A susceptibility locus for Parkinson's disease maps to chromosome 2p13.

Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.

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.

[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.

Familial Creutzfeldt-Jakob disease with a novel 120-bp insertion in the prion protein gene

The clinical course, neuropathological features, and genetic findings in 3 members of a German family carrying a novel 120-bp insertion in the prion protein (PrP) gene are described. Genetic analysis of the mutated allele revealed a sequence of five extra octapeptide repeats, distinct from those of the two previously reported families with an insertion of this size. There was distinctive variation in the clinical course and the onset and duration of the illness in the documented subjects. Neuropathological evaluation showed neuronal loss and gliosis in the neocortex of the 3 examined cases; spongiform degeneration was found in 2 of them. PrP immunoreactivity of unusual morphology and distinct distribution was present in the cerebellum and neocortex ("blurred staining") of 2 examined cases. One subject showed features usually found in sporadic Creutzfeldt-Jakob disease with a punctate type of PrP deposition in the cerebellum. In addition, there were some plaque-like PrP aggregates morphologically similar to the other 2 cases in the molecular layer of the cerebellum, and unusual PrP immunoreactivity ("fleecy staining") was found in the neocortex. The clinicopathological heterogeneity in the documented family is in accordance with the phenotypic variability associated with previously reported insertions.

Late cognitive event-related potentials in adult Down's syndrome.

Event-related electroencephalogram (EEG) potentials (ERPs) using two different tasks were measured in 14 adults with Down's syndrome (DS; mean age 32 years) without clinically detectable cognitive decline. Two groups, young healthy (YH) and old healthy (OH) adults, served as controls. In the oddball task, DS had prolonged N1 and earlier P2 latencies than the control groups. P3 latency was delayed in comparison to YH. In the PushWait task, P3 latency was later in DS than in YH and OH. In both tasks, DS showed a marked amplitude shift towards positivity overlapping the N1-P2 complex and seemingly also P3: The P3 amplitude evoked by target tones and by "Push" was shifted towards anterior sites resulting in a Cz maximum. Changes of the N1 latency and amplitude in DS may be related to enhanced arousal during stimulus processing, indicating a possible defect of central inhibitory mechanisms. The study suggests that differentiated ERP procedures provide information on adult DS cognition exceeding those given by mere P3 latency measurements. Such procedures may be useful in the evaluation of the cognitive decline due to precocious aging or Alzheimer-type dementia in DS.

Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia.

A novel neurological syndrome has recently been described to be associated with an expanded polyglutamine domain. The expansion results from partial duplication within the TATA-binding protein (TBP). By investigation of 604 sporadic and familial cases with various forms of neurological syndromes and 157 unaffected individuals, we found repeat expansions in the TBP in four patients of two families with autosomal dominant inheritance of ataxia, dystonia, and intellectual decline. Two different genotypes for the repetitive sequence could be demonstrated which led to elongated polyglutamine stretches between 50 and 55 residues, whereas normal alleles with 27 to a maximum of 44 glutamine residues were found in this study. The expansion to 50 or more glutamine residues results in a pathological phenotype and confirms the report of a new polyglutamine disease.

The diagnosis of 'essential palatal tremor'.

We report a patient with a 30-year history of progressive, involuntary movements of the left ear and clicking sounds in both ears for 2 years. The patient had rhythmic contractions of the tensor veli palatini muscle and could relieve palatal movements and ear clicks, but not ear movements, by pressing a pillow against the left ear or by finger pressure on the tragus or the retroauricular region. We discuss the significance of these sensory tricks and the nosology of the long-standing ear movements within a classification of essential and symptomatic palatal tremor. Current diagnostic criteria for both types of palatal tremor may not cover some atypical cases such as ours.

Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study.

BACKGROUND: An inverse association between cigarette smoking and the risk of idiopathic PD has been found in many epidemiologic studies. The therapeutic and possible neuroprotective effects of nicotine formulations on parkinsonian symptoms are controversial. METHODS: In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and tolerability of transdermal nicotine patches as an add-on treatment for cardinal symptoms were evaluated in 32 nonsmoking patients with PD. After a 1-week run-in phase, patients were randomized to receive nicotine patches (containing 17.5 mg nicotine in the first and 35.0 mg nicotine in the second and third weeks) or identically appearing placebo patches. After this treatment, 3 weeks without patch application followed. The same blinded examiner assessed the patients with the Columbia University Rating Scale, the Webster scale, the Schwab-England scale, a timed walking test, with an instrumental test for fine motor skills and hand tremor, and with the Hamilton Depression Scale. RESULTS: No significant drug effects between both groups were observed in any of the scores and quantitative tests. Side effects were mild and comparable in frequency between both groups. CONCLUSIONS: With the dosage and the period of treatment chosen, transdermal nicotine patches are not effective as an add-on treatment for symptoms of PD.

