Autosomal dominant Parkinson's disease in a large German pedigree.

OBJECTIVE: While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. METHODS: Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. RESULTS: Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. CONCLUSIONS: The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD.

Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci?

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.

High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening.

Mutations in GTP cyclohydrolase I (GCHI) are found in 50 to 60% of cases with dopa-responsive dystonia (DRD). Heterozygous GCHI exon deletions, undetectable by sequencing, have recently been described in three DRD families. We tested 23 individuals with DRD for the different mutation types by conventional and quantitative PCR analyses and found mutations, including two large exon deletions, in 87%. The authors attribute this high mutation rate to rigorous inclusion criteria and comprehensive mutational analysis.