Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Charcot-Marie-Tooth neuropathy (CMT) is an inherited degenerative disorder of the peripheral nervous system that results in slowly progressive distal muscle weakness, atrophy and loss of proprioception in the affected areas. X-linked CMT (CMTX) has been localized to the pericentric region of the X chromosome. CMTX neuropathy is usually associated with mutations in exon 2 of the gap junction protein beta1 (GJB1) gene. GJB1 is a gap junction protein expressed in various cells including oligodendrocytes, astrocytes and myelinating schwann cells. Here, we report a female case of CMTX with a GJB1 mutation. The patient was severely clinically affected and exhibited both the features of demyelination and axonopathy. This is the first female patient with CMTX who showed permanent atypical scattered lesions in cerebral white matter of the brain on T2-weighted magnetic resonance images (MRI), which is very rare. The existence of a female patient with severe clinical symptoms may show that gain of function mechanism also leads to the disorders seen in these patients.
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PMID:X-linked Charcot-Marie-Tooth disease (CMTX) in a severely affected female patient with scattered lesions in cerebral white matter. 1760 45

To further understand X-linked dominant Charcot-Marie-Tooth disease (CMTX1), we followed a family of 22 members in China, including 8 patients, 2 asymptomatic carriers and 12 normal family members. Twenty-two family members as well as 60 normal controls unrelated to this family were screened for point mutation by denaturing high performance liquid chromatography (DHPLC). All patients and asymptomatic carriers from this family, but none of the normal population controls, showed a T-C transition at position 266 in codon 89 of exon 2 of connexin 32, resulting in a leucine to proline (L89P) exchange. To study whether the immune system is involved in the pathogenesis of CMTX1 patients and asymptomatic carriers, we measured serum concentrations of antibodies to peripheral nerve myelin protein 22 (PMP22), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) by ELISA. Serological results were also compared with those from GBS patients (n=11) and with normal subjects (n=20). Our analysis showed anti-PMP22 sera reactivity in 50.0% of CMTX1 patients, 63.6% of GBS patients and 10% of normal controls. Our results also indicated that anti-PMP22 antibodies in the CMTX1 family varied with sex. Anti-PMP22 antibodies were found in all male patients but not in all females, which may be one of the reasons that male patients usually have more severe clinical symptoms than that of female patients. There was no statistical difference in serum concentrations of IL-6 and TNF-alpha between CMTX1 patients and normal subjects. In conclusion, we identified a L89P mutation for the first time in a CMTX1 family in China and an associated response to PMP22 in males.
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PMID:Study of antibodies to PMP22, IL-6 and TNF-alpha concentrations in serum in a CMTX1 family. 1771 66

X-linked Charcot-Marie-Tooth (CMTX) disease is a common inherited degenerative disorder of the peripheral nerve. Previously, our laboratory identified a large New Zealand/United Kingdom (NZ/UK) family mapping to the CMTX3 locus (Xq26.3-27.1). We have now identified a second large, Australian X-linked CMT family that links to the CMTX3 locus. This new family has the same phenotype as our previously described CMTX3 family, with slightly milder disease in males than CMTX1 and asymptomatic carrier females. This study also includes the re-analysis of one of the original US pedigrees reporting the CMTX3 locus. The large Australian family shared the complete disease haplotype with our original NZ/UK family, while the American family shared only the distal portion of the disease haplotype. Comparison of the frequency of the CMTX3 haplotype to the normal population showed strong statistical evidence (p < 0.0001) indicating that the smaller shared haplotype is identical by descent. This suggests that the new CMTX3 family, our previously reported family, and the original American CMTX3 family have a common ancestor, and the disease in these families is caused by a founder mutation. The ancestral recombination observed in the American family refines the CMTX3 interval to a 2.5 Mb region between DXS984 and DXS8106. In this region, 11 out of the 15 annotated genes have been excluded for pathogenic mutations.
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PMID:Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth (CMTX3) locus to a 2.5 Mb region. 1845 69

We report a patient of Charcot-Marie-Tooth disease (CMT) accompanied by transient splenium abnormality in brain MRI. A 34-year-old man suffered from chronic progressive unsteadiness and sensory disturbance of all limbs. Neurological examination showed muscle weakness and atrophy in the distal extremities with pes cavus, mild sensory disturbance of four extremities and generalized decreased reflexes. The nerve conduction study described the presence of sensory-motor polyneuropathy. We could not investigate his GJB1 gene. However, we suspected that he was X-linked CMT (CMTX), because his electrophysiological findings showed intermediate slowing of MCV, and auditory brain-stem response (ABR) demonstrated central conduction slowing. Brain MRI revealed the abnormal high signal intensity in the splenium of the corpus callosum on T2-weighted image. This lesion diminished two months later without any treatment. Recently, there had been reported transient splenium abnormality in CMTX cases, and there were clinical similarities between the cases of these reports and our case. We considered that the pathophysiology of this case was the disruption of gap junction communications expressed between oligodendrocyte and astrocytes induced by connexin 32 (Cx32) mutations. Furthermore, the transient functional disturbance of astrocytes would be another pathophysiologic mechanism of splenium abnormality.
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PMID:[Case report of transient splenium abnormality in Charcot-Marie-Tooth disease]. 1854 Mar 86

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.
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PMID:[Charcot-Marie-Tooth disease]. 1913 35

