NARCOLEPSY--MULTICENTER GENETIC AND FAMILY STUDY

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Narcolepsy, as presently understood, is a central nervous system disorder characterized by disabling dysregulation of sleep and wakefulness. Narcolepsy is not rare and afflicts about 1 of every 1000 to 2000 North Americans. While the inheritance of narcolepsy is not known, the disorder is strongly, but NOT always, associated with subtypes of the HLA region chromosome 6 [HLA-DR15(DRB1*1501) and HLA-DQ6(DQBl*0602)]. Thus, the presence of HLA-associated and non-HLA associated forms indicates that narcolepsy is at least two disorders. Further, both the HLA associated (H+) and the non-HLA associated ( H - ) form occur as sporadic isolated cases (F-) and family history positive cases. It is possible that each of the four types, (H+F-),(H+F+), (H-F-), (H-F+) represent different etiologies. This Multi-Center Clinical Study grant is based on several key findings: (a) the strong association with the same HLA alleles across several populations indicates a probable role for these alleles/haplotypes, ( b ) only 70 percent of the probands with narcolepsy have the HLA-associated alleles and they tend not to have affected relatives, (c) the majority of families with multiple affected members do not have the associated HLA haplotypes, (d) one pair of MZ twins differs with respect to clinical symptoms, with/without cataplexy, and (e) sleep studies of first degree relatives of probands reveal subtle sleep disturbances. Our overall goals are: (i) Ascertain an additional 113 probands and their families via a sequential sampling scheme which requires that all patients selected as probands meet the strict clinical criteria for narcolepsy (ignoring HLA type) and that all first degree relatives of probands be studied. Rigorous sampling in this manner avoids bias due to selecting "interesting" families and permits accurate evaluation of the proportion of narcoleptics patients with the associated HLA types, segregation analysis for narcolepsy and the related clinical subtypes, as well as linkage analyses. (ii) Identify the modes of inheritance for the two familial forms of narcolepsy. Determine the familial aggregation and inheritance of the related sleep disorder symptoms (e.g., excessive daytime sleepiness). (iii) Using both the proband series families and selected "high density" pedigrees, map the location of the non-HLA associated familial form via a genome DNA marker screen and linkage analyses. (iv) Examine the role of the HLA-associated alleles in narcolepsy through both co-segregation and association studies.