L444P Mutation Research Articles

Gaucher disease in Syrian children: common mutations identification, and clinical futures.

BACKGROUND AND OBJECTIVESGaucher disease (GD) is caused by the deficiency of glucosidase beta acid (GBA). Three clinical forms of GD are available. Some mutations in the GBA gene have a high frequency in specific populations. The aim of this study was to analyze the characteristics of phenotypes and genotypes of GD in Syrian pediatric patients and assess whether a genotype-phenotype relationship could be helpful in treatment decision-making.DESIGN AND SETTINGSA cross-sectional clinical genetic study of 19 Syrian children admitted to Children’s Hospital, Damascus University.PATIENTS AND METHODSNineteen Syrian children with GD were enrolled in the study; DNA was extracted from peripheral blood leukocytes. The GBA gene was amplified by polymerase chain reaction, and the 9 most common mutations were studied using a Gaucher Disease Strip Assay (ViennaLab Diagnostics GmbH, Vienna, Austria).RESULTSThe majority of children had an early age of onset. A total of 17 patients presented severe hematological and skeletal complications. Neurological involvement was encountered in 2 patients. Twelve patients (63, 2%) were homozygous for the L444P mutation, 1 patient (5.3%) was homozygous for the N370S mutation, and 1 patient (5.3%) was heterozygous for the N370S mutation. Five patients (26.3%) had unknown mutations.CONCLUSIONL444P/L444P was the most common genotype in the studied patients. GD3 with severe visceral presentation in childhood was the dominant phenotype; N370S was found in the heterozygote state in 1 case and in the homozygote state in 1 case. This phenotype and genotype pattern is encountered in the Middle East. There was no genotype-phenotype correlation.

Clinical, biochemical, and genetic features of non-classical 21-hydroxylase deficiency in Japanese children.

Non-classical 21-hydroxylase deficiency (NC21-OHD) is a mild form of 21-hydroxylase deficiency lacking apparent symptoms of androgen excess at birth. Most NC21-OHD cases are diagnosed after the onset of puberty, while a substantial number of patients are not diagnosed during childhood. Previous studies have reported ethnic differences in the prevalence of NC21-OHD. To date, the clinical features of NC21-OHD in Japanese children have not been systemically reported. Thus, we performed 3 independent analyses: retrospective analyses of newborn screening in 2 major Japanese cities (Sapporo and Niigata) and a national surveillance collecting clinical information from pediatric endocrinologists throughout the country. During the last 10 years, one case of NC21-OHD was diagnosed by newborn screening in each city, resulting in incidences of 2.0 (95% confidence interval = 0.0-5.9) and 2.1 (0.0-6.2) per 1,000,000 in Sapporo and Niigata, respectively. We collected information from 85% of the 135 Councilors of Japanese Society of Pediatric Endocrinology. Fifteen NC21-OHD patients were diagnosed during childhood, resulting in the estimated prevalence of 0.58 (0.28-1.1) per 1,000,000. Eleven patients were discovered by newborn screening, 7 patients developed hyperandrogenism symptoms (2-8 years of age, median 7), and 9 patients were treated with hydrocortisone at the time of the survey. Ten out of 13 patients showed compound heterozygosity for the P30L mutation of CYP21A2. Our study suggests that the prevalence/incidence of NC21-OHD is lower than that in Western countries, and that the age for initial onset of androgen excess symptoms varies during the prepubertal period.

Effect of GBA Mutations on Phenotype of Parkinson's Disease: A Study on Chinese Population and a Meta-Analysis.

GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = −3.10 [95% CI: −4.88, −1.32]), bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94]), having family history (OR = 1.50 [95% CI: 1.18, 1.91]), and dementia (OR = 3.21 [95% CI: 1.97, 5.24]) during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03]), the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: −0.06, 0.17]) and UPDRS-III (MD = 1.61 [95% CI: −0.65, 3.87]) and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84]) during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers.

Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.

Mutations of glucocerebrosidase (GBA) confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls) and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77–10.68, p<0.00001), and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23–26.06, p<0.00001). No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.

Mutations in the glucocerebrosidase gene are responsible for Chinese patients with Parkinson's disease.

