Recurrent stroke-like episodes in X-linked Charcot-Marie-Tooth disease

Basu, AP; Horvath, Rita; Esisi, Bernard; Birchall, D.; Chinnery, Patrick F.

doi:10.1212/wnl.0b013e31822f046e

Cited by 19 publications

(20 citation statements)

References 7 publications

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“…This is in line with most other reported cases of CNS involvement in CMT1X: typically older boys or young men with transient encephalopathy presentation and frequently without previous diagnosis of CMT1X because of only minor peripheral manifestations [6,7,10,26].…”

Section: Discussionsupporting

confidence: 91%

“…Here, we confirm that loss of Cx32 due to start codon mutation can cause similar CNS manifestations as other Cx32 mutants that are retained in the cytoplasm, supporting the conclusion that loss of Cx32 in oligodendrocytes is sufficient to cause CNS myelin dysfunction. Additional support for this conclusion comes from another case of recurrent stroke-like episodes associated with a frameshift mutation [26]. Although we cannot exclude the possibility that translation of this start codon mutant in oligodendrocytes in vivo could be different from the expression in HeLa cells reported here, this is unlikely given that all CMT1X mouse models generated so far to express Cx32 mutants showed comparable expression in vivo as shown by previous in vitro studies [2,14,21,22,27].…”

Section: Discussionsupporting

confidence: 65%

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A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32

et al. 2015

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X-linked Charcot-Marie-Tooth disease (CMTX1) results from numerous mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32) and is one of the commonest forms of inherited neuropathy. Owing to the expression of Cx32 not only in Schwann cells but also in oligodendrocytes, a subset of CMT1X patients develops central nervous system (CNS) clinical manifestations in addition to peripheral neuropathy. While most GJB1 mutations appear to cause peripheral neuropathy through loss of Cx32 function, the cellular mechanisms underlying the CNS manifestations remain controversial. A novel start codon GJB1 mutation (p.Met1Ile) has been found in a CMT1X patient presenting with recurrent episodes of transient encephalomyelitis without apparent signs of peripheral neuropathy. In order to clarify the functional consequences of this mutation, we examined the cellular expression of two different constructs cloned from genomic DNA including the mutated start codon. None of the cloned constructs resulted in detectable expression of Cx32 by immunocytochemistry or immunoblot, although mRNA was produced at normal levels. Furthermore, co-expression with the other major oligodendrocyte connexin, Cx47, had no negative effect on GJ formation by Cx47. Finally, lysosomal and proteasomal inhibition in cells expressing the start codon mutant constructs failed to recover any detection of Cx32 as a result of impaired protein degradation. Our results indicate that the Cx32 start codon mutation is equivalent to a complete loss of the protein with failure of translation, although transcription is not impaired. Thus, complete loss of Cx32 function is sufficient to produce CNS dysfunction with clinical manifestations.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 65%

A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32

et al. 2015

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“…2 Transient white-matter abnormalities with central nervous system (CNS) deficits have been reported. [3][4][5][6][7][8][9][10][11] A 14-year-old, right-handed Caucasian boy presented with a second episode of numbness and weakness. On examination, he was fully alert but had left facial weakness with dysarthria.…”

Section: Novel Familial Pathogenic Mutation In Gap Junction Protein mentioning

confidence: 99%

Novel familial pathogenic mutation in gap junction protein, beta‐1 gene (GJB1) associated with transient neurological deficits in a patient with X‐linked Charcot‐Marie‐Tooth disease

Appu

Mar

2014

Muscle and Nerve

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“…(See Abrams and Freidin8 for review and additional references.) Finally, a growing number of patients with otherwise typical CMT1X have been found with an acute, florid syndrome characterized by dysarthria, motor difficulties and variable alterations in level of consciousness315161718192021222324252627282930. These clinical phenomena are transient, generally lasting from hours to days, and are accompanied by longer lasting changes in brain MRI imaging, with prominent increased signal in the splenium of the corpus callosum and the deep cortical white matter on diffusion weighted imaging.…”

mentioning

confidence: 99%

Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations

Abrams

Goman

Wong

et al. 2017

Sci Rep

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CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These “PNS-only” mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function.

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Recurrent stroke-like episodes in X-linked Charcot-Marie-Tooth disease

Cited by 19 publications

References 7 publications

A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32

A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32

Novel familial pathogenic mutation in gap junction protein, beta‐1 gene (GJB1) associated with transient neurological deficits in a patient with X‐linked Charcot‐Marie‐Tooth disease

Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations

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