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PubMed2004

A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease.

Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched "claw foot" appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T-->A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; theta =0), and it very likely accounts for both CVT and CMT in heterozygotes.

Charcot-Marie-Tooth Disease↗
PubMed1985

Charcot-Marie-Tooth disease: study of a large kinship with an intermediate form.

A clinical, genetic, electrophysiological and ultrastructural study of a large kinship with peroneal muscular atrophy is reported. There was a noteworthy homogeneity in the phenotype as well as in the electrophysiological characteristics encountered in 15 affected members aged between 7 and 72 years. The symptoms appeared first in the second decade of life and stabilized by the fourth decade. There was no evidence of linkage of the neuropathy gene to the Duffy blood group locus on chromosome 1. The electrophysiological data in this family as well as the ultrastructural findings confirm that there is heterogeneity in hereditary motor and sensory neuropathy type I, and support the concept of an intermediate form of Charcot-Marie-Tooth disease.

Adolescent↗
PubMed1991

Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome 17p11.2.

Charcot-Marie-Tooth (CMT) disease type 1a has been previously localized to chromosome 17 using the markers D17S58 and D17S71. In that report we were unable to provide unequivocal localization of the CMT1A gene on either the proximal p or the q arm. Therefore, data from one additional CMT1A family and typing of other probes spanning the pericentromeric region of chromosome 17 (D17S73, D17S58, D17S122, D17S125, D17S124) were analyzed. Multipoint analysis demonstrates convincing evidence (log likelihood difference greater than 5) that the CMT1A gene lies within 17p11.2 and most likely between the flanking markers D17S122 and D17S124.

Charcot-Marie-Tooth Disease↗
PubMed2001

Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease.

Myotubularin is the archetype of a family of highly conserved protein-tyrosine phosphatase-like enzymes. The myotubularin gene, MTM1, is mutated in the genetic disorder, X-linked myotubular myopathy. We and others have previously shown that myotubularin utilizes the lipid second messenger, phosphatidylinositol 3-phosphate (PI(3)P), as a physiologic substrate. We demonstrate here that the myotubularin-related protein MTMR2, which is mutated in the neurodegenerative disorder, type 4B Charcot-Marie-Tooth disease, is also highly specific for PI(3)P as a substrate. Furthermore, the MTM-related phosphatases MTMR1, MTMR3, and MTMR6 also dephosphorylate PI(3)P, suggesting that activity toward this substrate is common to all myotubularin family enzymes. A direct comparison of the lipid phosphatase activities of recombinant myotubularin and MTMR2 demonstrates that their enzymatic properties are indistinguishable, indicating that the lack of functional redundancy between these proteins is likely to be due to factors other than the utilization of different physiologic substrates. To this end, we have analyzed myotubularin and MTMR2 transcripts during induced differentiation of cultured murine C2C12 myoblasts and find that their expression is divergently regulated. In addition, myotubularin and MTMR2 enhanced green fluorescent protein fusion proteins exhibit overlapping but distinct patterns of subcellular localization. Finally, we provide evidence that myotubularin, but not MTMR2, can modulate the levels of endosomal PI(3)P. From these data, we conclude that the developmental expression and subcellular localization of myotubularin and MTMR2 are differentially regulated, resulting in their utilization of specific cellular pools of PI(3)P.

Animals↗
PubMed2000

Characterization of gait parameters in patients with Charcot-Marie-Tooth disease.

The gait of five patients with Charcot-Marie-Tooth(CMT) disease was analyzed using light-emitting diodes and a force plate. The flexion-extension motions of the hips, knees, and ankles, as well as their moments (vector sums of forces acting at the joints) in the flexion-extension and abduction-adduction planes, were quantified. The gait of the CMT patients showed abnormalities consistent with both distal weakness (ankle dorsi- and plantar-flexors) and weakness of the hip abductor muscles. The latter weakness appeared to produce asymmetric hip moments and truncal instability in the mediolateral plane during ambulation. However, the extent to which the gait was abnormal appeared not to be exclusively related to the severity of the sensorimotor conduction deficits in the peripheral nerves. In the four patients for whom nerve conduction velocity studies were available, decrease in the lower-extremity distal conduction velocities and evoked motor amplitude potentials did not correlate with the severity and extent of the gait abnormalities.

Biomechanical Phenomena↗
PubMed2000

Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease.