Pathological mutations in the glucocerebrosidase gene (GBA) have been suggested to be associated with Parkinson's disease (PD) in various ethnic populations. Most studies on Chinese PD patients have only screened the N370S and L444P mutations in the GBA gene. To investigate the GBA mutations in Chinese population, we performed complete sequencing of the GBA gene in 184 Chinese PD patients and 130 Chinese control individuals. As a result, we identified three novel and nine reported GBA mutations. The novel mutations include 5-bp deletion (c.334_338delCAGAA), L264I and L314V and the nine reported GBA mutations are R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI and Q497R. The novel 5-bp deletion (CAGAA) produces a short truncated GBA protein of 142 amino acids, which loses major function domains of the 536 amino acids. Our data also reveals that the frequency of GBA mutations within this Chinese PD cohort was 8.7%, which is significantly higher than 1.54% observed in the Chinese control cohort (χ(2) = 7.22, P = 0.0072; odds ratio (OR) = 6.095, 95% confidence interval of OR = 1.546-24.030). The most common L444P mutation accounts 2.74%, which confer more genetic risk for PD in this Chinese population. In conclusion, novel and known GBA mutations were identified and were found to be associated to PD in this Chinese population.

Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease

Gaucher disease (GD) is the most common glycolipid storage disorder resulting from glucocerebrosidase deficiency due to mutations in the GBA gene. Study was performed in 33 unrelated patients with low β-glucosidase activity in leukocytes and/or fibroblasts. The exons and exon-intron boundaries of the GBA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and were looked up in public databases, and in silico analysis was carried for novel mutations. We identified two novel missense mutations G289A (c.866G>C) and I466S (c.1397T>G) in exons 7 and 10, respectively, in two (6.06%) patients that destabilize the protein structure. L444P (c.1448T>C) was the most common mutation identified in 20/33 (60.60%) non-neuronopathic and 1/33 (3.03%) sub-acute neuronopathic form based on clinical presentation at the time of investigation. Other nine rare mutations were: R463C (c.1504C>T), R395C (c.1300C>T), R359Q (c.1193G>A), G355D (c.1181G>A), V352M (c.1171G>A) and S356F (c.1184C>T) found in each patient (18.18%). Compound heterozygous mutation L444P (c.1448T>C)/R496C (c.1603C>T) in exon 10/11 and L444P (c.1448T>C)/R329C (c.1102C>T) were observed in exon 10/8 in one each patient (6.06%). Two patients (6.06%) from Sri Lanka showed E326K (c.1093G>A) mutation in exon 8. We conclude that L444P is the most common mutant allele with exons 8 and 10 as the hot spot region of GBA gene observed in Indian GD patients.

Direct Molecular Diagnosis of CYP21A2 Point Mutations in Macedonian and Serbian Patients with 21-Hydroxylase Deficiency.

SummaryBackgroundSteroid 21-hydroxylase deficiency is present in 90–95% of all cases with congenital adrenal hyperplasia (CAH), an autosomal recessive disorder. It can present as the severe classical salt wasting (SW) or simple virilising (SV) form, or the milder, nonclassical form. Nine pseudogene-derived point mutations account for about 80% of all defects in the CYP21A2 gene coding the 21-hydroxylase enzyme.MethodsWe have studied nine CYP21A2 point mutations in 61 Macedonian and 24 Serbian patients with different clinical presentations of CAH, using the PCR/ACRS method.ResultsSix different mutations were detected in 71.3% of alleles of the Macedonian patients. The most prevalent mutation was IVS2. Mutations were detected in 85.4% of the SW, 83.4% SV and 47.7% LO alleles. In the Macedonian patients the most common genotype was IVS2/IVS2. Five different mutations were detected in 64.6% of alleles of the Serbian patients. The most prevalent was P30L. Mutations were present in 83.3% SW, 80% SV and 50% of the LO alleles. In the Serbian patients, the P30L/P30L genotype was the most frequent.ConclusionsSpecific CYP21A2 mutations are involved in different clinical forms of CAH. High frequency of P30L was found in both populations. Also, high prevalence of the mild P30L mutation was found in both the Macedonian and Serbian classical SV patients. Our findings support the role of the P30L mutation in pronounced virilisation. An unusual finding is the low frequency of V281L in the Macedonian non-classical patients and its absence in the ones from Serbia.

Glucosylceramide Mimics: Highly Potent GCase Inhibitors and Selective Pharmacological Chaperones for Mutations Associated with Types 1 and 2 Gaucher Disease

A series of iminoxylitol derivatives carrying a C-linked di-O-acyl or di-O-alkyl glyceryl substituent were prepared and characterized. All of these compounds, which were designed as glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal β-glucosidase (glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di-O-hexyl ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di-O-decanoyl ester was a potent chaperone of the L444P hydrolase, capable of increasing the residual activity of the enzyme by a factor of two at a very low concentration (50 nM); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat-stress studies, the diether was found to be much more effective in stabilizing the wild-type enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of GlcCer synthase, because such compounds could find use in the substrate reduction therapy approach to treat lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di-C10 -ester constitute leads for the development of therapeutic agents for types 2 and 3 Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.

