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PubMed2006

Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease.

We review the putative functions and malfunctions of proteins encoded by genes mutated in Charcot-Marie-Tooth disease (CMT; inherited motor and sensory neuropathies) in normal and affected peripheral nerves. Some proteins implicated in demyelinating CMT, peripheral myelin protein 22, protein zero (P0), and connexin32 (Cx32/GJB1) are crucial components of myelin. Periaxin is involved in connecting myelin to the surrounding basal lamina. Early growth response 2 (EGR2) and Sox10 are transcriptional regulators of myelin genes. Mutations in the small integral membrane protein of lysosome/late endosome, the myotubularin-related protein 2 (MTMR2), and MTMR13/set-binding factor 2 are involved in vesicle and membrane transport and the regulation of protein degradation. Pathomechanisms related to alterations of these processes are a widespread phenomenon in demyelinating neuropathies because mutations of myelin components may also affect protein biosynthesis, transport, and/or degradation. Related disease mechanisms are also involved in axonal neuropathies although there is considerably more functional heterogeneity. Some mutations, most notably in P0, GJB1, ganglioside-induced differentiation-associated protein 1 (GDAP1), neurofilament light chain (NF-L), and dynamin 2 (DNM2), can result in demyelinating or axonal neuropathies introducing additional complexity in the pathogenesis. Often, this relates to the intimate connection between Schwann cells and neurons/axons leading to axonal damage even if the mutation-caused defect is Schwann-cell-autonomous. This mechanism is likely for P0 and Cx32 mutations and provides the basis for the unifying hypothesis that also demyelinating neuropathies develop into functional axonopathies. In GDAP1 and DNM2 mutants, both Schwann cells and axons/neurons might be directly affected. NF-L mutants have a primary neuronal defect but also cause demyelination. The major challenge ahead lies in determining the individual contributions by neurons and Schwann cells to the pathology over time and to delineate the detailed molecular functions of the proteins associated with CMT in health and disease.

Cell Cycle Proteins↗

PubMed1989

Phrenic involvement in Charcot-Marie-Tooth disease. A pathologic documentation.

A 69-year-old woman diagnosed as having Charcot-Marie-Tooth disease (CMT) for 30 years' duration died of respiratory failure secondary to diaphragmatic weakness. At autopsy, identical neuropathic changes were found in phrenic and other affected somatic peripheral nerves. We conclude that the phrenic nerve may be involved by the neuropathy of at least some forms of CMT.

Aged↗

PubMed1990

[Nephropathy and Charcot-Marie-Tooth disease. A case report].

A 12 year-old girl with a family of Charcot-Marie-Tooth neuropathy was referred to us with mild proteinuria without hematuria or renal insufficiency; a renal biopsy specimen showed focal glomerulosclerosis. Two years later, proteinuria and renal function were quite stable and there was no arterial hypertension. Of 13 other cases in the literature, the outcome of renal involvement has the same profile:proteinuria at onset with or without microhematuria, sometimes with nephrotic syndrome; the prognosis is often poor, since 9 out of 13 patients have end-stage renal failure after 6 months to 17 years of follow-up. The pathological examination show focal glomerulosclerosis in most cases. Nerve deafness is uncommon in Charcot-Marie-Tooth disease but was present in 7 out of 13 patients with the nephritis. Such an association may be a variant of the dominant autosomal form of the disease, whose gene is located on chromosome 1.

Charcot-Marie-Tooth Disease↗

PubMed1992

Charcot-Marie-Tooth disease with diaphragmatic weakness.

A 61-year-old man, who suffered from Charcot-Marie-Tooth disease (CMT) for 44 years, was evaluated for the respiratory disorder. He had diaphragmatic dysfunction induced by phrenic nerve disturbance. In this patient, central type apnea and hypopnea related to diaphragmatic weakness occurred during REM sleep, which induced accessory inspiratory muscle inhibition. Respiratory muscle dysfunction had not been generally recognized in CMT until recently, but its significance should be emphasized.

Charcot-Marie-Tooth Disease↗

PubMed1997

Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A.

Charcot-Marie-Tooth disease type 2 (CMT2) is characterized by a motor conduction velocity of the median nerve of > 38 m/sec and is a genetically heterogeneous disorder with at least three loci identified: CMT2A (1p35-36), CMT2B (3q13-22), CMT2C (not linked to any known loci), and CMT2D (7p14). In this study, we performed linkage analysis of two Japanese CMT2 families using markers flanking the CMT2A, CMT2B, and CMT2D loci. The highest cumulative multipoint lod score of 3.69 was obtained at D1S244. The CMT2B and CMT2D loci were excluded by the results of linkage analysis performed using markers D3S1551, D3S1290, and D7S484. The clinical features of the CMT2A affecting the two families include similar levels of muscle weakness of the posterior and anterior tibial muscles, tendon reflexes preserved in upper extremities but reduced or absent in lower extremities, no enlargement of the peripheral nerves, and mild sensory disturbance in only 20% of affected individuals.

Charcot-Marie-Tooth Disease↗

PubMed2003

Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.

