The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders characterized by onset with gait ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have demonstrated previously genetic heterogeneity within these disorders by excluding the disease locus from the documented spinocerebellar ataxia locus (SCA1) on chromosome 6p in a large Cuban founder population. We now report the assignment of a second locus for ADCA (SCA2) to chromosome 12q23-24.1 following linkage analyses carried out for the Cuban pedigrees, with probable flanking markers D12S58 and phospholipase A2. Investigation of linkage to the interval containing SCA2 for seven French ADCA families, previously excluded from linkage to SCA1, provides preliminary data suggesting the existence of a third ADCA locus (SCA3).

Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease.

Background— Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown. Methods and Results— We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P =0.005) and cholesterol (LOD, 2.2; P =0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P =0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P =0.0002). Conclusions— Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.