New Insights into the Pharmacological Chaperone Activity of C2‐Substituted Glucoimidazoles for the Treatment of Gaucher Disease

Mutations in acid β-glucocerebrosidase (GCase) lead to the accumulation of the sphingolipid glucosylceramide, thereby resulting in Gaucher disease (GD). Active-site-specific competitive GCase inhibitors are effective pharmacological chaperones (PCs) that act as folding agents for mutant GCase folding in the endoplasmic reticulum. In this study, we prepared a series of glucoimidazole C2-substituent derivatives, and evaluated their inhibition and PC properties with GCase. A cell-based assay with patient-derived lymphoblasts (N370S or L444P mutations) demonstrated that administration of these compounds can significantly increase GCase activity. Interestingly, the 3,3-dimethyl-N-phenyl-4-amide-1-butyl-substituted moderate inhibitor 11 had the greatest effect on activity: 2.1-fold increase in N370S lymphoblasts at 2.5 μM and 1.2-fold increase in L444P at 0.5 μM following a three-day incubation. Computer docking studies and a protease protection assay were used to elucidate the ligand-enzyme interactions responsible for the chaperone activity of 11. Western blot and immuno-fluorescence assays verified restoration of GCase trafficking to the lysosome. Together, these results indicate that 11 is a promising PC for GD treatment and provide direct evidence of the mechanism of GCase chaperoning.

Prevalence of P30L, V281L and P453S mutations of CYP21 gene in patients with nonfunctional adrenal incidentalomas

Prevalence of P30L, V281L and P453S mutations of CYP21 gene in patients with nonfunctional adrenal incidentalomas

Increased incidence of Parkinsonism among Chinese with β-glucosidase mutation in central Taiwan

BackgroundParkinson's disease (PD) is characterized by progressive neuronal cell loss and decline in movement. Recently, much attention has been focused on the dopaminergic neurotoxicity, which causes neurogeneration in the nervous system, thus implicating dysfunction in predisposition to PD pathogenesis. β-glucosidase (GBA), the enzyme deficient in Gaucher's disease, has been cited as linked with Parkinson's disease. We investigated whether GBA mutation is associated with PD patients in middle Taiwan. MethodsGBA mutation was detected by polymerase chain reaction and sequencing in 148 patients with PD and 120 normal controls. ResultsThe results revealed a significant difference between PD patients and normal controls in GBA mutation and a statistic correlation between GBA mutation L444P and PD formation. It could be concluded that patients who carry the T/C of GBA mutation, L444P, have a higher risk of developing PD in Chinese patients in middle Taiwan.

Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

New Derivatives of L-Idonojirimycin Working As Pharmacological Chaperones for the Treatment of Gaucher Disease

AbstractAbstract 3270 Introduction:Many of the mutations of the lysosomal acid b-glucosidase (b-glucocerebrosidase) associated with Gaucher disease (GD) translate into enzymes that retain partial catalytic activity in vitro but exhibit impaired cellular trafficking as a consequence of aberrant folding. Current investigational therapeutic strategies for include the development of ligands of the enzyme capable of promoting those conformational changes that are required for efficient folding, restoring trafficking. Although somewhat counter intuitive, competitive inhibitors of this b-glucocerebrosidase, at subinhibitory concentrations, can increase steady-state lysosomal levels of active enzyme through this rescuing mechanism, acting as “pharmacological chaperones”. At the massive lysosomal substrate concentration, the inhibitor would be replaced from the active site of the enzyme and the metabolic activity recovered. However, most of the pharmacological chaperones under study are iminosugars that behave as broad spectrum inhibitors, inhibiting simultaneously several glucosidases, which represents a serious inconvenient for clinical applications. An additional problem is that iminosugars and their derivatives are not active as pharmacological chaperones for glucocerebrosidase mutations located outside the domain containing the active site and are associated with neurological involvement, as the L444P mutation. Aim:The aim of this work is to present molecules with a high binding specificity towards b-glucocerebrosidase, with a high ratio of chaperone versus inhibitor activity and capable of producing an increased in the levels of mutant enzymes associated with Gaucher disease, including mutations located outside the catalytic domain. Methods:Different bicyclic derivatives of L-idonojirimycin were designed and chemically synthesized from D-glucose after in silico structural analysis and identification of the most favorable molecular features to interact with the active site of glucocerebrosidase. The chaperone potential of these compounds was evaluated at different concentrations in vitro using a cell model of GDcarrying the more frequent mutations in Gaucher disease, namely N370S and L444P. (P201230804). Results:The obtained results showed an increase in b-glucocerebrosidase activity at various chaperone concentrations, ranging from 1.96 to 4.98 folds for the L444P mutant and from 2.01 to 3.06 folds for the N370S mutation. Comments: The bicyclic derivatives of L-idonojirimycin could be considered as a therapeutic alternative for GD, mainly in patients with mutations located outside the active site of the enzyme and associated with neurologic involvement. Disclosures:Giraldo:Actelion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Genetic association study of glucocerebrosidase gene L444P mutation in essential tremor and multiple system atrophy in mainland China

