Mosaicism of alpha-synuclein gene rearrangements: Report of two unrelated cases of early-onset parkinsonism (original) (raw)
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alpha-Synuclein multiplication analysis in Italian familial Parkinson disease
Parkinsonism & related disorders, 2010
The alpha-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson Disease (PD): triplication is associated with early-onset rapidly progressing parkinsonism with a strong likelihood of developing dementia, while duplication is associated with a less severe phenotype similar to idiopathic PD. We tested for SNCA multiplication 144 unrelated PD patients with a dominant family history. We identified one patient with SNCA duplication (0.7%). The SNCA-duplicated patient was a woman of 45 years of age with PD onset at 41 years of age. She experienced a rapidly progressive disease with early motor complications (on/off fluctuations and dyskinesias). Medical records confirmed that the proband's mother developed PD at 47 years of age and died at 63 with dementia. She experienced rapid progression in both motor and cognitive symptoms: development of dementia at 54 years of age, 7 years after onset. Although SNCA duplication is an unusual cause of familial PD testing for i...
a-Synuclein multiplication analysis in Italian familial Parkinson disease q
The a-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson Disease (PD): tripli-cation is associated with early-onset rapidly progressing parkinsonism with a strong likelihood of developing dementia, while duplication is associated with a less severe phenotype similar to idiopathic PD. We tested for SNCA multiplication 144 unrelated PD patients with a dominant family history. We identified one patient with SNCA duplication (0.7%). The SNCA-duplicated patient was a woman of 45 years of age with PD onset at 41 years of age. She experienced a rapidly progressive disease with early motor complications (on/off fluctuations and dyskinesias). Medical records confirmed that the proband's mother developed PD at 47 years of age and died at 63 with dementia. She experienced rapid progression in both motor and cognitive symptoms: development of dementia at 54 years of age, 7 years after onset. Although SNCA duplication is an unusual cause of familial PD testing for it is worthwhile. The clinical presentation of duplicated cases may be more aggressive than usual.
Alpha-synuclein and familial Parkinson's disease
Movement Disorders, 2009
Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3′ region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r 2 > 0.95) and were analyzed as a haplotype.
Journal of Neurology, Neurosurgery & Psychiatry, 2001
Objective-An Ala53Thr mutation of the-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-synuclein mutation (-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-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-synPD were matched for duration of disease with 32 of the 52 patients with sporadic PD (MsPD group). Results-Patients with the-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-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-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 diVer significantly between patients with-synPD and those with sPD, or between patients with-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-synPD. The other symptoms and signs of the illness did not seem to diVerentiate the patients with-synPD from those with sPD.
Disorders with Synuclein Pathology and Parkinsonism
A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent α-synuclein pathology. These diseases include Parkinson disease (PD) and dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of α-synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the α-synuclein gene (SNCA). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of proto-fibrils. Duplications and triplications of SNCA lead to autosomal dominant PD with a gene dosage effect on age of onset and clinical severity; variants in the SNCA promoter which lead to an upregulation of SNCA expression are associated with an increased risk of sporadic PD.
α-Synuclein multiplication analysis in Italian familial Parkinson disease
Parkinsonism & Related Disorders, 2010
The α-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson Disease (PD): triplication is associated with early-onset rapidly progressing parkinsonism with a strong likelihood of developing dementia, while duplication is associated with a less severe phenotype similar to idiopathic PD.We tested for SNCA multiplication 144 unrelated PD patients with a dominant family history. We identified one patient with SNCA duplication (0.7%).The