Genetic screening for SACS, ABHD12 and PRICKLE1 mutations in ataxia patients from Southern Italy
de Leva, Maria Fulvia (2011) Genetic screening for SACS, ABHD12 and PRICKLE1 mutations in ataxia patients from Southern Italy. [Tesi di dottorato] (Inedito)
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Genetic screening for SACS, ABHD12 and PRICKLE1 mutations in ataxia patients from Southern Italy. INTRODUCTION Autosomal recessive (AR) spinocerebellar ataxias constitute a heterogeneous group of neurodegenerative disorders mainly characterized by ataxia due to progressive degeneration of the cerebellum, spinal cord tracts, and associated structures. The clinical phenotype of these disorders is broad and quite variable. The aim of our research was to study of three kind of AR ataxias in southern Italy patients referring to our center for neurodegenerative diseases: spastic ataxia of Charlevoix – Saguenay (ARSACS); polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC); PRICKLE1 - progressive myoclonus epilepsy (PME)-ataxia syndrome. METHODS ARSACS is an early-onset disorder showing pyramidal, cerebellar progressive involvement and peripheral neuropathy caused by mutation in SACS. We have recruited 23 patients with progressive early onset ataxia, pyramidal signs and clinical or neurophysiologic signs of peripheral neuropathy and performed direct sequencing of PCR products of SACS nine coding exons and intron-exon boundaries. We detected three mutated patients and 12 different SNPs. All mutations causes premature truncation of sacsin, coded by SACS, and probably its loss of function. PHARC is a disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia, caused by mutations of ABHD12. Eleven patients were selected in according to the following inclusion criteria: recessive inheritance, early onset ataxia, and ocular impairment. We performed direct DNA sequencing of sequencing of the 13 coding exons and the intron-exon boundaries of ABHD12. We found no mutation and 10 validated SNPs. PMEs are a group of rare inherited disorders characterized by epilepsy, myoclonus, and progressive neurological deterioration, particularly ataxia and dementia. One rare cause of AR PME has been recently identified and is due to mutations in PRICKLE1. Twenty index cases were selected according to the following criteria: early onset ataxia, myoclonus, and/or tonic-clonic seizures. Direct sequencing of the seven coding exons and the intron-exon boundaries of PRICKLE1 has been conducted. No mutations and five different SNPs were identified. CONCLUSION Aims of our research was to define the usefulness of genetic screening for three different kinds of AR ataxia. Regarding ARSACS, our results confirm the worldwide diffusion, the uniform clinical presentation of the disease and the prevalence of loss of function mutations, further confirming the value of genetic screening for SACS mutation in case of early onset spastic ataxia. As for PHARC we found no mutation in our selected patients, not confirming what already reported in literature, however our results are limited from the sample size of screened patients. Finally, according to our study, PRICKLE1 mutations are not a frequent cause of PME-ataxia in Southern Italy and indicate that routine screening for these mutations in Italian patients is of limited clinical value.
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