BACKGROUND: X-linked hereditary demyelinating neuropathies (Charcot-Marie-Tooth Disease [CMTX]) caused by mutations in the connexin 32 (Cx32) gene account for approximately 10% to 20% of all hereditary demyelinating neuropathies. Mild subclinical central nervous system (CNS) involvement has been previously described, and CMTX patients with transient white matter lesions allied to CNS symptoms have very recently been described. This is of potential interest, as Cx32 is widely expressed in both peripheral nerve and the brain. PATIENTS: We describe a family with hereditary demyelinating neuropathy and transient CNS symptoms. For this study, family members underwent genotyping and detailed clinical, electrophysiological, and magnetic resonance imaging examination. RESULTS: We present a CMTX family with a novel mutation in the Cx32 gene. Affected family members show, in addition to the classic polyneuropathy, transient and reversible white matter lesions on magnetic resonance imaging scans, correlating similarly transient CNS symptoms. CONCLUSION: Patients with CMTX can present with transient CNS symptoms and marked white matter lesions on magnetic resonance imaging scans.

Adult↗

PubMed2005

[The characteristics of gene mutations in Chinese patients with Charcot-Marie-Tooth disease].

OBJECTIVE: To study the characteristics of gene mutations in Chinese patients with Charcot-Marie-Tooth disease (CMT). METHODS: Real-time quantitative PCR, PCR-SSCP, and/or direct sequencing were used to analyze the mutation of the pathogenic genes PMP22, MPZ, CX32, EGR2, GDAP1, NEFL, HSP22 and HSP27 in 113 probands of CMT families, 45 of which had family history, from different provinces in China. The whole family members of the subjects with abnormal electrophoretic bands and 50 normal controls underwent the same examination. RESULTS: Thirty-six cases of PMP22 duplication, 7 cases of CX32 mutation, 1 case of HSP22 mutation, 1 case of HSP27 mutation, 1 case of MPZ mutation, and 1 case of GDAP1 mutation were found in the 113 CMT probands. No point mutation was found in PMP22, EGR2 and NEFL genes. CONCLUSION: Among the Chinese CMT patients 31.9% are caused by PMP22 duplication, 6.2% by CX32, and 0.9% by HSP22, HSP27, MPZ and GDAP1. Point mutations of PMP22, EGR2 and NEFL are rare.

Adolescent↗

PubMed1995

Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations.

Charcot-Marie-Tooth disease type 1A (CMT1A) or hereditary motor and sensory neuropathy type Ia (HMSN type Ia) is an autosomal dominant demyelinating polyneuropathy, which may result from duplications as large as 1.5 Mb on chromosome 17p 11.2-p12 encompassing the gene for the peripheral myelin protein PMP22, or from point mutations in this gene. In general, it is not possible to distinguish, by clinical and neurophysiological criteria, the cases associated with the duplication mutation from those associated with point mutations of the PMP22 gene, although the latter tend to be more severe. In this study we demonstrated that the two genotypes exhibit different morphological characteristics. In the PMP22 duplicated cases the mean g-ratio (axon diameter versus fibre diameter) is significantly lower than normal, while in cases of PMP22 point mutations nearly all myelinated fibers have an extremely high g-ratio. In cases with point mutations, onion bulbs are abundantly present from an early age, whereas onion bulbs in the duplicated cases develop gradually in the first years of life. Increase in total transverse fascicular area is most pronounced in the point mutation cases. The differences in pathology between these two very different types of mutations involving the same gene likely reflect differences in pathogenesis and may offer clues in understanding the function of PMP22.

Adolescent↗

PubMed2000

Microvascular decompression for trigeminal neuralgia in Charcot-Marie-Tooth disease.

The authors report on three patients suffering from coexistent trigeminal neuralgia (TGN) and Charcot-Marie-Tooth disease who, based on preoperative magnetic resonance tomographic angiography findings, underwent microvascular decompression. All patients had demonstrable neural compression and all experienced immediate postoperative pain relief. Symptoms recurred in one patient and required a second procedure in the form of a neurotomy. Two patients suffered from bilateral TGN. When a patient with TGN suffers coexistent neurological disease and experiences bilateral symptoms, preoperative imaging and subsequent decompressive surgery may avoid the unacceptable risk of morbidity associated with bilateral ablative procedures.

Adult↗

PubMed1993

Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A. METHODS: We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products. RESULTS: A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication. CONCLUSIONS: The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.

Amino Acid Sequence↗

PubMed1972

Pathology of peroneal muscular atrophy (Charcot-Marie-Tooth disease).

Four cases of peroneal muscular atrophy (Charcot-Marie-Tooth disease) are described in which observations were made from the necropsy examination of the central nervous system, the peripheral nervous system, and the skeletal muscles. The pattern of nerve degeneration in these various locations is described and the conclusion is drawn that the basis of the disease is a very chronic progressive neuropathy. To the pathological descriptions of previous observers is added the finding of fibrosis affecting the muscle spindles which was present in all four of the cases. The literature of the case reports with necropsy examination is reviewed.

