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• W1972503013 abstract "SIR–We read with interest the recent case report by Anand et al.1 of a 7-year-old male with X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) presenting with central nervous system (CNS) dysfunction. Although rare, both transient and persistent CNS involvement have been reported in individuals with CMT1X and the spectrum of these disorders is expanding.2,3 We report a 15-year-old male with CMT1X who presented with acute CNS dysfunction against a background of Asperger syndrome and mild learning difficulty who was found to possess a novel mutation in the GJB1 gene (encodes for connexin 32 protein). He first presented at 5 years of age with a history of difficulties with coordination. On examination he had depressed knee and ankle deep tendon reflexes, with normal muscle power in all limbs. Initial investigations including brain magnetic resonance imaging (MRI), nerve conduction studies, and creatine kinase were normal. There was no known family history to suggest a hereditary neuropathy. He was given a diagnosis of developmental coordination disorder. At 8 years of age he was diagnosed with mild learning difficulties and Asperger syndrome (by a specialist multidisciplinary assessment using history and clinical observation and satisfying International Classification of Diseases [ICD-10] criteria) and at 13 years of age was treated for depression. A repeat brain MRI was carried out because he showed cognitive decline, but his learning improved after treatment for depression. The MRI showed mild hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the parietal and occipital deep white matter regions (Fig. 1a). At 14 years of age he presented acutely with behavioural change (withdrawn), dysphagia, dysarthria, and a sensory ataxia following gastroenteritis. On examination he also had depressed reflexes and reduced tone and power in all four limbs. Brain MRI showed large, confluent, non-enhancing areas of hyperintensity on T2-weighted and FLAIR images in the parietal regions (Fig. 1b). The splenium of the corpus callosum and the posterior limb of the internal capsule also showed abnormal signals. The diffusion-weighted images showed evidence of restricted diffusion in the same areas (Fig. 1c). Brain magnetic resonance imaging at (a) age 13 years showing mild white matter signal changes; (b) age 14 years showing diffuse signal abnormalities in the deep cerebral white matter with a posterior predominance; (c) age 14 years showing restricted diffusion; and (d) age 15 years showing improvement of white matter signal changes. Repeat nerve conduction studies showed slowed sensory and motor conduction velocities and were consistent with a severe subacute demyelinating sensory and motor neuropathy. Extensive metabolic investigations were normal including negative cerebrospinal fluid oligoclonal bands. Mitochondrial DNA for NARP, MELAS, and MERRF were normal. He was given a 3-day course of intravenous methylprednisolone with good effect. Repeat brain MRI 1 year later showed improvement, with mild hyperintensity on T2-weighted and FLAIR images in the parietal regions (Fig. 1d) with no diffusion abnormalities. He continued to report difficulties with fatigue and walking. On examination he had developed pes cavus, deep tendon reflexes were absent, and he had wasting of the first dorsal interossei and weakness of ankle dorsiflexion. He had no objective sensory deficits. The rest of the neurological examination was normal. His mother was examined at this time and found to have pes cavus and depressed ankle reflexes. Nerve conduction studies for both of them were consistent with a severe (motor and sensory) demyelinating and axonal chronic peripheral neuropathy. Genetic sequence analysis of the index case revealed a heterozygous T to C nucleotide substitution in exon 1 of the GJB1 gene (c.80T>C) which was predicted to result in replacement of the amino acid valine with alanine at residue 27 (p.Val27Ala). This variant is not listed on the Inherited Peripheral Neuropathies Mutation Database (http://www.molgen.ua.ac.be) and to our knowledge this variant has not previously been reported in the literature. Several pathogenic missense mutations have been reported in codons 26 and 28 of the GJB1 gene suggesting that this is a functionally important domain of the protein and this variant has been found in one other CMT patient by the West Midlands Regional Genetics Laboratory (Brueton L, personal communication 2010). The missense variant identified was shown to be maternally inherited. A signed consent form for publication was obtained from the parents. CMT1X is one of the hereditary neuropathies inherited in an X-linked dominant manner causing a demyelinating and/or axonal neuropathy. CMTIX is caused by a mutation in the GJB1 gene which codes for the protein connexin 32 which is also expressed in myelinating Schwann cells of peripheral nerves and in oligodendrocytes in the CNS, explaining the peripheral and central myelination defects.4 Inflammatory factors may have contributed to the transient CNS findings as reported in forms of CMT5 which may be why the symptoms responded to immunotherapy in this patient. This case is of interest because the patient presented with an acute encephalopathic illness with white matter changes on brain MRI before the clinical manifestations of a chronic neuropathy were apparent and because he has a novel GJB1 mutation. The MRI changes were of similar distribution, although worse in severity than those described by Anand et al.1 The MRI changes are specific to this disorder and when identified in a child presenting acutely with encephalopathy and polyfocal neurological symptoms should promote investigation for CMT1X." @default.
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• W1972503013 date "2011-02-11" @default.
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• W1972503013 title "Hereditary motor sensory neuropathy (type 1) presenting with transient and persistent central nervous system manifestations: a novel genetic mutation" @default.
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• W1972503013 doi "https://doi.org/10.1111/j.1469-8749.2010.03901.x" @default.
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