Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations.

OBJECTIVE: To investigate substantia nigra (SN) echogenicity in members of a family with homozygous and heterozygous PTEN induced kinase (PINK1) mutations with or without signs of Parkinson's disease (PD). METHODS: Transcranial sonography (TCS) was used to investigate 20 members of a family with PINK1 mutations, including four homozygous and 11 heterozygous mutation carriers and five individuals with no mutation. For comparison, a healthy control group of 18 subjects without a positive family history of PD (control group) and a healthy control group of 15 subjects with a positive family history of sporadic PD (relative group) were investigated. For statistical analysis, the larger area of the two SNs echogenicity (aSNmax) of each individual was selected. RESULTS: A significantly increased aSNmax was found for all subgroups compared with the control group. The group of homozygous carriers of a PINK1 mutation had a significantly increased aSNmax compared with all of the other subgroups, except the group of heterozygous mutation carriers. CONCLUSIONS: These findings in carriers of a PINK1 mutation are comparable with those in carriers of Parkin mutations and non-genetic PD. The increased aSNmax in family members without a mutation suggests an additional contributing factor independent of the PINK1 mutation that may also play a role in relatives of patients with sporadic PD.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

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.

MECP2 mutations in Serbian Rett syndrome patients.

BACKGROUND: Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. Eight years ago, the MECP2 gene was associated with the devastating clinical features observed in Rett syndrome patients. OBJECTIVES: To investigate the spectrum and the frequency of MECP2 mutations in Serbian Rett syndrome patients. PATIENTS AND METHODS: We screened the MECP2 coding region by conventional mutational screening (single-strand conformation polymorphism/sequencing) in 24 patients of Serbian origin and in their 41 unaffected family members. In search for gene dosage alterations in seemingly mutation-negative girls, we developed a new, specific quantitative PCR method. RESULTS: Nineteen patients (79%) carried MECP2 mutations, five of which were novel (one nonsense mutation, one duplication and three deletions). Fourteen previously described disease-causing sequence changes and one polymorphism were also detected. Detailed case reports are given for the carriers of the novel mutations. Large MECP2 rearrangements cause Rett syndrome in a significant number of girls without 'classic' mutations in this gene. Therefore, we developed a specific quantitative PCR method, covering MECP2 exons 3 and 4, which previously has not been used for screening. No dosage alterations of the two exons were found in the four tested mutation-negative girls. CONCLUSIONS: This is the first genetic study of Rett syndrome in Serbian patients describing the MECP2 mutational and phenotypic spectrum in this population. Detailed clinical descriptions of this ethnically homogeneous patient population add to our knowledge of genotype/phenotype correlations in this severe condition.

DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease.

BACKGROUND: Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families. METHODS: To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described. RESULTS: The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene. CONCLUSIONS: Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

Spinocerebellar ataxia type 17 in the Yugoslav population.

OBJECTIVES: (1) Analysis of Spinocerebellar ataxia type 17 (SCA17) locus in a group of ataxic patients excluded on other known SCAs; (2) assessment of frequency distributions of SCA17 alleles in the Yugoslav population. MATERIAL AND METHODS: Study includes 115 non-related Yugoslav patients belonging to autosomal-dominant cerebellar ataxias or to sporadic idiopathic adult-onset ataxia and 115 controls. Analysis of SCA17 locus was performed using polymerase chain reaction. RESULTS: None of the analyzed patients show the presence of mutation in SCA17 locus. In the group of patients 12 different alleles in the range of 30-42 repeats were observed, while in healthy population eight alleles in the range of 30-40 repeats were detected. CONCLUSION: (1) None of 115 non-related Yugoslav ataxic patients belong to any known SCAs nor to DRPLA gene; (2) the distribution of SCA17 alleles in the Yugoslav population is consistent with the distribution in other populations and (3) the paucity of alleles with more than 39 repeats could suggest that SCA17 is very rare in the Yugoslav population.

SCA2 and SCA3 mutations in young-onset dopa-responsive parkinsonism.

In this study no one of our 85 patients of Serbian origin with young-onset (