1. Expanding glucocerebrosidase involvement in neurodegeneration: D419H mutation causing Dementia with Lewy Bodies
G. Palermo, A. Lo Gerfo, V. Nicoletti, U. Bonuccelli, G. Siciliano, M. Mancuso & R. Ceravolo
Unità di Neurologia,
Dipartimento di Medicina Clinica e Sperimentale,
Università di Pisa
III Meeting delle Neuroscienze Toscane SNO-SIN
Viareggio, 2019

2. Pedigree showing the GBA D419H variant segregating with Dementia with Lewy bodies. Alleles are shown as D419H or wt (wild type).

3. The G to C change at position 1255 of the cDNA (exon 9 of GBA) resulted in a substitution of aspartic acid to histidine at residue 419 of the protein (p.Asp419His; CM054757).
The variant is predicted to be pathogenic by both PolyPhen and the Mutation Taster and other computer prediction programs and occurs at a highly evolutionary conserved amino acid residue and nucleotide position

4. So far, more than 350 different GBA mutations have been identified, and several have been linked to PD
Even if the proportion of PD patients with GBA mutations varies depending on the
population studied (more common in Ashkenazi) and sequencing method, between 5% and 25% of PD patients carry GBA mutations.
Heterozygous mutations of GBA confer a 10% to 30% chance of developing PD by age 80 years: a 20-fold increase compared with non-carriers; GD patients and asymptomatic heterozygous gene mutation carriers are at almost equal risk for development of PD

5. 721 DLB pts  54 had GBA1 mutations (OR= 8,28)
Nalls et al.,
721 DLB pts  54 had GBA1 mutations (OR= 8,28)
151 PDD pts  9 had GBA1 mutations (OR= 6,48)
Focusing only on the 4 centers where full exon sequencing was performed on cases and controls  OR for DLB 14,20
This OR (14,20) could be due to the increased ability of exonic sequencing to detect more mutations or to the attenuated sample size in this statistical model.
It suggests that rarer variants are likely overrepresented in cases compared with equivalent controls.
Parallelamente the OR varied quite markedly by subgroup when stratified by study center, by genotyping method, or by a clinical or a pathological diagnosis

6. Anheim et al.,
Red line: GBA gene mutation carriers
Black line: 95%confidence interval
Blue line: non carriers
This
penetrance estimate is similar to that of the LRRK2
G2019S mutation, which is considered a dominant
PD gene
This relatively high penetrance estimate should lead to consideration of GBA as a PD causal dominant gene. Moreover, it should be taken into account for genetic counseling in relatives of patients with GD or with GBA-associated PD

7. Conclusions
This is the first report of the D419H GBA mutation in synucleinopathies.
Our report confirm the complex and heterogeneous genotype- phenotype correlation in GBA mutation carriers.
The pedigree analysis indicates a dominant inheritance pattern, suggesting that heterozygous GBA mutations may differently affect the risk of Parkinson-dementia syndromes.
This should be taken into account for genetic counseling in relatives of patients with GBA associated Parkinson’s Disease/DLB.
Gan-or et al.,
Gan-or et al.,