LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation.

BACKGROUND AND OBJECTIVE: Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families. DESIGN: We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations. RESULTS: Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A>C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37-72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease.

Ancient origin of the CAG expansion causing Huntington disease in a Spanish population.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, in Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (two mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCG-rs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking short tandem repeats (STRs) D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.

The SCOPA-Motor Scale for assessment of Parkinson's disease is a consistent and valid measure.

OBJECTIVE: The SCOPA-Motor Scale (S-MS) for assessment of Parkinson's disease (PD), contains 21 items in three domains: Motor examination, Disability, and Complications. Our objective was to validate the S-MS Spanish version. STUDY DESIGN AND SETTING: This validation study was based on a multicenter, cross-sectional, one-point-in-time evaluation design. The applied measures were: Unified Parkinson's Disease Rating Scale-3.0 (UPDRS); S-MS; PD Global Evaluation (PDGE); and Clinical Global Impression of severity (CGI). Completeness of data collection, floor and ceiling effect, internal consistency, precision, and construct and discriminative validity were analyzed in 151 PD patients. RESULTS: Scores from S-MS were fully computable. Floor effect was high for Complications (43.7%). Cronbach's alpha was > 0.90 for every domain, and item-total correlation was > 0.70 except for Examination. Standard error of measurement (SEM) ranged from 0.40 to 2.4. Convergent validity with corresponding UPDRS sections yielded coefficients > 0.90. Discriminative validity across Hoehn and Yahr (HY) and CGI stages was significant (Kruskal-Wallis, P < .0001). Insofar as internal consistency was concerned, alpha-values of the Examination sections were marginally higher for the UPDRS than for the S-MS (a finding perhaps accounted for by redundancy in this part of the UPDRS). CONCLUSION: The S-MS is a consistent and valid scale, shorter by almost half than the UPDRS.

Evolution of dose and response to botulinum toxin A in cervical dystonia: a multicenter study.

Botulinum neurotoxin (BoNT) is an effective treatment for cervical dystonia (CD). Long-term changes of several variables, including the dose of BoNT, in these patients is largely unknown. We reviewed the clinical charts of 275 patients with CD treated with BoNT type A (BoNT-A) for at least 5 years since 1989 at ten tertiary centers. The mean dose of BoNT-A per session during the first 5 years of treatment was calculated and the appearance of resistance was noted. The dose of BoNT-A for the whole group showed a significant trend to increase over time (year 1: 180 ± 65 U; year 5: 203 ± 63 U; ANOVA: p < 0.0001). However, when we studied the evolution of the dose of BoNT-A for those patients (n = 49) first injected after 2000 (introduction of current BOTOX preparation in our country), there was no significant increase in dose (year 1: 181.8 ± 75 U; year 5: 181.7 ± 75 U; ANOVA p: ns). A total of 19 patients became secondary nonresponders; all but one of these patients began BoNT-A treatment before 2000. In summary, there is a statistically significant increase of mean dose of BoNT-A per session over time, and this could be explained by the appearance of secondary nonresponders. On the other hand, those patients initially treated after 2000 did not show any statistically significant increase in dose for 5 years. This could be explained by better experience and techniques, fewer immunogenic problems with the current BoNT-A, and also less variability of the dose per vial.

Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis.

A 39-year-old asymptomatic man showed elevated serum ferritin levels, mild hypertransaminasemia and serum ceruloplasmin almost undetectable. There was histological iron accumulation within the hepatocytes and also in the central nervous system (MRI). A genetic analysis revealed a new missense mutation in the ceruloplasmin gene. Two of the other four siblings were also affected by this mutation.