Effect of GBA1 Mutations and APOE Polymorphisms on Survival and Progression Among Ashkenazi Jews with Dementia with Lewy Bodies.

BACKGROUND: Glucocerebrosidase 1 (GBA1) mutations are associated with reduced survival in Parkinson's disease but their effect on survival in dementia with Lewy bodies (DLB) is unclear. OBJECTIVE: To assess the impact of GBA1 mutations on survival among Ashkenazi Jews with DLB, while controlling for APOE status. METHODS: One hundred and forty participants from Tel Aviv Medical Center, Israel were genotyped for GBA1 mutations and APOE polymorphisms. Survival rates and follow-up cognitive screening scores were analyzed. RESULTS: GBA1 mutation carriers had a two-fold increased risk of death (HR = 1.999), while APOE status did not independently affect survival. In a subset of patients with available clinical data (N = 63), carriers of the APOE ε4 allele showed faster cognitive deterioration, while GBA1 mutation carriers also declined more rapidly albeit not significantly. CONCLUSION: Understanding the genetic effects on survival and progression is crucial for patient counseling and inclusion in clinical trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.

OBJECTIVES: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. METHODS: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)). RESULTS: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively). CONCLUSIONS: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity.

BACKGROUND: Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD). OBJECTIVE: To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes. METHODS: Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected. RESULTS: One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 ± 0.85 µmol/L/h), GBA-NMC (3.23 ± 0.91 µmol/L/h), and GBA-LRRK2-NMC (3.20 ± 0.93 µmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype. CONCLUSIONS: Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The GBA-370Rec Parkinson's disease risk haplotype harbors a potentially pathogenic variant in the mitochondrial gene SLC25A44.

GBA variations are common risk factors for Parkinson's disease (PD), and are found in 21.7% of Ashkenazi PD patients (AJ-PD), 4.23% of them carry an allele, 370Rec, which is different from the common GBA-N370S allele. Using whole-genome-sequencing of 370Rec carriers, N370S carriers, and non-carriers, we characterize the unique 370Rec haplotype in AJ-PDs, and show that it harbors a missense variant replacing the highly conserved methionine-27 with valine in the transmembrane domain of the mitochondrial SLC25A44.

The effect of polyhydramnios degree on chromosomal microarray results: a retrospective cohort analysis of 742 singleton pregnancies.

PURPOSE: To analyze the risk for clinically significant microarray aberrations in pregnancies with polyhydramnios. METHODS: Data from all chromosomal microarray analyses (CMA) performed due to polyhydramnios between January 2013 and December 2019 were retrospectively obtained from the Ministry of Health Database. The rate of clinically significant (pathogenic and likely pathogenic) CMA findings in isolated and non-isolated polyhydramnios cohorts was compared to a local control group of 5541 fetuses with normal ultrasound, in which 78 (1.4%) abnormal results were demonstrated. Subgroup analyses were performed by the degree of polyhydramnios, week of diagnosis, maternal age, and the presence of additional sonographic anomalies. RESULTS: In the isolated polyhydramnios cohort, 19/623 (3.1%) clinically significant CMA aberrations were noted, a significantly higher rate compared to the control population. However, the risk for abnormal CMA results in the 158 cases with mild polyhydramnios (AFI 25-29.9, or maximal vertical pocket 8-11.9 cm) did not significantly differ from pregnancies with normal ultrasound. Of 119 cases of non-isolated polyhydramnios (most frequently associated with cardiovascular (26.1%) and brain (15.1%) anomalies), 8 (6.7%) abnormal CMA findings were noted, mainly karyotype-detectable. CONCLUSION: Mild polyhydramnios was not associated with an increased rate of clinically significant microarray results, compared to pregnancies with normal ultrasound. An extensive anatomical sonographic survey should be performed in pregnancies with polyhydramnios, with consideration of fetal echocardiography.

A Possible Modifying Effect of the G2019S Mutation in the LRRK2 Gene on GBA Parkinson's Disease.

BACKGROUND: The phenotype of Parkinson's disease (PD) is milder among patients with LRRK2-PD and more severe among patients with GBA-PD; however, whether an additive phenotypical effect occurs among dual-mutation carriers requires validation. OBJECTIVE: The objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single-mutation presentation. METHODS: Patients with PD were genotyped for the G2019S-LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA-PD, severe GBA-PD, LRRK2-PD, and LRRK2+GBA-PD. Clinical symptoms were evaluated using performance-based measures. RESULTS: A total of 1090 patients with idiopathic PD, 155 patients with LRRK2-PD, 155 patients with mild GBA-PD, 56 patients with severe GBA-PD, and 27 patients with LRRK2+GBA-PD participated in this study. The patients with LRRK2-PD and LRRK2+GBA-PD exhibited lower scores on total Unified Parkinson's Disease Rating Scale (P < 0.01) and better olfaction (P < 0.01) compared with GBA-PD. CONCLUSIONS: Patients with LRRK2+GBA-PD were symptomatically similar to patients with LRRK2-PD, suggesting a dominant effect of LRRK2 over GBA in the phenotypic presentation. © 2020 International Parkinson and Movement Disorder Society.

