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.

[Hirayama disease in Germany: case reports and review of the literature]. / Hirayama-Syndrom in Deutschland : Fallberichte und Literaturübersicht.

Hirayama disease is a juvenile benign distal upper limb muscular atrophy rarely observed in Europe, usually monomelic involving C7-Th1 innervated muscles. It is characterized by insidious onset and a self-limited course within a few years. The pathogenesis of this mostly sporadic disease is not fully clarified. Cervical flexion myelopathy with mechanical ischemic damage of spinal motoneurons is the best established pathogenetic hypothesis, but neurodegenerative and autoimmune causes are also debated. Typically, young men of Asian origin are affected. Here we describe three German Caucasian patients with Hirayama disease and provide an up-to-date review of the literature.

[When should we start medical treatment in Parkinson disease]. / Wann sollten wir mit der medikamentösen Therapie beim Morbus Parkinson beginnen?

There is still uncertainty when to start medical treatment in Parkinson disease (PD). Lack of availability of an unambiguous neuroprotective treatment and concern of potential short or long term adverse effects of medication often lead to an "wait and see" policy regarding initiation of medical treatment. This can result in insufficient symptom control and potentially reduced quality of life. There is increasing evidence of negative influence on disease progression by delayed onset of medical drug treatment in PD. It is under discussion whether symptomatic treatment in PD supports compensatory mechanisms of the cortico-basalganglionar system which might have been responsible for a physically intact motor function despite considerable and increasing nigro-striatal dopaminergic deficit during the preclinical phase of the disease. Therefore, symptomatic treatment might modify disease progression by supporting compensatory mechanisms within the basal ganglia. In this paper we discuss pro and contra of early medical treatment onset in PD under consideration of hitherto available scientific investigations.

[Gait disturbances in neurology]. / Gangstörungen in der Neurologie.

Gait disorders lead to loss of mobility and therefore of an individual's autonomy. The greatest risk factor for gait disorders is old age. Other important factors include drugs and their side effects, cognitive impairment, and alcohol abuse. In successful aging there is only a slight decline in gait velocity. The classification into lower- (peripheral), middle- (spinal, basal ganglia), and higher-level gait disorders (e.g. frontal or psychogenic) is still common but contradictory. Gait disorders in neurology are frequent. Detailed descriptions of gait patterns in hypokinetic gait disorders, dystonic, hemi-, and paraparetic gait, ataxia, vestibular, neuromuscular, and psychogenic gait are given. Besides reduction of risk factors, improving the physical state (physiotherapy, sports), descriptions of walking aids, and the prevention of falls are extraordinarily important for the therapy of gait disorders.

[Chorea]. / Chorea.

Chorea (from the greek word "dance") is characterized by short, involuntary, irregular, nonrepetitive, adventitious muscular contractions. The resulting movements may occur abruptly at any part of the body, but may also spread from one body part to another. The most important condition showing chorea as its core symptom is Huntington's disease. It is inherited as an autosomal dominant trait. During its course it presents as an admixture of neurological and psychiatric features. Several rare neurodegenerative diseases and conditions of inborn errors of metabolism present with chorea mostly between childhood and adolescence. Among these, the paroxysmal choreoathetoses are important for the differential diagnosis of seizures and transitory ischaemic attacks later in life. In adults, symptomatic chorea may occur in many drug-induced, metabolic, infectious, immunological, toxic, and vascular conditions. In addition to the basic treatments of these illnesses there are selected drugs to provide satisfactory symptomatic relief from the abnormal movement.

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Effects of dyskinesias in Parkinson's disease on quality of life and health-related costs: a prospective European study.

The treatment of Parkinson's disease (PD) with l-DOPA leads to involuntary movements (dyskinesias). This 6-month observational study in three European countries in PD patients with various degrees of motor complications examined the effects of dyskinesias on the quality of life (QoL) of patients and health care costs. Retrospective and prospective health economic data were collected, and QoL of patients was measured using the Short Form-36 (SF-36) and the PD Quality of Life (PDQL) Scale. Regression analysis was used to estimate the adjusted effects of dyskinesias on QoL and costs, whilst accounting for the potentially confounding effects of disease progression, motor fluctuations and country. Increasing dyskinesia scores on either the Unified PD Rating Scale or the Goetz Dyskinesia Rating Scale were associated with significant reductions in QoL scores on the SF-36 and PDQL Scale. Increasing dyskinesia severity was also associated with increased depression scores on the Montgomery-Asberg Depression Rating Scale along with significant increases in health care costs. The effects of dyskinesia on QoL, depression and costs decreased but remained significant after adjustment for the confounding effects of disease progression and motor fluctuations. In conclusion, dyskinesias may adversely affect QoL and increase health care costs in patients with PD. Future studies should evaluate the potentially beneficial effects in terms of QoL and health care costs of strategies to delay the onset of, or the treatment of, dyskinesias.