Parkinson's disease in twins: a follow-up study.

OBJECTIVE: To reevaluate concordance rates in 9 monozygotic (MZ) and 12 dizygotic (DZ) twin pairs with PD 8 years after the initial study. BACKGROUND: Longitudinal investigations increase accuracy in clinical diagnosis of PD. METHODS: Follow-up by personal interview and clinical examination. RESULTS: Concordance rates were not different between MZ (3/9) and DZ (5/12) twin pairs at follow-up, even when PD-associated dementia and isolated postural tremor were considered diagnostic of familial Lewy body parkinsonism. Evaluation of medical history, personality traits, and blink rate did not reveal putative early or premorbid parkinsonism in 9 co-twins who were motor-asymptomatic during the follow-up interval. However, these co-twins had reduced semantic fluency in comparison with a healthy control group of similar age. None of 7 co-twins without motor signs who underwent PET investigation 6 years previously showed signs of extrapyramidal disease at follow-up, but verbal memory continued to be reduced in 5 of these co-twins. CONCLUSION: Based on concordance rates only, the findings in our twin sample do not support a major genetic impact for the motor expression of PD.

Parkinson's disease in twins.

Among nine monozygotic (MZ) and 12 dizygotic (DZ) twin pairs in which an index case had typical Parkinson's disease (PD) or PD with associated dementia, three MZ and three DZ pairs were concordant. Three of the six affected co-twins were first diagnosed during the study. Occurrence of PD in families of MZ and DZ index cases was more frequent than expected from population rates. The study underlines the need for personal examination using defined criteria in a cross-sectional twin study on PD. Although the study did not establish a major genetic impact in the etiology of PD, a genetic predisposition for the disease cannot be ruled out for some individuals.

Parkin mutations in a patient with hemiparkinsonism-hemiatrophy: a clinical-genetic and PET study.

The authors describe a 37-year-old woman with early-onset hemiparkinsonism (HP) and ipsilateral body hemiatrophy (HA). Genetic analysis revealed a missense mutation (Arg275Trp) and a duplication of exon 7 of parkin. The complementary metabolic and receptor pattern of PET ligands corresponded to that typically found in idiopathic PD, although tracer binding asymmetry was lacking. Parkin mutations should be considered in HPHA, particularly when there is a younger age at onset and dystonia is an early sign.

Diet and Parkinson's disease. I: A possible role for the past intake of specific foods and food groups. Results from a self-administered food-frequency questionnaire in a case-control study.

In a case-control study, we compared the past dietary habits of 342 Parkinson's disease (PD) patients recruited from nine German clinics with those of 342 controls from the same neighborhood or region. Data were gathered with a structured interview and a self-administered food-frequency questionnaire, and analyzed using multivariate conditional logistic regression to control for educational status and cigarette smoking. There was no significant difference between cases and controls in the consumption of fruits and vegetables, although there was a negative trend for the consumption of raw vegetables. Controls reported a higher potato consumption than patients (OR = 0.43, 95% confidence interval [CI]: 0.24-0.74, highest versus lowest quartile). Patients reported eating significantly larger quantities of sweet foods as well as having more snacks than controls. This may, however, be the result of an illness-related change in dietary habits leading to a selective recall effect, since sweet foods may enhance the transport of L-dopa across the blood-brain barrier. We also found that patients consumed less beer (OR = 0.26, 95% CI: 0.14-0.49) and spirits (OR = 0.56, 95% CI: 0.36-0.86), but not wine, and they consumed less coffee (OR = 0.27, 95% CI: 0.14-0.52, highest versus lowest quartile), but not tea, than controls. This may relate to a possible interaction between dopaminergic activity and the intake of ethanol or caffeine. Significantly more patients than controls reported ever consuming raw meat (OR = 1.78, 95% CI: 1.21-2.63). These results suggest that the intake of certain foods may be associated with the development of PD.

Diet and Parkinson's disease. II: A possible role for the past intake of specific nutrients. Results from a self-administered food-frequency questionnaire in a case-control study.

