Mosaicism of alpha-synuclein gene rearrangements: Report of 2 unrelated cases of early-onset parkinsonism

PERANDONES CLAUDIA; GIUNI JC; CALVO DS; GABRIELA BEATRIZ RAINA; DE JORGE LOPEZ L.; V. VOLPINI; RADRIZZANI M; FERNANDEZ MATA I·; MICHELI FE

Dublin

Congreso; 16th International Congress of Parkinson?s Disease and Movement Disorders; 2012

The Movement Disorder Society

In genetics, the term ?mosaicism? describes a situation in which groups of cells have a different genetic composition to other cells in an organism. Somatic gene rearrangements due to multiplication or deletion of genes (copy number variation) and/or sections of chromosomes can lead to mosaicism. The presence of multiple copies of the alpha-synuclein gene (SNCA) is known to be associated with Parkinson?s disease (PD) and the severity of symptoms increases with the number of copies of the gene.[1] While the features of PD associated with duplication of SNCA are usually (but not always) typical of the condition,[2?5] patients with triplicate copies have atypical features including rapidly evolving symptoms, severe cognitive impairment, limited response to levodopa, more severe symptoms of dementia and more frequent urinary incontinence [2]. A lack of studies in this area means that the prevalence and mechanism of these rearrangements have not been elucidated. Recently, two unrelated cases with early-onset parkinsonism presented in our clinic and underwent extended testing to investigate the presence of SNCA mosaicism. Here we report genetic and immmunohistochemical findings and describe the clinical phenotype for each case. Case 1: A 40-year-old man, diagnosed with PD 8 years previously, had recently progressed with autonomic failure, marked rigidity and bradykinesia, freezing of gait, occasional myoclonic jerks and severe dementia. At that stage, his symptoms were poorly responsive to dopaminergic drugs. His paternal grandfather had also been diagnosed with PD, and died at 60 years of age. Case2: A 23-year-old male who was diagnosed with PD at 18 years of age. He presented with dystonic posturing in the left foot and asymmetric bradykinesia. He subsequently developed rigidity and resting tremor and later autonomic failure and behavior disorders with rage episodes, panic attacks, hallucinations and impulse control disorders (hypersexuality) as well as cognitive decline. He responded well to treatment, but promptly developed end of dose deterioration and peak-dose dyskinesias. He had no family history of PD. The patients? legal representatives provided informed consent on their behalf. The study was approved by the ethics committee of the Hospital de Clínicas José de San Martín, University of Buenos Aires, Argentina. Lymphocytes and cells from the oral mucosa of both cases were screened for multiplication of the 4q22.1 locus of SNCA using multiplex ligation-dependent probe amplification (MLPA) and fluorescence in-situ hybridisation (FISH). The SALSA MLPA P051-C1 Parkinson 1 probemix kit (MRC-Holland) was selected because it contains probes for five SNCA exons as well as probes for all the exons for the PARK2 and PINK1 genes. FISH was conducted using SNCA probes rhodamine-labeled at 4q22.1 (BAC RP11-614o7, 151kb) and 4q21.3 (BAC-RP11-711j3, 192kb - control). Both probes were supplied by CHORI (CA, USA). Samples were considered duplicated/triplicated if they had three or four FISH probe signals, respectively, in greater than 20% of interphase cells scored in 100 interphase nuclei examined.