Carson Reider

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Predictors of nursing home placement in Huntington disease

Objective: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. Methods: Subjects were participants in the Huntington Study Group’s Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using χ2 and Student’s t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. Results: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents’ average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. Conclusions: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

PARK3 Influences Age at Onset in Parkinson Disease: A Genome Scan in the GenePD Study

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

Epidemiologic study of 203 sibling pairs with Parkinson’s disease: The GenePD study

Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

Electrocardiography in epilepsy patients without cardiac symptoms.

Sudden unexpected death in epilepsy (SUDEP) has been ascribed to cardiac arrhythmia, possibly triggered by cerebral events. Young, noncompliant, substance-abusing males with convulsions may be at risk. EEG/ECG studies have not shown significant cardiac arrhythmias in these and other seizure patients. We reviewed resting ECGs in 75 epilepsy patients and compared ventricular rate, PR interval, QRS duration, and QT interval corrected for heart rate (QTC) with normal ECGs recorded in age-matched patients without cardiac or neurologic disorders. No potentially lethal arrhythmias were noted in the seizure patients. Patients who fit the previously-described profile of high risk of SUDEP had more abnormal ECGs and ventricular rate was faster in these patients than in other epileptics. Patients with complex partial and secondarily generalized seizures had faster ventricular rates than other epileptics. No differences were noted in QRS duration or PR interval. QT was longer in patients with complex partial seizures than in control ECGs or other epileptic patients. These findings suggest that resting ECG has low diagnostic yield in epilepsy patients without cardiac symptoms. The factors possibly predisposing to SUDEP may relatively increase resting heart rate, however, and relatively increased QT interval with complex partial seizures may indicate some differences, possibly neurally-mediated, in cardiac excitability which could contribute to SUDEP.

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinsons disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinsons disease in our large sample of familial PD patients.

Reliability of reported age at onset for Parkinson's disease

An individuals age at onset of Parkinson disease (PD) can be collected through a variety of sources, including medical records, family report, and clinical observation. The most common source of PD age at onset information in the research setting is family‐report, which is then typically used to classify a subject as juvenile, young, or late age at onset. The reliability of the family‐reported age at onset of PD has not been rigorously examined. The present study used data from individuals diagnosed with PD to evaluate the reliability of age at onset information by comparing data obtained from three sources: 1) the subjects medical records, 2) a Family History Questionnaire, and 3) a Subject History Questionnaire. Among the 149 subjects with data for all three age at onset sources, the estimated reliability was R = 0.94. Similar reliability was observed when the sample was stratified based on gender, age at examination, disease duration, first symptom of PD, and years of education. The three measures of age at onset of PD show excellent agreement, strengthening confidence in the reliability of the reported age of clinical onset for PD.

Pramipexole in levodopa-treated Parkinson disease patients of African, Asian, and Hispanic heritage

Background: Little is known regarding the effects of antiparkinsonian drugs in US racial or ethnic minorities. Objective: To evaluate the safety, tolerability, and efficacy of adjunctive pramipexole in Parkinson disease (PD) patients of African, Asian, or Hispanic heritage stably treated with levodopa. Design: Multicenter, parallel-group, double-blind, randomized, placebo-controlled trial. Setting: Seventeen Parkinson Study Group sites in the United States and Puerto Rico. Patients: One hundred forty-four PD patients of African, Asian, or Hispanic heritage enrolled from January 1997 to August 1998 and observed until October 1998. Intervention: Subjects received pramipexole or placebo (3:1 ratio), 0.375 mg/d to a maximum tolerated dose (≤4.5 mg/d) over a 6-week period, achieving optimum levels (0.375, 1.5, 3.0, or 4.5 mg/d) in the 4-week maintenance period. Main Outcome Measure: Change in the sum of the Unified Parkinsons Disease Rating Scale parts 2 (activities of daily living) and 3 (motor) from baseline to week 10. Results: Parkinsonism improved (mean [SD] reduction in Unified Parkinsons Disease Rating Scale activities of daily living + motor score at 10 weeks, 10.27 [11.96] pramipexole vs 6.54 [13.58] placebo, P = 0.012) and was similar in each group. Adverse events occurred in 85.3% on pramipexole and 68.6% on placebo. Hallucinations and insomnia were more common on pramipexole than placebo (18 vs 0, P = 0.023, and 15 vs 0, P = 0.045, respectively). Conclusions: Pramipexole is an effective adjunctive antiparkinsonian therapy in PD patients of African, Asian, and Hispanic heritage. Tolerability and safety overall were similar among the groups, but differences in profiles of adverse effects and tolerability were suggested.

Test-retest reliability of an epidemiological instrument for Parkinson's disease

Reliability testing was conducted on a survey instrument for a genetic epidemiological study of Parkinsons disease (PD). Information on demographics, medical history, places of residence, and occupations was collected. The instrument was administered to 11 pairs of siblings discordant for PD and then re-administered after 4 weeks. Twenty of 22 (91%) subjects completed and returned the retest questionnaire. Overall reliability of the instrument was acceptable (kappa = 0.88). This instrument could be used to elicit reliable information from similar profiled subjects in future investigations.