The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells. Individuals carrying mutations in the gene encoding connexin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells, develop a peripheral neuropathy - the X-linked form of Charcot-Marie-Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identified. Some mutations will lead to complete loss of function with no possibility of expression of functional channels. Some mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 or to interference with trafficking of other proteins. On the other hand, many mutant forms of Cx32 can form functional channels. Some functional mutants have conductance voltage relationships that are disrupted to a degree which would lead to a substantial reduction in the available gap junction mediated communication pathway. Others have essentially normal steady-state g-V relations. In one of these cases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 A for the wild-type channel to less than 3 A for Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in some, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX.

Charcot-Marie-Tooth Disease↗
PubMed1994

A connexin-32 mutation associated with Charcot-Marie-Tooth disease does not affect channel formation in oocytes.

Members of the connexin family differ most in their carboxy-termini, both with respect to sequence and length. In order to assess the contribution of this region to channel function, a series of carboxy-terminal deletion mutants were tested in the paired-oocyte expression system. Connexin-32 can be truncated by 64 amino acids without detectable loss of its known channel properties. Removal of additional amino acids results in a progressive loss of function over a stretch of 4 amino acids. In addition to this effect of length the charge of the carboxy-terminus appears to be another determinant of channel function. One of the fully functional deletion mutants, carrying a stop codon after amino acid-219, had been reported to be associated with Charcot-Marie-Tooth disease. The implications of this finding are discussed.

Amino Acid Sequence↗
PubMed2006

Overexpression of ErbB2 and ErbB3 receptors in Schwann cells of patients with Charcot-Marie-tooth disease type 1A.

Axon-derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal-glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot-Marie-Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage.

Animals↗
PubMed2001

Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.

The kinesin superfamily motor protein KIF1B has been shown to transport mitochondria. Here, we describe an isoform of KIF1B, KIF1Bbeta, that is distinct from KIF1B in its cargo binding domain. KIF1B knockout mice die at birth from apnea due to nervous system defects. Death of knockout neurons in culture can be rescued by expression of the beta isoform. The KIF1B heterozygotes have a defect in transporting synaptic vesicle precursors and suffer from progressive muscle weakness similar to human neuropathies. Charcot-Marie-Tooth disease type 2A was previously mapped to an interval containing KIF1B. We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene. This is clear indication that defects in axonal transport due to a mutated motor protein can underlie human peripheral neuropathy.

Amino Acid Sequence↗
PubMed1996

Cation binding at the node of Ranvier in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies.

The node of Ranvier in myelinated fibers is known to have an affinity to bind cations. Demyelination and remyelination due to abnormal expression of a myelin protein may affect cation binding or vice versa under pathological conditions. To study the cation binding at the node of Ranvier in inherited demyelinating neuropathies associated with over- and under-expression of the peripheral myelin protein 22 (PMP-22), the reaction with ferric ion and ferrocyanide was used to visualize the cation binding sites in biopsied nerves of four patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and two patients with hereditary neuropathy with liability to pressure palsies (HNPP), and the results were compared with those of four patients having acquired neuropathies with normal PMP-22 expression. In CMT1A, nodal widening or paranodal demyelination was associated with dense precipitates focally on both sides of the widened node. Although fainter precipitates were present at the node between remyelinated internodes, the percentage of nodes exhibiting the reaction product between normal and remyelinated internodes was not statistically different from that between normal internodes in CMT1A. In acquired neuropathies, on the other hand, the difference was significant between the two (P < 0.05), with reduction between normal and remyelinated internodes. At the nodes neighboring demylinated internodes, the percentage of nodes exhibiting the reaction product was reduced significantly in both CMT1A and acquired neuropathies, but to a lesser degree in CMT1A. Precipitates were clearly seen at the nodes neighboring a tomaculum in HNPP. The results suggest that preserved cation binding at the node may allow nerves to keep the electrical excitability in CMT1A and HNPP where myelin remodeling takes place at high frequency.

Adolescent↗
PubMed1990

Isolation of a marker linked to the Charcot-Marie-Tooth disease type IA gene by differential Alu-PCR of human chromosome 17-retaining hybrids.

