title: PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family.
abstract: SYNJ1 has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same SYNJ1 homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the SYNJ1 homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.forename: Anna
authors.initials: A
authors.lastname: De Rosa
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Marina
authors.initials: M
authors.lastname: Picillo
authors.forename: Sabina
authors.initials: S
authors.lastname: Pappatà
authors.forename: Mario
authors.initials: M
authors.lastname: Quarantelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D001921:Brain / Q000378:metabolism; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases