The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3 Hz spike-wave EEG is one of the most common human epilepsies, and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike-wave EEG, with frequencies in the range of 5-7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3 Hz spike-wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming alpha1A subunit of CaV2.1 channels (CaV2.1alpha1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1alpha1, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.

Central pontine myelinolysis (CPM) can be regarded as one of the demyelinating syndromes. First described by Adams et al. in 1959 in their chronic alcoholic patients, it has now been described in the malnourished, the chronically debilitated, the renal, the hepatic and the transplant patient among others. Pathologically, it is defined as a symmetric area of myelin disruption in the center of the basis pontis, although similar symmetric lesions have also been described occurring with CPM as well as independently in other brain areas (extrapontine myelinolysis or EPM) including the cerebellar and neocortical white/gray junctional areas, thalamus and striatum. Possible mechanisms include a hyperosmotically induced demyelination process resulting from rapid intracellular/ extracellular to intravascular water shifts producing relative glial dehydration and myelin degradation and/or oligodendroglial apoptosis. The process most often occurs during rapid rebalancing of the electrolyte parameters in the hyponatremic patient. Avoidance of CPM/EPM is dependent upon recognizing those patients with conditions pre-disposing them to osmotic myelinolysis and then moderating the rate of normalization of the electrolyte imbalance. The morbidity and mortality of CPM/EPM has been greatly reduced by recognition of pre-disposing conditions, increased understanding of the pathophysiology, intensive treatment, and rapid diagnosis and monitoring with advanced neuroimaging.

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Our objective was to study a possible contribution of major histocompatibility complex (MHC) genes to soluble HLA-I synthesis in patients with systemic lupus erythematosus (SLE). Solid-phase enzyme-linked immunoassay (ELISA) was used to measure sHLA-I in the sera of 20 patients with SLE and 76 normal controls with known HLA phenotypes. Serial serum samples ( n=108) from the above group of patients ( n=19) were further investigated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. Soluble HLA-I levels were abnormally higher in patients with SLE than normal controls ( P<0.0002). No complete HLA haplotype has been identified to be correlated with high or low sHLA-I secretion. Only the sera of HLA-A23- or -A24- (splits of HLA-A9) positive individuals were found to contain high sHLA-I concentrations in both populations studied. The difference between sHLA-I of HLA-A24 patients ( n=7) and HLA-A24 normal controls ( n=19) was statistically highly significant ( P<0.0079). The results suggest that HLA-A24 may confer additional risk of more severe disease expression in female patients with SLE. The data imply that SLE patients carrying 39-kDa sHLA-I have increased risk of developing renal disease. A higher prevalence of 35-37 kDa was observed in patients with mild disease. Interestingly, 44-46 kDa was the predominant molecular form of sHLA-I in SLE patients with lymphocytosis with no evidence of organ involvement. Notably, all these variations were not reflected by differences in HLA phenotypes, with the exception of HLA-A24-positive patients, in whom the 44-46-kDa form occurs consistently but not exclusively. In summary, the results show a genetic heterogeneity of SLE with MHC control of the expression of sHLA-I concentrations and possible involvement of disease-associated factors that might potentiate a specific sHLA-I molecule synthesis.

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