Adult↗

PubMed1991

The hand in Charcot-Marie-Tooth disease.

The upper extremity was evaluated in 68 symptomatic individuals previously diagnosed as having Charcot-Marie-Tooth disease. Consistent patterns of motor and sensory involvement were found noted as well as a predictable progression of neuromuscular deficits. Improved understanding of the clinical behaviour of this disorder is necessary to develop better treatment strategies.

Adolescent↗

PubMed1980

Pattern shift visual evoked potentials in Charcot-Marie-Tooth disease, HMSN type I.

Pattern shift visual evoked potentials were investigated in 9 subjects with Charcot-Marie-Tooth disease, who were classified as HMSN I on clinical, genetic and electromyographic criteria. The latency of the second positive peak was increased in 7 eyes of 5 subjects. These results suggest that patients with HMSN I the optic nerves may be affected more frequently than suspected on clinical examinations.

Adult↗

PubMed2003

Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene.

OBJECTIVE: To report the clinical and electrophysiological characteristics of a family presenting Charcot-Marie-Tooth disease (CMT) associated with autonomic nervous system disturbances. METHODS: We studied nerve conduction values, postural adaptation, sympathetic skin reflex, the variation in heart rate by the Valsalva ratio and pupillometry in 7 members of a French family in which CMT due to a Thr124Met mutation in the myelin protein zero (MPZ) gene was diagnosed. RESULTS: Clinical and laboratory evidence of autonomic nervous system disturbances were found in the affected individuals. The clinical phenotype was characterized by sensorimotor peripheral neuropathy, defined as axonal type by electrophysiological studies, and was associated with severe pain, bladder dysfunction, sudorimotor disturbances and abolished pupillary reflex to light. Moreover, two patients had severe restrictive respiratory insufficiency requiring noninvasive mechanical ventilation. CONCLUSIONS: Our study demonstrates that autonomic disturbances may be one of the major clinical signs associated with CMT secondary to MPZ gene mutation in codon 124. Testing of pupillary reflex allows the discrimination of affected and unaffected subjects in our family. However, involvement of the autonomic nervous system in this type of neuropathy is unclear and further studies are required to elucidate the role of the MPZ gene in the autonomic nervous system.

Adult↗

PubMed1995

Vincristine neuropathy in type I and type II Charcot-Marie-Tooth disease (hereditary motor sensory neuropathy).

A patient with Ewing's sarcoma and demyelinating type Charcot-Marie-Tooth disease (CMT) developed severe neuropathy after receiving a total vincristine dose of 6 mg. Recovery was slow and incomplete. A second patient with axonal type CMT developed moderate neuropathy but tolerated extended vincristine administration and recovered quickly. Possible underlying neuropathy should be excluded before vincristine treatment is begun by careful examination including inspection of the feet, followed by electrophysiologic studies as indicated. In demyelinating CMT, vincristine should be avoided; in axonal form cautious use may be considered.

Adolescent↗

PubMed1996

X-linked Charcot-Marie-Tooth disease: molecular analysis of interfamilial variability.

This report describes two families with type 1 Charcot-Marie-Tooth disease (CMTX), or hereditary motor sensory neuropathy type 1. Pedigree analysis is consistent with X-linked recessive inheritance in one family and X-linked dominant inheritance in the second. In the first family, a mutation in the connexin32 gene has been demonstrated and analyzed in family members. In the second family, linkage analysis is consistent with a mutation at the same locus. This report demonstrates the interfamilial variability in X-linked CMT and underscores the observation that regardless of the pattern of inheritance, X-linked CMT constitutes a single, variable disorder.

Charcot-Marie-Tooth Disease↗

PubMed1994

[Charcot-Marie-Tooth disease, dilated myocardiopathy and cardiac conduction disorders].

We describe the case of two brothers with Charcot-Marie-Tooth disease, dilated cardiomyopathy and disorders in the cardiac conduction. We review the literature in order to find physiological grounds for these associations. Despite the absence of consolidated data on this question, the genetic grounds could play some role here. In this sense, our cases contribute with the novelty that the disease affects two brothers. This has never been described before and could contribute, along with future observations, to clarify some etiopathogenic aspects of the disease.

Adult↗

PubMed2003

Connexin 32 mutation in a Turkish family with X-linked Charcot-Marie-Tooth disease.

In the present work, we describe a large Turkish family (N=39) with Charcot-Marie-Tooth disease, which is the most commonly inherited peripheral neuropathy. The subjects were from four generations, including six hemizygote patients and nine heterozygote carrier females. Symptoms appeared in late childhood in males (mean age=13.5) but later in carrier females (mean age=33.5). The peripheral nerve conduction was more severely affected in males than females. Genomic DNA was isolated from peripheral white blood cells. Using SSCP technique (single strand conformation polymorphism analysis), abnormal patterns of migration were observed in 15 subjects: 6 of them were hemizygote males and 9 were heterozygote carrier females. We identified a mutation of the Cx32 gene, consisting of a guanine to adenine transition at position 271 (271G-A). The results suggested relations between degenerative processes and position of Cx32 mutations.

Adolescent↗