Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.

α-Synuclein rs356219 polymorphisms in patients with Gaucher disease and Parkinson disease.

Mutations in ß-glucocerebrosidase, the genetic defect in Gaucher disease (GD), are an important susceptibility factor for Parkinson disease (PD). A PD effector is α-synuclein (SNCA) hypothesized to selectively interact with ß-glucocerebrosidase under lysosomal conditions. SNCA polymorphism rs356219 may be associated with early-age-onset PD, common among patients with GD+PD. The objective of this study was to ascertain rs356219 genotypes of GD+PD patients. All GD+PD patients at our Gaucher referral clinic were asked to participate. A GD-only sex-, age-, GD genotype-, and enzyme therapy (ERT)-matched control was found for each GD+PD participant. Student's t-test was used (p-value <0.05 as significant). There were 14 GD+PD patients: all Ashkenazi Jewish; 11 males (78.6%); mean (range) age diagnosed GD 34.2 (5-62) years; 50% N370S homozygous; mild to moderate GD; 3 asplenic and only these have osteonecrosis; 5 received ERT; mean age (range) diagnosed PD was 57.8 (43-70) years; first PD sign was tremor in 9 (64.3%); cognitive dysfunction in all. In GD+PD, frequency for AG+GG (9) was greater than AA (5); in GD only, there was equality (7). Odds Ratio risk for PD increases with number minor alleles: but not significantly greater among GD+PD than GD only; in aggregate, there was no difference between cohorts for frequency of minor alleles. The limitation of this study is few GD+PD, albeit virtually all the GD+PD cohort >500 adult GD patients in our clinic. Nonetheless, as a foray into potential genetic GD susceptibility for a synucleinopathy, this study suggests the need for collaboration to achieve larger sample size.

Prenatal healthcare providers' Gaucher disease carrier screening practices.

PURPOSE: Gaucher disease carrier screening is controversial in the medical community. The goal of this study was to explore current Gaucher disease carrier screening practices of prenatal healthcare providers. METHODS: Prenatal healthcare providers were invited by email to complete an electronic-based survey. RESULTS: A total of 1,454 prenatal healthcare providers, including 209 genetic counselors, 450 midwives, and 795 physicians, completed the study. The majority of genetic counselors (n = 208/209, >99%), physicians (n = 415/450, 92%), and midwives (n = 634/795, 80%) currently offer Jewish ancestry disease carrier screening to couples in whom one or both partners are Jewish. Of providers who offer Jewish ancestry disease screening, the majority of genetic counselors (n = 199/208, 96%) and physicians (n = 352/415, 85%) always or sometimes offer Gaucher disease screening whereas the majority of midwives (n = 357/634, 56%) never offer Gaucher disease screening. CONCLUSION: This study presents the first report of Gaucher disease carrier screening practices of the prenatal healthcare providers in North America. Our results indicate that Gaucher disease carrier screening is being offered at a high rate within the scope of Jewish ancestry-based carrier screening. This may highlight a need to move away from the debate as to whether Gaucher disease carrier screening should be offered and, instead, focus on how best to provide Gaucher disease carrier screening services.

Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

Mutations in GBA1 gene result in defective acid ß-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at P value 1.26 × 10(-6) . Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients, in whom CLN8 risk alleles were overrepresented. In an in vitro cell model of GD, CLN8 expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.

Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes.

BACKGROUND: Type 1 Gaucher disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption. METHODS: Prenatal carrier screening of 8069 AJ adults for 6 common GD mutations was performed. Gaucher disease manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory, and imaging studies. RESULTS: Among the 8069 AJ screenees, 524 GD carriers (1:15) and 9 previously unrecognized GD homozygotes (1:897) were identified, consistent with the rate expected (1:949; P > .99). Six of these homozygotes and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York City metropolitan area were evaluated (age range of the homozygotes, 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P, or R496H mutations. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%), and bone infarcts (14%). Dual energy X-ray absorptiometry studies of 25 homozygotes found 60% with osteopenia or osteoporosis. CONCLUSION: Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical treatment.

Sixteen years of prenatal consultations for the N370S/N370S Gaucher disease genotype: what have we learned?

