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BackgroundWe aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.MethodsFifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.ResultsWe included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0–75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A(16%), followed by KCNQ2(5.6%) and SCN2A(5%).ConclusionOur study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.

Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). We found a significant inverse association between smoking initiation and PD (ORIVWper 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

IMPORTANCE While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING Eleven centers from sites around the world performing genotyping. PARTICIPANTS Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.

Early genomewide association GWA studies on Parkinsons disease PD have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the metaanalysis of the first two GWA investigations might be replicable in different populations. We examined six singlenucleotide polymorphisms SNPs rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626 that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the “Genetic Epidemiology of Parkinsons Disease” GEOPD consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs 599 PD cases, 592 controls and 443 sibling pairs were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets excluding the original GWA data were very close to 1.00 range 0.98–1.09 and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques. © 2009 WileyLiss, Inc.

DJ‐1 gene mutations have been found to cause early‐onset Parkinson's disease. We report a family from southern Italy with three brothers affected by early‐onset parkinsonism, dementia, and amyotrophic lateral sclerosis. Molecular analysis of the DJ‐1 gene in two living patients showed a novel homozygous mutation in exon 7 (E163K) and a new homozygous mutation (g.168_185dup) in the promoter region of the gene. Both mutations cosegregated with the disease and were detected in a heterozygous state in the patients' mother and their healthy siblings. Our findings expand the spectrum of clinical presentations associated with mutations in DJ‐1 gene. Ann Neurol 2005;58:803–807

We report on 2 brothers (aged 19 and 12 years) with Marinesco‐Sjögren syndrome who also had very low serum vitamin E concentrations with an absence of postprandial chylomicrons. The molecular study ruled out ataxia with isolated vitamin E deficiency, abetalipoproteinemia, and hypobetalipoproteinemia. The electron microscopy of the intestinal mucosa was consistent with a chylomicron retention disease. We speculate that both chylomicron retention disease and Marinesco‐Sjögren syndrome are related to defects in a gene crucial for the assembly or secretion of the chylomicron particles, leading to very low serum levels of vitamin E. Ann Neurol 2000;47:260–264

We report on 2 brothers (aged 19 and 12 years) with Marinesco-Sjögren syndrome who also had very low serum vitamin E concentrations with an absence of postprandial chylomicrons. The molecular study ruled out ataxia with isolated vitamin E deficiency, abetalipoproteinemia, and hypobetalipoproteinemia. The electron microscopy of the intestinal mucosa was consistent with a chylomicron retention disease. We speculate that both chylomicron retention disease and Marinesco-Sjögren syndrome are related to defects in a gene crucial for the assembly or secretion of the chylomicron particles, leading to very low serum levels of vitamin E. Ann Neurol 2000;47:260–264

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the ‐141C Ins/Del and the Ser311/Cys311variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B1 allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08–2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12–3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.

We investigated 30 patients with familial essential tremor (ET) for spinocerebellar ataxia type 12 (SCA-12) mutations. No patient presented a CAG repeat larger than 19, suggesting that familial ET and SCA-12 are distinct diseases. © 2002 Movement Disorder Society

We investigated 30 patients with familial essential tremor (ET) for spinocerebellar ataxia type 12 (SCA-12) mutations. No patient presented a CAG repeat larger than 19, suggesting that familial ET and SCA-12 are distinct diseases. © 2002 Movement Disorder Society

We investigated 30 patients with familial essential tremor (ET) for spinocerebellar ataxia type 12 (SCA‐12) mutations. No patient presented a CAG repeat larger than 19, suggesting that familial ET and SCA‐12 are distinct diseases. © 2002 Movement Disorder Society