Revisiting the non-Gaucher-GBA-E326K carrier state: Is it sufficient to increase Parkinson's disease risk?

BACKGROUND: GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. METHODS: 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. RESULTS: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). CONCLUSIONS: Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.

Distinguishing Dementia With Lewy Bodies From Alzheimer Disease: What is the Influence of the GBA Genotype in Ashkenazi Jews?

Cognitive deficits beyond memory impairment, such as those affecting language production or executive functioning, can be useful in clinically distinguishing between dementia syndromes. We tested the hypothesis that Ashkenazi Jewish (AJ) patients who have dementia with Lewy bodies (DLB) and carry glucocerebrosidase (GBA) mutations will have verbal fluency deficits different from those found in Alzheimer disease (AD), whereas AJ patients with DLB who have no GBA mutations will have similar deficits in verbal fluency to those found in AD. We compared performance in phonemic and semantic verbal fluency tasks in 44 AJ patients with DLB and 20 patients with AD, matched for age, education, and age of immigration. All groups were found to have a deficit in semantic verbal fluency. On conducting the phonemic task, patients with DLB who carried GBA mutations scored more poorly than patients with AD, whereas DLB-noncarriers performed similarly to patients with AD. We suggest that verbal fluency tasks could serve as a possible clinical marker to subtype patients with DLB, with phonemic fluency being a marker for GBA-associated DLB.

Survival rates among Parkinson's disease patients who carry mutations in the LRRK2 and GBA genes.

BACKGROUND: The G2019S mutation in the LRRK2 gene generates a milder PD phenotype compared with GBA-PD; however, genetic based survival studies are lacking. OBJECTIVES: To compare mortality rates between LRRK2-PD, GBA-PD, and idiopathic PD patients (iPD). METHODS: Patients were screened for the G2019S mutation in the LRRK2 gene and the seven common GBA mutations among Ashkenazi Jews, classified as mild and severe (mGBA, sGBA). Motor symptoms onset and date of death were ascertained, with mortality rates calculated for each group of patients. RESULTS: Overall, 380 of 1,086 idiopathic PD patients, 49 of 159 LRRK2-PD, 56 of 148 mGBA-PD, and 13 of 49 sGBA-PD participants died by the time of analysis. LRRK2-PD tended to have longer survival compared to idiopathic PD whereas GBA status did not affect mortality. Genetic status did not predict mortality in a multivariate analysis. CONCLUSION: Survival of patients with PD does not seem to be related to GBA status, whereas LRRK2 might confer higher survival rates.

Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers.

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD. OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters. METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point. RESULTS: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers. CONCLUSIONS: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis.

BACKGROUND: Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. OBJECTIVE: The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis. STUDY DESIGN: During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data. RESULTS: Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. CONCLUSION: Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice.

Association of aberrant right subclavian artery with abnormal karyotype and microarray results.

OBJECTIVES: The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan. METHODS: The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed. RESULTS: Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray. CONCLUSION: Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. © 2017 John Wiley & Sons, Ltd.

Two Ethnic Clusters with Huntington Disease in Israel: The Case of Mountain Jews and Karaites.

BACKGROUND: Worldwide prevalence estimates of Huntington disease (HD) vary widely, with no reliable information regarding the Jewish population in Israel. METHODS: This specialized tertiary single-center cross-sectional study assessed clinical, cognitive, and demographic characteristics of 84 HD patients who were treated at the Movement Disorder Unit of the Tel Aviv Medical Center, Israel. RESULTS: Our cohort was composed of one-third Ashkenazi Jews, 27% Mountain Jews (Caucasus Jews), 18% Sephardi Jews, and 21% Karaites, with both Mountain Jews and Karaites over-represented compared to their relevant proportion in the population of the state of Israel, which is less than 1%. No between-group differences were detected regarding the number of CAG (cytosine-adenine-guanine) repeats, age at onset, disease duration, years from symptom onset to diagnosis, gender, years of education, Unified Huntington Disease Rating Scale scores, or the Montreal Cognitive Assessment scores. CONCLUSION: We detected clustering of HD among the population treated at our Medical Center, which has the only specialized HD clinic in the country, with a high percentage of HD among 2 relatively small subpopulations of Jews: Mountain Jews and Karaites.

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

Down-regulation of B cell-related genes in peripheral blood leukocytes of Parkinson's disease patients with and without GBA mutations.