The glucocerebrosidase (GBA) gene mutation is emerging as an important risk factor for Parkinson’s disease. We previously reported that the GBA gene L444P mutation is an important risk factor for PD in the Chinese population. The prevalence of this mutation in other neurodegenerative diseases and movement disorders remains completely unexplored in mainland China. In the present study, we extended the screening of GBA gene L444P mutation to Chinese patients with essential tremor (ET) and multiple system atrophy (MSA). We searched for the GBA gene L444P mutation in 109 patients with ET, 54 patients with MSA, and 657 controls from mainland China. None of the 109 patients with ET or 54 patients with MSA carried the GBA gene L444P mutation. Among the 657 controls, we found one L444P heterozygote. The difference in mutation frequencies between patients with ET or MSA and the control group was not statistically significant (chi-squared test, p=1, respectively). The results suggest that the GBA gene L444P mutation may be not responsible for ET in mainland China. Whether the GBA gene L444P mutation modifies the risk for MSA deserves further study in larger samples.

Potent Aminocyclitol Glucocerebrosidase Inhibitors are Subnanomolar Pharmacological Chaperones for Treating Gaucher Disease

Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) of 1 nM using isolated enzyme and an IC(50) of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment.

Diagnostic moléculaire de la maladie de Gaucher en Tunisie

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid β-glucosidase. In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in 30 Tunisian patients with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing had shown that N370S was the most frequent mutation (22/50 mutant alleles, 44%), followed by L444P mutation, which is found in 16% (8/50 mutant alleles). The recombinant allele (RecNciI) represented 14%. Our findings revealed that the genotype N370S/RecNciI was mosst frequent in patients with childhood onset and it was associated with severe visceral involvement. The screening of these three mutations provided a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allowed also genetic counselling for their family members.

Glucocerebrosidase L444P mutation confers genetic risk for Parkinson’s disease in central China

BackgroundMutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD.MethodsIn this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W).ResultsOur data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects.ConclusionsOur observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.

Gaucher disease: a pyrosequencing frequency analysis of the N370S and L444P mutations in the Spanish population

Gaucher disease: a pyrosequencing frequency analysis of the N370S and L444P mutations in the Spanish population

Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course

Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia.

Neurological manifestations in patients with Gaucher disease and their relatives, it is just a coincidence?

Gaucher disease (GD) is an autosomal recessive disorder characterized by defective function of glucocerebrosidase. GD presents a wide spectrum of manifestations, and patients and their relatives may develop neurological abnormalities more frequently than the general population. This study aims to determine the presence of neurological symptoms (NS) and Parkinson's disease (PD) in Spanish GD patients and their relatives. We surveyed 87 GD Spanish families and validated the information obtained on the neurological involvement through their physicians, as well as the historical data included in the Spanish Gaucher Disease Registry. Neurological abnormalities were correlated with the genetic characteristics. Statistical analyses included descriptive parameters, ANOVA, t-test, correlation study and Pearson coefficient. Information was obtained from 118 patients and 324 relatives. Out of 110 patients with type 1 GD, 32 (29.1%) reported NS and 7 (6.4%) had PD. In relatives, a total of 39 (13.1%) subjects had NS, including 16 with PD (5.3%). The prevalence of NS in genetic carriers (15.9%) was greater than that in non-carriers (5.9%; p < 0.01). Patients with PD carried the following GBA mutations: S364R, D409H, L444P, R257Q, IVS4-2A > G, c.500insT, and L336P. Relatives with PD exhibited a wide spectrum of mutations: L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT. We observed a high incidence of PD in type 1 GD and relative's carriers. PD was more frequent in carriers of L444P and other rare GBA mutations. Therefore, it is important to perform a systematic neurological exam in patients with type 1 GD and carriers with high risk mutations.