmr13/Sbf2-deficient mice. These animals reproduced myelin outfoldings and infoldings in motor and sensory peripheral nerves as the pathological hallmarks of CMT4B2, concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. Prolonged F-wave latency indicated a mild NCV impairment. Loss of Mtmr13/Sbf2 did not affect the levels of its binding partner Mtmr2 and the Mtmr2-binding Dlg1/Sap97 in peripheral nerves. Mice deficient in Mtmr13/Sbf2 together with known Mtmr2-deficient animals will be of major value to unravel the disease mechanism in CMT4B and to elucidate the critical functions of protein complexes that are involved in phosphoinositide-controlled processes in peripheral nerves.

Neuropathy as a presenting feature in fragile X‐associated tremor/ataxia syndrome

Peripheral neuropathy is common among patients with fragile X-associated tremor ataxia syndrome (FXTAS). Four patients with FXTAS are described with neuropathy as the presenting feature, two having received a prior diagnosis of Charcot-Marie-Tooth (CMT) disease. A fifth is described with neuropathy as the only clinical feature. A functional connection between FXTAS and neuropathy has been suggested by the presence of lamin A/C in the intranuclear, neuronal and astrocytic inclusions of FXTAS, since mutations in lamin A/C are known to give rise to an axonal form of CMT.

Charcot–Marie–Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect

Charcot-Marie-Tooth (CMT) diseases are the most common heritable peripheral neuropathy. At least 10 different mutant alleles of GARS (the gene for glycyl-tRNA synthetase) have been reported to cause a dominant axonal form of CMT (type 2D). A unifying connection between these mutations and CMT has been unclear. Here, mapping mutations onto the recently determined crystal structure of human GlyRS showed them within a band encompassing both sides of the dimer interface, with two CMT-causing mutations being at sites that are complementary partners of a "kissing" contact across the dimer interface. The CMT phenotype is shown here to not correlate with aminoacylation activity. However, most mutations affect dimer formation (to enhance or weaken). Seven CMT-causing variants and the wild-type protein were expressed in transfected neuroblastoma cells that sprout primitive neurites. Wild-type GlyRS distributed into the nascent neurites and was associated with normal neurite sprouting. In contrast, all mutant proteins were distribution-defective. Thus, CMT-causing mutations of GlyRS share a common defect in localization. This defect may be connected in some way to a change in the surfaces at the dimer interface.

Mutations in FGD4 Encoding the Rho GDP/GTP Exchange Factor FRABIN Cause Autosomal Recessive Charcot-Marie-Tooth Type 4H

Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.