The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease.

Mutations in glucosidase, beta, acid (GBA) are associated with cognitive impairment in Parkinson disease (PD) as well as dementia with Lewy bodies. For both of these diseases, dementia and hallucinations are typically treated with cholinesterase inhibitors and antipsychotics. However, in some lysosomal storage disorders certain antipsychotic medications are poorly tolerated. This study examined cholinesterase inhibitor and antipsychotic use in monoallelic GBA-related PD to explore potential pharmacogenetic relationships. Monoallelic GBA mutation carriers with PD (GBA-PD) with at least two clinic visits (n = 34) were matched for age-of-onset and gender to GBA and leucine-rich repeat kinase 2 (LRRK2) mutation negative idiopathic PD subjects (IPD) (n = 60). Information regarding cholinesterase inhibitor and antipsychotic use as well as impaired cognition (UPDRS Mentation >1) and hallucinations (UPDRS Thought Disorder >1) were obtained. GBA-PD more frequently reported hallucinations (HR = 5.0; p = 0.01) and they were more likely to have cognitive impairment but this was not statistically significant (HR 2.2, p = 0.07). Antipsychotic use was not significantly different between GBA-PD and IPD (HR = 1.9; p = 0.28), but GBA-PD were more likely to have sustained cholinesterase inhibitor use (HR = 3.1; p = 0.008), even after adjustment for cognition and hallucinations. Consistent with reports of worse cognition, GBA-PD patients are more likely to use cholinesterase inhibitors compared to IPD. While there was no difference in antipsychotic use between IPD and GBA-PD, persistent use of quetiapine in GBA-PD suggests that it is tolerated and that a significant interaction is unlikely. Further prospective study in larger samples with more extensive cognitive assessment is warranted to better understand pharmacogenetic relationships in GBA-PD.

Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease.

BACKGROUND: Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described. METHODS: To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [(18)F]-fluorodeoxyglucose or [(18)F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations. RESULTS: Parkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [(18)F]-fluorodeoxyglucose (n = 3) and [(18)F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease. CONCLUSIONS: Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects.

Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study.

OBJECTIVE: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). METHODS: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. RESULTS: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). CONCLUSION: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.

OBJECTIVE: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research. METHODS: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations. RESULT: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies. CONCLUSION: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.

Gender differences in the IL6 -174G>C and ESR2 1730G>A polymorphisms and the risk of Parkinson's disease.

The -174G>C (rs1800795) single nucleotide polymorphism (SNP) in the promoter of the interleukin-6 (IL6) gene and the 1730G>A (rs4986938) SNP in the estrogen receptor beta (ESR2) may influence the risk of Parkinson's disease (PD). We investigated these SNPs in 380 unrelated US Caucasian PD cases and 522 controls, including 452 individuals of Ashkenazi Jewish (AJ) origin (260 PD, 192 controls). The G allele of the -174G>C SNP was more common in AJ PD cases (p=0.033) as well as in Non-Jewish (NJ) men with PD (p=0.022). The GG genotype increased the risk of PD by over two fold in NJ men (OR=2.11, 95%CI: 1.14-3.89, p=0.017), and approached significance in the total AJ group with PD (OR=1.42, 95%CI: 0.97-2.06, p=0.067). The A allele of the ESR2 1730G>A SNP was associated with a decreased risk for PD in AJ women, and in this group, having the AA genotype decreased the risk of PD by half (OR=0.45, 95%CI: 0.22-0.92, p=0.029). Our data supports a role for the IL6 -174G>C G allele in AJ individuals overall. In NJ Caucasians, this role appears to be gender mediated. In both groups, the effect is independent from ESR2 1730G>A. A separate association for the ESR2 1730G>A SNP was found exclusively in women of AJ descent. Other polymorphisms in tight linkage disequilibrium with the SNP differentially influencing expression, ethnic differences in allele distribution, and gender differences in genetic load related to PD, may underlie our findings. Larger studies in diverse populations, including analysis of surrounding regions are recommended.

