X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study.

OBJECTIVE: To relate X-linked Charcot-Marie-Tooth disease (CMTX) phenotypes to gender and type of neuropathy by the study of a large series of CMTX patients with proven Cx32 point mutations. BACKGROUND: CMTX is an X-linked form of Charcot-Marie-Tooth disease, caused by mutations in the connexin 32 gene. Males are usually more severely affected and have slower nerve conduction velocities than females. METHODS: Forty-eight patients from 10 families with Cx32 mutations were examined clinically and electrophysiologically. Mutations were characterized in index cases by automatic sequencing and detected in at-risk individuals by polymerase chain reaction (PCR)-restriction or single strand conformation polymorphism (SSCP) analysis. Two patients from different families had light and electron microscopy examination of a sural nerve biopsy. RESULTS: Males (n = 21) were more severely affected than females (n = 27), although six of the females were severely disabled. In the majority of males, the median motor nerve conduction velocity (MNCV) was between 30 and 40 m/s, whereas in females it ranged from 30 to normal values. Two children with mutation, a 6-year-old boy and a 7-year-old girl, were normal clinically and electrophysiologically. In most patients, the amplitude of motor nerve compound muscle action potentials (CMAP) was reduced in all nerves tested. MNCV was reduced as a function of the degree of axonal loss. A significant correlation was found between the decrease in CMAP amplitude and MNCV in the median, ulnar, and peroneal nerves. Sural nerve biopsies in one patient with a missense and one with a nonsense mutation both showed axonal neuropathy. CONCLUSION: Electrophysiologic and histologic findings support primary axonal neuropathy in CMTX with Cx32 mutations. Clinical and electrophysiologic data in males with different missense mutations in the of Cx32 gene differed significantly. Furthermore, males with a nonsense mutation (Arg22Stop) had earlier onset and a more severe phenotype than males with missense mutations.

[Pauci-symptomatic sensory polyneuropathy in Refsum's disease]. / Polyneuropathie sensitive pauci-symptomatique au cours d'une maladie de Refsum.

Refsum's disease is an autosomal recessive disease caused by defective alpha-oxidation of phytanic acid. The usual clinical presentation is the association of retinitis pigmentosa, ataxia and chronic severe sensorimotor polyneuropathy. A case of mild purely sensory neuropathy in a 40-year-old patient associated to high CSF protein level led to the diagnosis of Refsum's disease. The paucity of sensory symptoms and signs of neuropathy contrasted with severe reduction of motor and sensory nerve conduction velocities and markedly signs of sensory neuropathy observed in the nerve biopsy. Typical ring-scotomas, retinitis pigmentosa, anosmia, deafness, and high plasma phytanic acid level were present in extensive examination. There was no other case in the family.

Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection?

BACKGROUND: The prevalence of hepatitis C virus (HCV) infection has been estimated at 43 to 84% in patients with essential mixed cryoglobulinaemia in recent large series. Some of these cases have been successfully treated with interferon-alpha. The objective was to evaluate the prevalence and the possible role of HCV infection in essential mixed cryoglobulinaemia. METHODS: Fifteen patients (eight men and seven women; mean age: 61.2 (SD 16.5) years) with peripheral neuropathy (10 polyneuropathies and five multifocal mononeuropathies) and essential mixed cryoglobulinaemia were tested for serum anti-HCV antibodies. RESULTS: Antibodies were found in 10 of 15 patients involving either polyneuropathies (seven patients) or multifocal mononeuropathies (three patients). Electrophysiological studies and teased nerve fibre studies (in seven patients) allowed neuropathies to be classified as predominantly sensory axonopathies. Compared with HCV-negative (HCV -) patients, HCV-positive (HCV +) patients had a more pronounced and more widespread motor deficit; motor nerve conduction velocities in peroneal and median nerves were more impaired in HCV + patients, although significance was not reached except for the mean value of the amplitude of the compound muscle action potentials of the median nerves (P < 0.05); necrotising vasculitis was found in two of nine nerve biopsies from the HCV + patients studied and in none of the three HCV - patients. In addition, HCV + patients had more frequent cryoglobulin related cutaneous signs, higher aminotransferase and serum cryoglobulin concentrations, lower total haemolytic complement concentrations, and more frequent presence of rheumatoid factor. A liver biopsy performed in eight HCV + patients disclosed a range of lesions, from chronic active hepatitis (six patients) to persistent hepatitis (two patients). Lastly, treatment with interferon-alpha conducted over six months in two patients seemed to improve the peripheral neuropathy. CONCLUSIONS: Patients with peripheral neuropathy and essential mixed cryoglobulinaemia should be tested for anti-HCV antibodies to determine the appropriate treatment.

[Leptomeningeal gliomatosis. 2 clinicopathological cases]. / Gliomatose leptoméningée. Deux cas clinico-pathologiques.

Leptomeningeal gliomatosis is a diffuse glial infiltration of the subarachnoid space. It is primary and very rare when primary astrocytoma arises in the leptomeninges from heterotopic neuroglial tissue; it is secondary and more frequently reported when associated with a medullar or cerebral intraparenchymal astrocytoma and secondary involvement of the leptomeninges. Primary and secondary forms are difficult to differentiate before neuropathological examination. The authors report 2 anatomo-clinical cases of leptomeningeal gliomatosis in adults, with clinical courses of 6 months and 40 days respectively. The initial clinical picture was aseptic chronic or subacute meningitis. Cytologic examinations of the cerebrospinal fluid (CSF) showed moderate lymphocytosis, with elevated protein and low glucose levels, without abnormal cells. On case 2 CT scan and in case 1 spinal MRI isolated diffuse meningeal contrast enhancement was present, without intraparenchymal lesion. The neuropathological study revealed a diffuse astrocytoma glial leptomeningeal tumour with a focal involvement of the central nervous system (spinal cord in one case, temporal lobe in the other). In conclusion, an isolated aseptic lymphocytosis meningitis with meningeal abnormal signal may reveal leptomeningeal gliomatosis. Neuropathological examination can distinguish primary from secondary forms.

Duplication within chromosome 17p11.2 in 12 families of French ancestry with Charcot-Marie-Tooth disease type 1a. The French CMT Research Group.

Hereditary motor and sensory neuropathy type I (HMSN I), also designated Charcot-Marie-Tooth disease type 1 (CMT1), is a peripheral neuropathy frequently inherited as an autosomal dominant trait, characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity. A duplication within chromosome 17p11.2, cosegregating with the disease, has recently been reported in several CMT1a families. In order to estimate the frequency of this anomaly and determine the location of a duplication in this region, 12 CMT1 families were analysed with polymorphic DNA markers located within 17p11.2-12. Duplications were found in all families including loci D17S61 (EW401), D17S122 (VAW409R3a and RM11-GT), and D17S125 (VAW412R3). The duplications were completely linked and associated with the disease (lod score of 20.77 at zero recombination). Screening for the RM11-GT microsatellite showed that most of the duplicated haplotypes were heterozygous, supporting the hypothesis that the duplication resulted from an unequal crossing over. There was no significant haplotype association within the duplicated region suggesting that the duplication resulted de novo as an independent event in each family. In one family, recombination within the duplicated region was observed, indicating that genetic instability in 17p11.2 might be related to a high recombination rate. Since most cases of CMT1a seem to result from this segmental trisomy, it can be used as a basis for DNA diagnosis of the disease.