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Central nervous system involvement in four patients with Charcot-Marie-Tooth disease with connexin 32 extracellular mutations
  1. MARIOS PANAS,
  2. CHARALAMBOS KARADIMAS,
  3. DIMITRIS AVRAMOPOULOS,
  4. DEMETRIS VASSILOPOULOS
  1. Clinical and Molecular Neurogenetics Unit, Department of Neurology of Athens National University (Eginition Hospital), Greece
  1. Professor Demetris Vassilopoulos, Department of Neurology of Athens National University (Eginition Hospital), 74 Vas. Sophias Av. Athens 115 28, Greece tel.-fax: x30–1–7244917.

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In a recent issue of this Journal 1there was a report of two cases of multiple sclerosis with duplicated CMT1A. Here we present four additional patients with Charcot-Marie-Tooth disease with CNS involvement as shown by electrophysiological studies and the presence of myelin lesions in brain MRI. In our patients point mutations were identified in GJB1, a gene coding for connexin 32 (GenBank acc number 117688). We also point to the possible importance of the position (intracellular or extracellular) of the mutations in the involvement or not of the CNS.

In the process of investigating a panel of patients with Charcot-Marie-Tooth disease for mutations leading to the disease, we have screened the GJB1 gene for mutations in six patients (C12, C64, C10, and C13 (all unrelated), and C2–1 and C2–2 (brothers) who did not have a CMT1A duplication and had a family history compatible with an X linked mode of transmission. GJB1 is a gene coding for connexin 32 (Cx32), a gap junction protein that is found in both the peripheral and the central nervous systems2 and that has been reported by many to be responsible for CMTX, the X linked subtype of Charcot-Marie-Tooth disease. We performed our search using SSCP and nucleotide sequencing when additional bands were detected.3 Mutations leading to amino acid sequence changes and transmitted with the disease were detected in all six patients, whereas these nucleotide variations were not detected in 150 healthy control X chromosomes. Because Cx32 is a protein expressed in both the peripheral and the central nervous systems we proceeded to test for CNS involvement in those patients using electrophysiological (table) and MRI techniques. The clinical and laboratory findings for our patients were as follows.

Patient C2–1, a 19 year old man, had a history of 5 hour to 3 day long episodes of weakness—generalised or at other times localised to the left or right half of the body—dysarthria, and difficulty in swallowing. Neurological clinical examination showed muscle weakness and peripheral atrophy of the limbs, absence of tendon reflexes, distal loss of vibration in the legs, indifferent plantar response, and bilateral pes cavus. The CSF was normal. Brain SPECT (Tc-99m HMPAO{15 mCi}) showed significant reduction of blood flow in the left parietal lobe. Brain MRI showed bilateral symmetric areas in the central white matter supraventricularly with high intensity signal in T2 weighted images. Electrophysiological studies (table) showed that both the central and peripheral nervous systems were affected. The patient had a C to T transition at position 164 (novel mutation).

Patient C2–2, the 21 year old brother of C2–1, had the same symptoms (multiple episodes of muscle weakness) since the age of 10 years. The clinical findings were also the same. In this case the CSF showed IgG oligoclonal bands. Brain MRI was normal. Electrophysiological studies also showed that both the central and peripheral nervous systems were affected. The patient had the same mutation as his brother C2–1, as was expected.

Patient C12, a 63 year old man, had progressive muscle weakness and peripheral atrophy of the extremities since the age of 9 years. When admitted he had severe muscle weakness, absence of tendon reflexes, distal loss of vibration in the legs, dysmetria, fine tremor, positive Romberg’s sign, and bilateral pes cavus. The CSF showed an IgG index of 1.0 (normal<0.85) and oligoclonal bands. Brain MRI showed foci of demyelination in the white matter of the cerebral hemispheres. Electrophysiological studies also showed that both the central and peripheral nervous system were affected. The patient had the same mutation as patient C2–1.

Patient C64, a 58 year old man, presented with progressive muscle weakness and peripheral atrophy since the age of 10 years. His CSF was not sampled. Brain MRI showed high density areas of demyelination in the white matter on the left side in the frontoparietal area. The patient had a G to A transition at position 491 (novel mutation).

Patient C10, a 78 year old man, presented with progressive muscle weakness and peripheral atrophy of the legs since the age of 11. The clinical picture was the same as that of patient C64. The CSF and brain MRI were normal. The patient had a T to A transition at position 359 (novel).

Patient C13, a 40 year old man, presented with progressive muscle weakness and peripheral atrophy starting at the age of 7 years. His CSF and brain MRI were normal. The patient had a C to T transition at position 43 (already reported4). Sural nerve biopsy performed in patients C2–1, C2–2, C64, and C10 showed loss of muscle fibres and “onion bulb” formation. It is of particular interest, possibly implying an underlying mechanism, that the four patients with evidence of CNS involvement (C2–1, C2–2, C12, and C64 ) had mutations in the extracellular domain of Cx32, and by contrast, in the two patients with no evidence of CNS involvement (C10, C13) the mutations were in the intracellular domain of the protein.

Electrophysiological data from the six patients

The exact pathogenetic mechanisms of the various types of myelin damage are not yet fully understood. Therefore, we cannot reach any convincing conclusions about the possible relations between those degenerative processes and the position of Cx32 mutations. However, we hope that our findings will contribute to a better understanding of some myelin damage mechanisms.

References

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