The relation between depression and parkin genotype: the CORE-PD study.

BACKGROUND: Mutations in parkin are a known genetic risk factor for early onset Parkinson's disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. METHODS: We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. RESULTS: Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2-163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0-332.0), depression (score ≥ 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1-657.4), and BDI-II total depression score (ß = 8.4; 95% CI 2.4-11.3) compared to those without parkin mutations. CONCLUSIONS: Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD.

Olfactory dysfunction in LRRK2 G2019S mutation carriers.

BACKGROUND: Olfactory dysfunction is an established nonmotor feature of idiopathic Parkinson disease (PD), which may precede disease onset. Olfaction is likely disturbed in patients with PD with leucine-rich repeat kinase (LRRK2) G2019S mutations, although the degree of impairment is debated. It is also unclear whether mutation carriers who have not yet manifested with PD have olfactory disturbances. METHODS: Thirty-one subjects with LRRK2 G2019S mutation-related PD (PD-manifesting carriers [PD-MC]), 30 subjects with PD without mutations (PD noncarriers [PD-NC]), 28 mutation carrier family members (nonmanifesting carriers [NMC]), and 46 controls completed the University of Pennsylvania Smell Identification Test (UPSIT). Generalized estimating equations were applied to determine whether olfactory score was associated with PD and LRRK2 mutation status. RESULTS: As expected, having PD was associated with impaired olfaction regardless of LRRK2 mutation status. More importantly, however, impaired olfaction was increased overall in LRRK2 carriers both with and without PD, though the impairment was only present in a subset of NMCs. Compared to controls, the mean score was lower among NMC (difference = -3.518, p = 0.006), MC (difference = -7.677, p < 0.0001), and idiopathic PD (PD-NC) (difference = -13.810, p < 0.0001). Olfaction was better among MC (PD-MC) than non-LRRK2 PD (PD-NC) (difference = 6.13, p = 0.0012). Group differences from the continuous analysis were maintained in dichotomous analysis stratifying at 15th percentile for age and gender. CONCLUSION: Olfaction is impaired in LRRK2 G2019S-mutation related PD, although less overall than other PD. Further, olfaction is impaired in a subset of LRRK2 NMC, suggesting that olfaction may be a marker for development of PD in this group, and that longitudinal studies are warranted.

Gender differences in the risk of familial parkinsonism: beyond LRRK2?

G2019S mutations in the LRRK2 gene are responsible for up to 18% of PD in individuals of Jewish descent. While a male preponderance of Parkinson disease (PD) has been consistently reported, this gender difference is not noted in LRRK2 G2019S mutation carriers. In order to test whether there is an increased genetic component in women of Jewish background in general, we examined family history of parkinsonism in 175 Jewish PD patients (82 female and 93 male) and assessed whether parkinsonism was more frequent in family members of women with PD in comparison with family members of men with PD, adjusting for LRRK2 G2019S mutations in the proband. Using Cox proportional hazard models to evaluate the risk of parkinsonism among family members of PD subjects, having a daughter with PD compared with a son was associated with increased risk of parkinsonism in the parent (HR 2.59, p=0.014) as was having a child with a LRRK2 G2019S mutation (HR 3.19, p=0.003). The increased risk among parents of women with PD persisted when adjusting for LRRK2 status (HR 2.19, p=0.023). Among individuals of Jewish descent, there is a relatively greater genetic load in women with PD, and this is not fully accounted for by the G2019S mutation. Further study that evaluates family information bias and assesses the role of glucocerebrosidase mutations is indicated.

Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.

BACKGROUND: While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown. OBJECTIVE: To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives. METHODS: We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking. RESULTS: Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001). CONCLUSION: Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia.

DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of approximately 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia. We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%. Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia.

OBJECTIVE: To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia. METHODS: Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia mutations were scanned with [(11)C] raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions. RESULTS: Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations. CONCLUSIONS: Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.