We report the isolation of a new marker (S6.1) from band p11.2 of human chromosome 17 by differential Alu-polymerase chain reaction (Alu-PCR) of both a monochromosomal hybrid retaining a single human chromosome 17 and a hybrid retaining a del(17)(p11.2p11.2) in addition to other human chromosomes. The method is based on the preferential PCR amplification of human DNA in rodent/human hybrids when primers specific to the human Alu repeat element are used. MspI and SstI RFLPs associated with S6.1 were identified and used in linkage analysis of both a previously reported and a newly identified French-Acadian kindred segregating autosomal dominant Charcot-Marie-Tooth disease (CMT). A cumulative peak lod score of 3.41 at a peak recombination fraction of .12 indicates that this marker is linked to the CMT 1A locus but is at a distance from the disease gene. Thus, the marker S6.1 will be useful in further delineating the candidate region for the CMT gene when its location with respect to pA10-41 and 1516, two other markers from 17p11.2 which have previously demonstrated close linkage to the CMT locus, has been determined.

Animals↗
PubMed1994

Molecular genetics of Charcot-Marie-Tooth disease and related neuropathies.

Collectively, the inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5 megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX) is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type II (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine-Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene of the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5 Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.

Charcot-Marie-Tooth Disease↗
PubMed2000

[A case of Charcot-Marie-Tooth disease 1 B with Val 146Phe mutation of myelin protein zero showing a severe clinical phenotype].

A 15-year-old boy had complaints of progressive gait disturbance and foot deformity. He started to walk at the age of 18 months. Since two years of age, he had noticed unstable gait. He showed evident scoliosis and enlarged great auricular nerves. Moderate to slight degrees of muscular atrophy and weakness of distal upper, and proximal and distal lower limbs were observed. Pes equinovarus deformity of both feet was obvious. Muscle stretch reflexes were absent in both limbs except decreased triceps brachii reflex. Vibratory sensation was decreased severely in the toes and mildly in the fingers. In cerebrospinal fluid, protein was mildly elevated. Median nerve motor conduction velocity was 5.0 m/sec. On sural nerve biopsy, both demyelinated and remyelinated axons and onion-bulbs without hypomyelination were observed. Therefore, the diagnosis of Charcot-Marie-Tooth disease 1 was made. The direct sequencing of the genomic DNA encoding the Po gene revealed a mutant allele, a guanine to thymine substitution of nucleotide position 436, which caused a substitution of phenylalanine for valine at amino acid position 146. This type of Po mutation is different from any type of Po mutation reported in the literature.

Adolescent↗
PubMed1999

Edg-2 in myelin-forming cells: isoforms, genomic mapping, and exclusion in Charcot-Marie-Tooth disease.

Edg-2 is an heptahelical receptor whose spatio-temporal distribution during rat brain development is consistent with a role in the control of myelination. We have now identified two splice variants of Edg-2 mRNA in rat brain that encode two receptor isoforms differing by a stretch of 18 amino acids in the NH2-terminal extracellular tail of the receptor. Prenatally (i.e., before oligodendrocyte myelination), the two variants detected by selective in situ hybridization are equally abundant, vary in parallel, and remain restricted to proliferative zones in the brain. Postnatally, the long isoform becomes predominant in myelinating structures, where its abundance increases sharply during the period of myelination. In the adult human brain, only the long variant was detected, while in situ hybridization showed it selectively expressed in the white matter and in clusters of cells showing features of oligodendrocytes of the temporal cerebral cortex. Consequently, the human Edg-2 gene was studied to assess its possible contribution in inherited neuropathies. The coding sequence was found to be contained in three exons and to map to chromosome 9q31.3-32 by using radiation hybrid panel and Yeast-Artificial Chromosomes. Two intragenic bi-allelic polymorphisms and a rare mutation were identified. As a first application to molecular genetic studies, they were used to exclude the Edg-2 gene in six families with phenotype of demyelinating Charcot-Marie-Tooth disease of unknown origin.

Adult↗
PubMed2000

Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy.

