Biallelic mutations in the Glucocerebrosidase gene (GBA) cause autosomal recessive Gaucher Disease. More recently, heterozygous rare variants of GBA have been consistently associated with increased risk to develop Parkinson Disease (PD) and Lewy Body Dementia (LBD). All exons and exon/intron boundaries of GBA gene were sequenced in familial and sporadic patients with early onset parkinsonism (EOP, 130), PD (408) and LBD (70) from Central-Southern Italy. GBA mutations were detected in 71/608 probands (11,68%; 27 EOP, 39 PD and 5 LBD), all but five in heterozygous state. Among homozygous patients (2 EOP, 1 PD and 1 LBD), none had features of Gaucher features. Overall, 27 distinct mutations were identified. The two recurrent mutations L444P and N370S overall accounted only for less than 40% of mutated cases (15/71, 21%, and 13/71, 18% respectively). A third mutation, E326K, was also common (10/71, 14%), while three mutations (p.G232R, p.C381F and p.M400Lfs*2) were novel. No specific genotype-phenotype correlations emerged. Frequencies of mutation carriers were 7,1% among LBD, 9,6% among PD and up to 20,8% among EOP patients. In fact, 38% of GBA mutation carriers had a diagnosis of EOP. Among PD and EOP patients, non-motor signs, such as cognitive impairment, psychiatric and autonomic dysfunctions were more frequently reported in mutated than not mutated cases, although this difference did not reach statistical significance. GBA mutations were significantly more frequent in patients with positive family history (15,9%) than sporadic cases (9%). About half mutated cases (34/71) originated from Campania, while the others came mostly from Lazio, Abruzzo and Sicily. These findings suggest that sequencing of the whole GBA gene should be considered in patients with PD, LBD and especially EOP if other monogenic forms have been excluded, even more in case of positive family history and if coming from high prevalence regions such as Campania.
Frequency and clinical features of GBA mutations in Italian patients with Parkinson disease / Petrucci, Simona; Colosimo, Carlo; Fabbrini, Giovanni; Berardelli, Alfredo; Ginevrino, Monia; Pellecchia, Maria Teresa; Altavista, Maria Concetta; Bove, Francesco; Cozzolino, Autilia; Criscuolo, Chiara; De Rosa, Anna; Morgante, Francesca; Martina, ; Squillante, Massimo; Volpe, Giampiero; Barone, Paolo; Valente, Enza Maria. - STAMPA. - (2015). (Intervento presentato al convegno Congresso Accademia LIMPE-DISMOV tenutosi a Torino nel 28-30 Settembre 2015).
Frequency and clinical features of GBA mutations in Italian patients with Parkinson disease
PETRUCCI, SIMONA;COLOSIMO, Carlo;FABBRINI, Giovanni;BERARDELLI, Alfredo;
2015
Abstract
Biallelic mutations in the Glucocerebrosidase gene (GBA) cause autosomal recessive Gaucher Disease. More recently, heterozygous rare variants of GBA have been consistently associated with increased risk to develop Parkinson Disease (PD) and Lewy Body Dementia (LBD). All exons and exon/intron boundaries of GBA gene were sequenced in familial and sporadic patients with early onset parkinsonism (EOP, 130), PD (408) and LBD (70) from Central-Southern Italy. GBA mutations were detected in 71/608 probands (11,68%; 27 EOP, 39 PD and 5 LBD), all but five in heterozygous state. Among homozygous patients (2 EOP, 1 PD and 1 LBD), none had features of Gaucher features. Overall, 27 distinct mutations were identified. The two recurrent mutations L444P and N370S overall accounted only for less than 40% of mutated cases (15/71, 21%, and 13/71, 18% respectively). A third mutation, E326K, was also common (10/71, 14%), while three mutations (p.G232R, p.C381F and p.M400Lfs*2) were novel. No specific genotype-phenotype correlations emerged. Frequencies of mutation carriers were 7,1% among LBD, 9,6% among PD and up to 20,8% among EOP patients. In fact, 38% of GBA mutation carriers had a diagnosis of EOP. Among PD and EOP patients, non-motor signs, such as cognitive impairment, psychiatric and autonomic dysfunctions were more frequently reported in mutated than not mutated cases, although this difference did not reach statistical significance. GBA mutations were significantly more frequent in patients with positive family history (15,9%) than sporadic cases (9%). About half mutated cases (34/71) originated from Campania, while the others came mostly from Lazio, Abruzzo and Sicily. These findings suggest that sequencing of the whole GBA gene should be considered in patients with PD, LBD and especially EOP if other monogenic forms have been excluded, even more in case of positive family history and if coming from high prevalence regions such as Campania.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