Etiology of musician's dystonia: familial or environmental?

OBJECTIVE: To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician's dystonia (MD) and to identify possible environmental triggers. METHODS: The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH-]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD. RESULTS: A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH- families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members. CONCLUSION: Our results suggest a genetic contribution to musician's dystonia with phenotypic variability including focal task-specific dystonia.

Sixty hertz pallidal deep brain stimulation for primary torsion dystonia.

OBJECTIVE: To evaluate the safety and efficacy of 60 Hz deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 15 consecutive patients with primary dystonia. METHODS: We conducted a retrospective analysis of clinic charts relative to 15 consecutive patients with medically refractory primary dystonia who underwent stereotactic implantation of DBS leads within the GPi. Twelve had the DYT1 gene mutation. Frame-based MRI and intraoperative microelectrode recording were employed for targeting. All patients were treated exclusively with stimulation at 60 Hz from therapy outset. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary measure of symptom severity at baseline and 1, 3, 6, and 12 months after treatment. RESULTS: All patients tolerated DBS treatment well and showed a progressive median improvement of their BFMDRS motor subscores from 38% at 1 month to 89% at 1 year (p < 0.001, Wilcoxon rank sum test). The disability subscores were similarly improved. The clinical response to DBS allowed seven patients to completely discontinue their medications; six additional patients had reduced their medications by at least 50%. Surgical complications were limited to two superficial infections, which were treated successfully. CONCLUSIONS: Stimulation of the internal globus pallidus at 60 Hz is safe and effective for treating medically refractory primary dystonia.

Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers.

Although myoclonus and dystonia are the hallmarks of myoclonus-dystonia (M-D), psychiatric features, particularly obsessive-compulsive disorder and alcohol dependence, have been reported in three families linked to chromosome 7q21. As the epsilon sarcoglycan (SGCE) gene for M-D was subsequently identified, we evaluated the relationship between psychiatric features and SGCE mutations in these original and two additional families and confirm that OCD and alcohol dependence are associated with manifesting mutated SGCE.

Genetics of dystonia.

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.

Dominantly transmitted focal dystonia in families of patients with musician's cramp.

Musician's dystonia is generally considered a sporadic disorder. We present three families with the index patient affected by musician's dystonia, but other forms of upper limb focal task-specific dystonia (FTSD), mainly writer's cramp, in seven relatives. Our results suggest a genetic contribution to FTSD with phenotypic variability, including musician's dystonia.

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia.

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.

A new screening tool for cervical dystonia.

BACKGROUND: Family studies of dystonia may be limited in part by small family size and incomplete ascertainment of dystonia in geographically dispersed families. Further, prevalence estimates of dystonia are believed to be underestimates, as most studies are clinic-based and many individuals do not present to a physician or are misdiagnosed. As a low-cost highly sensitive screening tool is needed to improve case detection for genetic and epidemiologic studies, the authors developed the Beth Israel Dystonia Screen (BIDS), a computer-assisted telephone interview. OBJECTIVE: To evaluate the validity and utility of a computer-assisted telephone interview in screening for cervical dystonia. METHODS: The BIDS was administered and videotaped neurologic examinations performed on 193 individuals from 16 families with cervical and cranial dystonia. With use of a final rating of definite dystonia, as determined by video review of a systematic neurologic evaluation, as the gold standard, the predictive value of a subset of questions from the BIDS was assessed. RESULTS: A positive response to at least two of five screening questions had a sensitivity for cervical dystonia of 100% and a specificity of 92%. With use of a positive response to three or more questions, definite dystonia was determined with 81% sensitivity and 97% specificity. CONCLUSIONS: The Beth Israel Dystonia Screen (BIDS) identifies cervical dystonia with excellent sensitivity and specificity in a family-based sample. The authors recommend the BIDS for family studies, but cross-validation in a population sample is advisable before applying this method to epidemiologic studies.

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.