Charcot-Marie-Tooth (CMT) neuropathy is inherited with genetic and clinical heterogeneity. The X-linked form (CMTX) is linked to mutations in the GJB1 gene. However, the genotype-phenotype correlation between variants in the non-coding region of GJB1 gene and CMTX is unclear. We found two structural variants (-459C>T and -713G>A) in the 5' non-coding region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its association with CMTX in two Chinese families. All family members who carried the -459C>T variant either were symptomatic or had abnormal electrophysiological studies compatible with CMTX, whereas all the non-symptomatic family members who had normal electrophysiological studies and 10 healthy unrelated controls did not have this variant. The other variant in the 5'-flanking region of the gene was found to be a benign polymorphism, although it had been earlier reported to be associated with CMTX in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA using M fold and RNA structure softwares indicates that the -459C>T mutation may reduce translation efficiency of the GJB1 gene by changing its 5'-untranslated region secondary structure and abolishing the internal ribosome entry site at the initialization of its translation in Schwann cells. Our study can help clarify the causal mutations of CMTX in the non-protein coding region of GJB1.
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PMID:-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy. 1933 35

X-linked Charcot-Marie-Tooth (CMTX) disease is a hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 gene (GJB1 codes for connexin 32). In this study we report six novel mutations p.Met1Arg, p.Leu9Phe, p.Ser17Tyr, p.Val63Phe, p.Val170Ile, and p.Leu212Phe in GJB1 and their phenotypic expression. These mutations affect both intracellular and extracellular parts of the GJB1 protein. The screened patients had previously excluded the duplication/deletion on 17p11.2 and the male-to-male transfer in the pedigree. Except p.Val170Ile, all reported mutations segregated with the CMT phenotype in the families and caused CMTX1 neuropathy. Mutations were not found in 200 control DNA samples. Additionally, we performed in silico analysis of the novel mutations with the program PANTHER. The PANTHER scored five mutations, all but p.Val170Ile, as likely deleterious and supported the pathogenicity of the found mutations. These results provided evidence that these five mutations are causative for CMTX1.
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PMID:Six new gap junction beta 1 gene mutations and their phenotypic expression in Czech patients with Charcot-Marie-Tooth disease. 2003 84

Charcot-Marie-Tooth disease (CMT) is the most common form of inherited motor and sensory neuropathy. Moreover, CMT is a genetically heterogeneous disorder of the peripheral nervous system, with many genes identified as CMT-causative. CMT has two usual classifications: type 1, the demyelinating form (CMT1); and type 2, the axonal form (CMT2). In addition, patients are classified as CMTX if they have an X-linked inheritance pattern and CMT4 if the inheritance pattern is autosomal recessive. A large amount of new information on the genetic causes of CMT has become available, and mutations causing it have been associated with more than 17 different genes and 25 chromosomal loci. Advances in our understanding of the molecular basis of CMT have revealed an enormous diversity in genetic mechanisms, despite a clinical entity that is relatively uniform in presentation. In addition, recent encouraging studies - shown in CMT1A animal models - concerning the therapeutic effects of certain chemicals have been published; these suggest potential therapies for the most common form of CMT, CMT1A. This review focuses on the inherited motor and sensory neuropathy subgroup for which there has been an explosion of new molecular genetic information over the past decade.
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PMID:Charcot-marie-tooth disease: seventeen causative genes. 2039 92

Both the myotonic dystrophy type 1 (DM1) and the X-linked dominant Charcot-Marie-Tooth disease (CMTX1) are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. The underlying causes of the DM1 and CMTX1 are mutations in the DMPK and GJB1 gene, respectively. A patient with both DM1 and CMTX1 inherited these from his father and mother, respectively. Histopathological and electrodiagnostic studies revealed both chronic neuropathic and myopathic features. Physical disabilities were more severe than seen with either DM1 or CMTX1 alone. In addition, the present case reveals an asymmetric atrophy (22%) of the right calf muscle compared to the left side.
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PMID:Myotonic dystrophy type I combined with X-linked dominant Charcot-Marie-Tooth neuropathy. 2044 38

X-linked hereditary motor sensory neuropathy type 1 (CMTX 1) is caused by mutation in the GJB1 gene that codes for the connexin 32 protein. Central nervous system involvement with or without white matter changes on magnetic resonance imaging (MRI) has rarely been reported in this condition. We report the case of a 7-year-old, previously well male who presented with a stroke-like episode that manifested as left hemiparesis and dysphasia. An initial brain MRI showed white matter signal changes affecting the corpus callosum and periventricular areas with a posterior predominance. Our patient made a complete clinical recovery in 36 hours. Clinical examination at this stage showed no evidence of a peripheral neuropathy. A repeat brain MRI 6 weeks later showed almost complete resolution of the changes seen initially. Subsequent investigations showed a Val177Ala mutation in the GJB1 gene. This mutation has so far not been described in the Caucasian population and has been only described once before. Electrophysiological studies showed a mixed demyelinating and axonal sensorimotor neuropathy in keeping with CMTX 1. Five months after the initial presentation our patient developed clinical evidence of a peripheral neuropathy in the form of absent ankle reflexes, weak dorsiflexors, and evertors of both feet.
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PMID:X-linked hereditary motor sensory neuropathy (type 1) presenting with a stroke-like episode. 2130 65


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