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Background: Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by paresthesias and an intense urge to move the legs with a considerable familial aggregation. To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5). Patients/Methods: We identified a four-generational German RLS family with 37 family members including 15 affected cases. We performed linkage analysis using microsatellite markers at the five known loci. Prompted by the identification of a potentially shared haplotype near the RLS3 locus, we expanded the investigated linkage region on chromosome 9p using additional DNA markers. Results: Mode of inheritance in our RLS family was compatible with an autosomal dominant pattern, and disease onset was mainly in childhood or adolescence. We excluded linkage to the RLS1, RLS2, RLS4, and RLS5 loci. However, we identified a likely new RLS gene locus (RLS3*) on chromosome 9p with a maximum lod score of 3.60 generated by model-based multipoint linkage analysis. A haplotype flanked by D9S974 and D9S1118 in a 9.9-Mb region, centromeric to RLS3, was shared by all 12 investigated patients. In addition, 11 of them carried a common haplotype extending telomeric to D9S2189 that is located within RLS3. Conclusions: We demonstrate linkage to a locus on chromosome 9p that is probably distinct from RLS3. Our family with a rather homogeneous phenotype and very early disease onset represents a unique opportunity to further elucidate the genetic causes of the frequent restless leg syndrome.

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease.

A novel Val154--Ile mutation in the D2 dopamine receptor (DRD2) on chromosome 11q23 has recently been shown to be associated with myoclonus dystonia (M-D) in one large family. Sequence analysis of the DRD2 gene in 5 M-D patients from different families did not reveal any mutations, nor was there evidence of linkage to the 11q23 region in the DRD2 gene in four other families. Receptor binding and signal transduction assays of the DRD2 mutant and wild-type receptors revealed identical agonist and antagonist affinities and functional responses. These studies suggest that M-D is genetically heterogeneous. The molecular mechanisms through which the Val--Ile mutation may contribute to M-D remain to be determined.

To map a gene for cataracts in a family with congenital nuclear and sutural cataracts and to examine candidate genes in the linked region.A large family with autosomal dominant congenital nuclear and sutural cataracts was identified and characterized. A genome-wide screen was conducted with a set of markers spaced at 10- to 15-cM intervals, and linkage was assessed using standard LOD score analysis.Fifteen (15) affected individuals were identified. This form of congenital cataracts maps to a 12-cM region on chromosome 3q21.2-q22.3 between markers D3S3674 and D3S3612, with a maximum multipoint LOD score of 6.94 at D3S1273. The crystallin gene, CRYGS, was excluded as a candidate gene for this locus.There are now more than 12 different genetic loci that cause congenital cataracts. The most recent locus to be identified is on chromosome 3q21.2-q22.3, in a family with congenital nuclear and sutural cataracts.

Rapid-onset dystonia-parkinsonism (RPD) is an autosomal dominant movement disorder characterized by sudden onset of persistent dystonia and parkinsonism, generally during adolescence or early adulthood. Symptoms evolve over hours or days, and generally stabilize within a few weeks, with slow or no progression. Other features include little or no response to L-dopa, and low levels of homovanillic acid in the central nervous system. Neuroimaging studies indicate no degeneration of dopaminergic nerve terminals in RDP, suggesting that this disorder results from a functional deficit, as in dystonia, rather than neuronal loss, as in Parkinson's disease. We studied 81 members of two midwestern US families with RDP, 16 of whom exhibited classic features of RDP. We found significant evidence for linkage in these two families to markers on chromosome 19q13, with the highest multipoint LOD score at D19S198 (z = 5.77 at theta = 0.0). The flanking markers D19S587 and D19S900 define a candidate region of approximately 8 cM. Although RDP itself is a rare condition, it is important because it has clinical and biochemical similarities to both Parkinson's disease and dystonia. Identification of the genetic defect in RDP holds promise for understanding the underlying disease processes of both of these more common diseases.

Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait (McKusick 277600). We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals.

Idiopathic torsion dystonia (ITD) is characterized by sustained, involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Most familial forms of ITD display autosomal dominant inheritance with reduced penetrance. Linkage analysis has been previously used to localize a dystonia gene to the 9q32-34 region in a large non-Jewish family and in a group of Ashkenazi Jewish families. Utilizing GT repeat polymorphisms from this region, here we demonstrate that the gene causing dystonia in Ashkenazi Jews can be localized to the 11-cM interval between AK1 and D9S10. Linkage analysis in the non-Jewish family is also consistent with occurrence of the gene in this region, although positive lod scores extend over a greater than 20-cM interval in that family. These results set the stage for positional cloning of the dystonia gene. Currently there are no known candidate genes in this region.

We report the results of a simulation study designed to assess the capability of segregation analysis to detect Mendelian transmission and to estimate genetic model parameters for complex qualitative traits, characterized by heritability in the range 0.20-0.45 and low heterozygote penetrance. The pedigree analysis package, PAP, was used to perform the analyses. For all data sets, models of no transmission could be rejected. In most cases, models of Mendelian transmission could not be rejected; however, several samples approached significance levels. When Mendelian transmission was assumed, reasonably good parameter estimates were obtained, although heterozygote penetrances were often overestimated. Different sampling schemes were imposed on the simulated data in order to examine the extent of information loss with the reduction in sample size. One of these strategies (a sequential sampling scheme) appears to have resulted in critical loss of information in some cases.

We analyzed disease-marker associations in Problem 3 for the Genetic Analysis Workshop II, using PAP for segregation analysis and LIPED for linkage analysis. In this report we present aspects of our analyses that are not reported in the summary [MacCluer et al, 1984]. Certain features that we added to the running of LIPED to facilitate the analysis are discussed. Furthermore, we tested for Mendelian transmission in the hypothetical trait locus and we calculated modified relative risks for marker-trait genotypes. Some of the problems involved in analyzing complex associations among loci are discussed.

Multi-point linkage analyses of autosomal dominant form of torsion dystonia with linkage groups on chromosomes 11p, 13q, 21q are reported. Analyses are based on family data from a single, large, non-Jewish pedigree. Large portions of chromosomes 11p and 13q, and virtually the entire long arm of chromosome 21 are excluded from linkage with dystonia. Practical aspects of designing multi-point analyses are discussed.

This study examined the method of simultaneous estimation of recombination frequency and parameters for a qualitative trait locus and compared the results with those of standard methods of linkage analysis. With both approaches we were able to detect linkage of an incompletely penetrant qualitative trait to highly polymorphic markers with recombination frequencies in the range of .00-.05. Our results suggest that detecting linkage at larger recombination frequencies may require larger data sets or large high-density families. When applied to all families without regard to informativeness of the family structure for linkage, analyses of simulated data could detect no advantage of simultaneous estimation over more traditional and much less time-consuming methods, either in detecting linkage, estimating frequency, refining estimates of parameters for the qualitative trait locus, or avoiding false evidence for linkage. However, the method of sampling affected results.