BACKGROUND: Severe up to life-threatening neuropathy has been observed in patients with hereditary neuropathies receiving vincristine. CASE REPORT: A 52-year-old female painter suffering from high-grade non-Hodgkin's lymphoma (stage IVB) was treated with a total of 4 mg of vincristine during two courses of CHOP chemotherapy (cyclophosphamide, vincristine, adriamycin, prednisone). At onset of treatment no neurological problems were reported. There was good lymphoma response to chemotherapy. At the same time, however, the patient gradually developed dysphagia, dysarthria, muscular weakness of both lower and upper extremities, areflexia, paraesthesia of the fingertips and bilateral sensory impairment of feet and lower legs. These symptoms continually worsened over a period of seven weeks until she was unable to walk or to perform her work. Electrophysiological studies showed peripheral axonal and demyelinative sensorimotor neuropathy in correlation to histological findings. Molecular analysis revealed 17p11.2 duplication typical for Charcot-Marie-Tooth disease IA. While continuing chemotherapy without the use of vincristine the patient's neurologic symptoms slowly recovered within six months. CONCLUSION: Prior to administration of vincristine family and patient history as well as physical examination should be performed carefully to look for underlying hereditary neuropathy. For those patients with a clinical history or symptoms suggestive for CMT nerve conduction velocity studies and on an individual base even molecular genetic analysis are necessary to prevent serious neurologic complications. worsened significantly resulting in dependency on a wheelchair and inability to perform her work as a painter. Finally she consulted a neurologist and was admitted to hospital for further diagnostic studies and continuation of treatment for her lymphoma in March 1998 with a provisional diagnosis of severe vincristine-induced neuropathy. Medical history at time of admission included hyperthyroidism, that was currently treated with propylthiouracil, a MALT lymphoma 1983, that was treated surgically only, and a meningoencephalitis in 1968. No further medication was taken. In addition she had a history of Lyme disease since 1993 with positive IgM-titer until December 1997, when antibiotic therapy with doxycycline and ceftriaxone was administered successfully. Family history obtained on admission revealed that her mother had non-specific neuropathic symptoms as well as a poorly defined foot deformities of the mother's father. The patient's brother does not show any neurologic impairment and is in good physical health.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Brain white matter lesions in an italian family with charcot-marie-tooth disease.

Type 1A, the most common form of Charcot-Marie-Tooth (CMT1A) disease, is characterized by demyelination of the peripheral nervous system. So far, only a few cases of the disease with concomitant brain white matter lesions have been described. We report an Italian family with CMT1A disease, consisting of the proband and 4 affected members, presenting with concomitant brain white matter lesions at magnetic resonance imaging. The association is particularly fascinating and might depend on an autoimmune mechanism, not yet clarified.

Adult↗
PubMed2003

Auditory processing in patients with Charcot-Marie-Tooth disease type 1A.

HYPOTHESIS: It is unclear whether Charcot-Marie-Tooth (CMT) disease, type 1A, causes auditory processing disorders. Therefore, auditory processing abilities were investigated in five CMT1A patients with normal hearing. BACKGROUND: Previous studies have failed to separate peripheral from central auditory processing disorders. MATERIALS AND METHODS: Five genetically confirmed CMT1A cases in patients with normal hearing underwent behavioral and objective testing. Pure tone audiometry, speech audiometry, and OAE assessment were followed-up by an auditory processing test battery comprising sentences-in-noise test, pattern recognition tests, words-in-noise test, dichotic digit test, filtered speech test, binaural fusion test, and categorical speech perception test. Subsequently, ABR and ERP measurements were conducted. RESULTS: Either the behavioral or objective test scores of 4 out of the 5 CMT1A patients did not differ significantly from those of subjects with normal hearing. Significantly lower scores of one patient on auditory processing tests and ABR measurements could be ascribed to subnormal hearing. CONCLUSION: The authors conclude that CMT1A patients with normal peripheral hearing have auditory processing abilities that were not indicative for an auditory processing disorder. Furthermore, the presence of a peripheral hearing loss complicates the interpretation of auditory processing abilities.

Acoustic Stimulation↗
PubMed2002

[Molecular genetic diagnosis of Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies].

Charcot-Marie-Tooth (CMT) disease is the most commonly inherited disorder of the peripheral nervous system; in Norway, the estimated prevalence is approximately one in 2,500. CMT has been classified into a demyelinating form (CMT1) and an axonal form (CMT2). Around 70-80% of CMT1 cases are caused by a dominantly inherited 1.5 Mb duplication at 17p11.2-12 (CMT1A), encompassing the peripheral myelin protein 22 (PMP22) gene. In contrast, hereditary neuropathy with liability to pressure palsies (HNPP) is caused by the reciprocal deletion of the same 1.5 Mb region. We recently developed a method by real-time quantitative polymerase chain reaction (PCR) for detecting CMT1A duplication and HNPP deletion. Real-time quantitative PCR is very sensitive for identifying PMP22 gene copy number in CMT1A duplication and HNPP deletion. We discuss molecular genetic testing of CMT1A duplication and HNPP deletion. Real-time quantitative PCR should find broad application in clinical and research settings, not only in CMT1A duplication and HNPP deletion, but also in other diseases involving gene copy number or gene expression.

Charcot-Marie-Tooth Disease↗