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

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.

[Diagnosis and treatment of parkinsonian syndrome]. / Diagnose und Therapie des Parkinson-Syndroms. Die Rolle des Hausarztes: aufmerksamer Beobachter.

Parkinsonian syndrome is a clinical diagnosis. The appropriate selection of the diagnostic and therapeutic regime and its continuous monitoring are tasks for the specialist. The observations of the familydoctor can provide important information when the clinical course does not develop as expected. For idiopathic parkinsonian syndrome a wide range of medicinal, surgical and physical treatments are available. Physiotherapeutic and, where indicated, ergotherapeutic measures should form a regular component of the prescribed treatment.

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.

Mutations in DYT1: extension of the phenotypic and mutational spectrum.

BACKGROUND: Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three-base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD). OBJECTIVE: To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls. METHODS: The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases. RESULTS: The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1. CONCLUSIONS: In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD.

A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study.

OBJECTIVE: To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13. METHODS: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. RESULTS: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005). CONCLUSIONS: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Differentiation of parkinsonian syndromes according to differences in executive functions.

Groups of patients with Parkinson's disease (PD), striatonigral degeneration-type multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) with motor disability stages II and III according to Hoehn and Yahr, and a healthy control group were compared using neuropsychological tests of executive functions. The results indicate that all three patient groups were impaired in the tests of executive functions. In comparison with healthy subjects, the three patient groups showed impaired performance regarding verbal fluency, problem solving and verbal and figural working memory. Patients with PD differed significantly from healthy subjects in a test of verbal recency, while patients with MSA or PSP were unimpaired. The comparison of patient groups revealed no differences between PD and MSA patients. However, patients with PSP showed greater impairment in both phonemic and semantic fluency than patients with PD or MSA. Using discriminant function analysis, it was found that variables derived from four verbal fluency tasks (simple and alternate semantic and phonemic fluency) discriminated among the three patient groups at a level significantly exceeding chance. Over 90% of patients with PSP were correctly classified. Patients with PD and MSA were correctly classified in over 70% of cases. These results suggest that verbal fluency tasks may be sensitive measures in the differential diagnosis of PD, MSA and PSP.

Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region.

Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant disorder mapped to chromosome 16q22.1 in a large Utah kindred. The clinical phenotype is characterized by cerebellar ataxia with sensory neuropathy. We describe a five-generation family from northern Germany with similar clinical findings linked to the same locus. Haplotype analyses refined the gene locus to a 3.69 cM interval between D16S3019 and D16S512. Analysis of nine CAG/CTG tracts in this region revealed no evidence for a repeat expansion.

Focal and segmental primary dystonia in north-western Germany--a clinico-genetic study.

OBJECTIVES: To determine the frequency of familial focal and segmental dystonias in a large patient cohort with primary dystonia from north-western Germany. MATERIALS AND METHODS: In this study, 130 patients with focal or segmental dystonia were examined and a family history was obtained. Whenever possible, affected relatives were examined (a total of 789 first-degree relatives). Data on disease duration, age at disease onset and age of the patients were investigated by Student's t-test and a segregation analysis was performed by Weinberg's proband method. RESULTS: Age at onset of disease was significantly later in the blepharospasm group. Only in the writer's cramp group were women outnumbered by men. A positive family history was found in 15 of the 130 index patients (11.5%). None of 102 index patients tested carried the GAG deletion in the DYT1 gene. CONCLUSIONS: In accordance with previous series our study provides evidence that primary focal dystonia may have a genetic etiology, most probably caused by an autosomal dominant trait with reduced penetrance.

[Pesticide exposure and Parkinson's syndrome - the epidemiological and experimental evidence]. / Pestizidexposition und Parkinson-Syndrom Zur epidemiologischen und experimentellen Evidenz.

Retrospective case-control studies among patients with idiopathic Parkinson's syndrome (IPS) show a positive association to the existence of a - mostly premorbid - exposure to pesticides. In acute pesticide intoxications, usually symptoms other than parkinsonism are found. Therefore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) continues to be the agent best documented both experimentally and clinically to cause a clinical syndrome comparable to IPS. It is debated whether still unknown effects between exogenous pesticide exposure and the xenobiotic enzyme system may lead to IPS in single genetically susceptible individuals. In practice, the present data on the problem of pesticide exposure in IPS are irrelevant for medicolegal considerations.