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An Ala53Thr mutation of the alpha-synuclein has been recently identified as a rare cause of familial Parkinson's disease (fPD). In the present study, the clinical characteristics of Parkinson's disease (PD) patients with Ala53Thr alpha-synuclein mutation (alpha-synPD) were compared with fPD patients without any known mutation. An investigator blinded to the results of the genetic analysis examined 15 alpha-synPD patients and 43 consecutive fPD patients. Demographic data, age at onset of the illness, duration of the disease and modality of presentation were collected. Segregation ratios for both sexes in individuals at risk of developing alpha-synPD were estimated. The Unified Parkinson's disease rating scale (UPDRS) was also completed. The 15 alpha-synPD patients were matched for duration of the disease and age at onset with 15 of the 43 fPD patients (MfPD). Comparisons were also made between 14 patients belonging to three multicase families with patterns of inheritance similar to alpha-synPD. The alpha-synPD patients were significantly younger (mean difference 11.8 years) and showed the first sign of the disease earlier in life (mean difference 12.7 years) as compared with the fPD patients. Tremor at onset was present in only one (6.7%) of the alpha -synPD patients compared with 18 (41.9%) of the fPD patients (P = 0.01). At the time of examination rigidity, postural instability, orthostatic hypotension and the overall clinical severity did not differ significantly either between alpha-synPD and fPD or between alpha-synPD and MfPD groups. Nevertheless, some clinically relevant trends concerning the psychiatric symptoms and complications of therapy were recognized. The overall clinical severity and the progression of the disease in patients with alpha-synPD did not differ from that of the fPD patients. The alpha-synPD patients presented the illness at a younger age and also had lower prevalence of tremor when compared with the fPD patients.

The motor and neuropsychological abnormalities in eight Greek patients with Parkinson's disease (PD) carrying the alpha-synuclein gene mutation (G209A) were studied. These patients (five men, three women) belonged to six different families. Their symptoms started between 32-50 years of age (mean +/- SD, 39.7 +/- 7.6 years) and they had a mean disease duration of 5.4 +/- 2.1 years (range, 2-9 years) at the time of examination. Rigidity and bradykinesia predominated both at disease onset as well as in the later stages and rest tremor was relatively uncommon. Neuropsychological assessment showed that one patient was mildly demented while another had impairment in memory, visuoconstructive abilities, and executive function. Depression was present in only one patient. Our findings indicate that genetic forms of parkinsonism share common motor and cognitive characteristics with sporadic PD but raise the possibility that greater cognitive impairment and the relative rarity of tremor may be distinctive features worthy of further investigation., (Copyright 2001 Movement Disorder Society.)

Objective: An Ala53Thr mutation of the alpha-synuclein gene has been recently identified as a rare cause of autosomal Parkinson's disease (PD). The clinical characteristics of 15 patients with PD living in Greece with the Ala53Thr alpha-synuclein mutation (alpha-synPD) were compared with patients with sporadic Parkinson's disease (sPD)., Methods: An investigator, blind to the results of the genetic analysis, examined 15 patients with alpha-synPD and 52 consecutive patients with sPD. Demographic data, age at onset of the illness, modality of presentation, and duration of PD were collected. The unified Parkinson's disease rating scale, the Hoehn and Yahr scale, and the Schwab-England scale were completed. The patients with alpha-synPD were matched for duration of disease with 32 of the 52 patients with sporadic PD (MsPD group)., Results: Patients with the alpha-synuclein mutation were significantly younger (mean 7.6 years), showed the first sign of the disease significantly earlier in life (mean 10.8 years), and had significantly longer duration of the disease compared with patients with sPD. Tremor at onset of the disease was present in only one (6.7%) of the patients with alpha-synPD, whereas it was present in 32 (61.5%) of the patients with sPD (p=0.0006). During the course of the disease one patient in the alpha-synPD group went on to develop tremor compared with six patients in the sPD group. Rigidity, bradykinesia, postural instability, orthostatic hypotension, intellectual impairment, depression, complications of therapy, and clinical severity of the disease at the time of examination did not differ significantly between patients with alpha-synPD and those with sPD, or between patients with alpha-synPD and the MsPD group., Conclusion: The younger age at onset of the illness, the much lower prevalence of tremor, and the longer duration of the disease characterise the clinical phenotype in this sample of patients with alpha-synPD. The other symptoms and signs of the illness did not seem to differentiate the patients with alpha-synPD from those with sPD.

We describe an Australian family of Greek origin with a parkinsonian syndrome and an Ala53Thr alpha-synuclein gene mutation. Five of 9 siblings were affected, the average age of onset was 45 years, and the initial symptoms were variable, including resting tremor, bradykinesia, and gait disturbance, as previously described in families with the same point mutation. Affected family members responded well to levodopa, developed progressive cognitive impairment, and had a disease duration of 5 to 16 years. Pathologic features typical of idiopathic Parkinson's disease were found at autopsy. However, there were several additional features not previously reported in families with this gene mutation. These features included severe central hypoventilation, orthostatic hypotension, prominent myoclonus, and urinary incontinence. An abundance of alpha-synuclein-immunoreactive Lewy neurites were found in the brainstem pigmented nuclei, hippocampus, and temporal neocortex. The Lewy neurites were associated with temporal lobe vacuolation. Subcortical basal ganglia cell loss and gliosis were seen. These additional clinical and pathological features suggest that the Ala53Thr alpha-synuclein mutation can produce a more widespread disorder than found in typical idiopathic Parkinson's disease.

The G209A mutation in the alpha-synuclein gene has been associated with autosomal dominant PD (ADPD) in a family from Contursi, Italy, and three apparently unrelated Greek families. Several groups around the world failed to identify the G209A mutation in a sizable series of familial and sporadic cases of PD. The authors present two additional Greek families with ADPD associated with the G209A mutation. In both families, asymptomatic carriers older than the expected age at onset were found.

Objective: To determine whether the G-to-A substitution at nucleotide 209 (G209A) mutation in the alpha-synuclein gene is responsible for familial Parkinson disease (PD) in the US population., Design: Polymerase chain reaction-based DNA analysis of consecutive patients with PD and family history of PD., Setting: A university-affiliated movement disorder clinic and a Veterans Affairs clinical research laboratory., Patients: Forty-four patients with PD and family history of PD and 29 patients with sporadic PD, all with no known Greek and/or Italian background., Results: None of the DNA samples showed the G209A mutation., Conclusion: The G209A mutation is rare in US patients with familial PD.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.