In a case-control study, we compared the past dietary habits of 342 Parkinson's disease (PD) patients recruited from nine German clinics with those of 342 controls from the same neighborhood or region. Data were gathered with a structured interview and a self-administered food-frequency questionnaire. Nutrient intakes were calculated from the reported food intakes through linkage with the German Federal Food Code and analyzed using multivariate conditional logistic regression to control for total energy intake, educational status, and cigarette smoking. At the macronutrient level, patients reported higher carbohydrate intake than controls after adjustment for total energy intake, smoking, and educational status (OR = 2.74, 95% confidence interval [CI]: 1.30-6.07, for the highest versus lowest quartile, p trend = 0.02). This was reflected in higher monosaccharide and disaccharide intakes at the nutrient level. There was no difference between patients and controls in protein and fat intake after adjustment for energy intake. We found an inverse association between the intakes of beta-carotene (OR = 0.67, 95% CI: 0.37-1.19, p trend = 0.06) and ascorbic acid (OR = 0.60, 95% CI: 0.33-1.09, p trend = 0.04) by patients, although only the trend for ascorbic acid intake reached statistical significance. There was no difference between groups for alpha-tocopherol intake after adjustment for energy intake. We also found that patients reported a significantly lower intake of niacin than controls (OR = 0.15, 95% CI: 0.07-0.33, p trend < 0.00005). Our results suggest that if antioxidants play a protective role in this disease, the amounts provided by diet alone are insufficient. Although the interpretation of the inverse association between niacin intake and PD is complicated by the high niacin content in coffee and alcoholic beverages, which were also inversely associated with PD in this study, the strength of this association and its biologic plausibility warrant further investigation.

Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany.

In a case-control study, we investigated the possible etiologic relevance to Parkinson's disease (PD) of rural factors such as farming activity, pesticide exposures, well-water drinking, and animal contacts; toxicologic exposures such as wood preservatives, heavy metals, and solvents; general anesthesia; head trauma; and differences in the intrauterine environment. We recruited 380 patients in nine German clinics, 379 neighborhood control subjects, and 376 regional control subjects in the largest case-control study investigating such factors and collected data in structured personal interviews using conditional logistic regression to control for educational status and cigarette smoking. The latter was strongly inversely associated with PD. There were significantly elevated odds ratios (OR) for pesticide use, in particular, for organochlorines and alkylated phosphates, but no association was present between PD and other rural factors. A significantly elevated OR was present for exposure to wood preservatives. Subjective assessment by the probands indicated that exposure to some heavy metals, solvents, exhaust fumes, and carbon monoxide was significantly more frequent among patients than control subjects, but this was not confirmed by a parallel assessment of job histories according to a job exposure matrix. Patients had undergone general anesthesia and suffered severe head trauma more often than control subjects, but a dose-response gradient was not present. Patients reported a significantly larger number of amalgam-filled teeth before their illness than control subjects. The frequency of premature births and birth order did not differ between patients and control subjects. Patients reported significantly more relatives affected with PD than control subjects. These results support a role for environmental and genetic factors in the etiology of PD.

Direct genetic evidence for involvement of tau in progressive supranuclear palsy. European Study Group on Atypical Parkinsonism Consortium.

OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.

A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism.

OBJECTIVE: To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS: A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS: We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS: This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms.

OBJECTIVE: To evaluate smoking habits in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in a multicenter case-control study to determine whether these two forms of atypical parkinsonism share the inverse association with smoking previously found in PD. BACKGROUND: No epidemiologic studies have been performed on smoking habits in MSA. A previous investigation in PSP revealed no differences in smoking habits between patients and hospital control subjects. METHODS: Seventy-six MSA patients, 55 PSP patients, 140 PD patients, and 134 healthy control subjects were enrolled consecutively at seven neurologic clinics from January 1, 1994, to July 31, 1998. Detailed information on smoking habits was obtained using a structured questionnaire. RESULTS: The comparison between frequencies of never-smokers versus ever-smokers (ex-smokers/current smokers; adjusted odds ratio [ORadj], 0.56; 95% CI, 0.29 to 1.06) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.64; 95% CI, 0.31 to 1.32), and heavy smokers (ORadj, 0.47; 95% CI, 0.21 to 1.05) suggest that MSA patients smoke less than population control subjects. By contrast, the comparison of frequencies of never-smokers versus ever-smokers (ORadj, 0.91; 95% CI, 0.42 to 1.98) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.68; 95% CI, 0.27 to 1.69), and heavy smokers (ORadj, 1.24; CI 95%, 0.51 to 3.06) revealed no differences in smoking habits between PSP patients and population control subjects. CONCLUSIONS: The fact that the inverse association with smoking found previously in PD is shared by multiple system atrophy but not by progressive supranuclear palsy lends epidemiologic support to the notion that different smoking habits are associated with different groups of neurodegenerative disease.

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.