Parkinson's disease (PD) is a common neurodegenerative disorder, caused by aging, genetic and environmental factors. Many genes and genetic loci have been implicated in autosomal dominant and recessive PD, among them SNCA, LRRK2, GBA, Parkin, DJ1 and PINK1. Mutations in the LRRK2 and GBA genes are especially common among PD patients of Ashkenazi-Jewish (AJ) origin, accounting for over a third of the patient population. We aimed to identify genes and cellular pathways that may be involved in GBA-associated PD. Whole genome expression analysis was performed using peripheral blood leukocytes (PBLs) of PD patients with mutations in the GBA gene (PD-GBA, n = 59) compared to healthy controls (n = 59). Significant expression changes were detected in 26 genes, most of them were down-regulated in patients and annotated to B cell or immune-related functions. The expression levels of five membrane-bound B cell genes (FCRL1, CD19, CD22, CD79A and CD180) were further analyzed in four distinct populations: (1) Healthy controls (n = 20), (2) PD-GBA (n = 20), (3) PD patients who do not carry LRRK2 or GBA mutations (PD-NC, n = 20), (4) Asymptomatic 1st degree family members, with (n = 15) or without (n = 15) GBA mutations. In qRT-PCR analysis, all five genes were down-regulated in patients (PD-GBA and PD-NC) compared to controls. These changes in expression were not observed when comparing family members who carry GBA mutations to non-carrier family members. Furthermore, these expression levels were disease-duration dependent: the most significant decreased expression occurred after the first two years of onset, and remained steady after 6 years. These results further support the involvement of B cell-related genes in PD and correlate the level of reduced expression to disease duration.

Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene.

BACKGROUND: The asymptomatic carriers of the Leucine rich repeat kinase 2 (LRRK2) G2019S mutation represent a population at risk for developing PD. The aim of this study was to assess differences in nonmotor symptoms between nonmanifesting carriers and noncarriers of the G2019S mutation. METHODS: Two hundred fifty-three subjects participated in this observational cross-sectional multicenter study. Standard questionnaires assessing anxiety, depression, cognition, smell, nonmotor symptoms, and rapid eye movement (REM) sleep behavior were administered. Analyses were adjusted for age, sex, family relations, education, and site. RESULTS: One hundred thirty-four carriers were identified. Carriers had higher nonmotor symptoms score on the Nonmotor symptoms (NMS) questionnaire (P = 0.02). These findings were amplified in carriers older than age 50 y, with higher nonmotor symptoms scores and trait anxiety scores (P < 0.03). CONCLUSIONS: In this cross-section study, carriers of the G2019S LRRK2 mutation endorsed subtle nonmotor symptoms. Whether these are early features of PD will require a longitudinal study. © 2015 International Parkinson and Movement Disorder Society.

Microscopic chromosome Xp distal deletions--a challenging issue in prenatal genetic counseling.

OBJECTIVE: A prenatal diagnosis of chromosome X short arm deletions may present a challenge in prenatal genetic counseling. We present clinical and molecular data of carriers of Xp distal deletions. METHODS: We assessed prenatal and postnatal phenotypes of individuals from three families with large Xp distal deletions and from a fourth family with a small Xp distal deletion. The work-up included karyotyping, chromosomal microarray analysis, and assessment of the X inactivation pattern. RESULTS: Five out of eight women with large deletions had a short stature (<3rd percentile). Subjects from one family had developmental and emotional problems. All female carriers with small deletions had markedly short stature, whereas the men had mildly short stature. Chromosomal microarray analysis revealed 11.7-19.3 Mb deletions in three families and a small ~1 Mb deletion in the fourth. The pseudoautosomal region 1 of the X chromosome was deleted in two families with large deletions. X inactivation was skewed in all tested cases with large deletions. CONCLUSION: Xp distal deletions are mainly associated with short stature. Skewing of the abnormal X chromosome may attenuate the phenotype in cases with large deletions. We suggest that prenatal evaluation in such cases should include sonographic follow-up and assessment of the X inactivation pattern.

Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.

Fall risk and gait in Parkinson's disease: the role of the LRRK2 G2019S mutation.

Patients with Parkinson's disease (PD) who carry the G2019S mutation (a glycine to serine substitution at amino acid 2019) in the leucine-rich repeat kinase 2 (LRRK2) gene are generally believed to be clinically indistinguishable from patients with sporadic PD. There are, however, conflicting reports on the relationship between the mutation and the motor phenotype. We quantitatively compared gait and mobility in patients with PD carriers of the G2019S mutation to non-carrier patients with PD to better understand the genotype-phenotype relationship. Fifty patients with PD carriers of the G2019S LRRK2 mutation and 50 age, disease duration, and disease severity matched PD non-carriers were studied. An accelerometer quantified gait under three walking conditions: usual-walking, dual-tasking, and fast-walking. The Unified Parkinson's Disease Rating Scale classified patients into PD sub-types and the Timed Up and Go quantified mobility and fall risk. In all three walking conditions, gait variability was larger and the walking pattern was less consistent among the PD mutation carriers (P < 0.016). The PD carriers also took longer to complete the Timed Up and Go (P = 0.011) and were more likely to report having fallen in the previous year (P = 0.018). 64% of the PD carriers were classified as belonging to the postural-instability-gait-difficulty (PIGD) sub-type compared to only 17% of the PD non-carriers (P < 0.0001). Among patients with PD, the G2019S mutation in the LRRK2 gene is apparently associated with increased gait variability, an increased fall risk, and the PIGD sub-type. Therapeutic approach specifically designed to delay gait disturbances and falls may be justified in patients who carry the G2019S mutation.