OBJECTIVE: Although prenatal diagnosis and genotyping are available for Gaucher disease, genetic counseling for an affected child's parents reflects the inability to predict disease course with certainty. The purpose of this survey is to ascertain disease status of children identified by prenatal screening. METHODS: All carrier couples for glucocerebrosidase mutations who were counseled at our large Gaucher Clinic were included; none had genotyped the fetus. Medical status of children was assessed by questionnaires and data were collected from clinic charts and/or telephone contact with the parents. RESULTS: Of 34 children born, 1 died in utero, 5 fetuses (N370S/N370S) aborted. Of 21 genotyped N370S/N370S, 7 children had Gaucher-like symptoms/signs but for only one child (two symptoms) were these ascribable to Gaucher disease; four children had non-Gaucher symptoms/signs. CONCLUSION: Of 21 children whose parents pursued prenatal counseling for Gaucher disease and were found to have the N370S/N370S genotype, none has presented with severe disease with follow-up of 15 years. The Israeli experience shows that Gaucher disease N370S screening does not identify children requiring treatment, but rather leads to termination of asymptomatic fetuses; this may lead to reconsideration of guidelines regarding Gaucher screening.

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent.

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with low-dose ERT and re-evaluating the use of ERT in asymptomatic patients.

Glucocerebrosidase gene mutations in black South Africans with Gaucher disease.

Gaucher disease (GD) is caused by mutations in the glucocerebrocidase gene (GBA) and presents with variable severity. Type 1 is characterized by the lack of neurological symptoms in childhood, whereas types 2 and 3 are early onset neuronopathic forms and result in premature death. Only type 1 GD has been reported in black South Africans and the cases are clinically severe. In this study both GBA mutations were identified in 18/19 black GD patients. Two mutations accounted for 2/3 of all observed disease causing alleles: p.T36del (c.222-224delTAC) (17/38 alleles) and RecNcil (8/38 alleles). Three novel variants were identified and assessed as being likely pathogenic mutations: c.413delC, W357C and D405V. Haplotype analysis supported a single origin for the p.T36del mutation in black South Africans on a haplotype background that is rare in the present population. We hypothesise that the p.T36del results in intracellular mislocalisation of the protein, but confirmation of the altered function of this allele awaits functional studies. A diagnostic test for GD has been implemented for black South Africans.

[An analysis of mutations causing Gaucher disease in Chinese population].

OBJECTIVE: To review and investigate the relationship of genotype and phenotype in Chinese patients with Gaucher disease (GD). METHODS: The samples were first screened for known mutations as reported previously in Chinese population. Long chain PCR and nested PCR were employed to amplify the segments of glucocerebrosidase functional gene in patients with unknown mutant alleles. The products of nested-PCR were subjected to DNA sequencing to detect the new mutations. RESULTS: Forty kinds of mutations were detected in this panel of patients. The L444P mutation was the most common one accounting for 33.0% of mutant alleles. It was followed by F213I, N188S, V375L and M416V. CONCLUSION: There are at least 40 mutations in Chinese GD patients. The spectrum of mutation is significantly different from that in Caucasians. 70% of mutant alleles have been characterized. It becomes feasible to make clinical and prenatal diagnoses through gene analysis.

Gaucher disease in Arab patients at an Israeli referral clinic.

BACKGROUND: With regard to ethnic predilections for Gaucher disease, the most common storage disorder, Ashkenazi Jews are at risk for the non-neuronopathic form (type I), Norbottnian Swedes are at risk for the subacute neuronopathic form (type III), and perhaps Arabs are at risk for the very rare cardiac variant of the subacute neuronopathic form (type IIIc) for which there is a relatively tight genotype-phenotype correlation. Type II, the acute infantile form, being the rarest form, has not been associated with any ethnic predilection. OBJECTIVES: To examine whether Arab ethnicity influences the Gaucher phenotype. METHODS: We reviewed the records of all Arab patients in a referral clinic of 586 patients in Israel. RESULTS: There were 46 patients (7.8%) of Arab ethnicity: 23 (50%) had type I disease, 16 (34.8%) had type IIIc disease, 4 (8.7%) had type IIIb disease, and 3 (6.5%) had type II disease. Type IIIc disease was characterized by genotype-phenotype correlation with homozygosity for the D409H (1342C) mutation. All five Bedouin patients (10.9%) had the R48W (C259T) mutation on at least one allele. CONCLUSIONS: For all genotypes, disease severity among Arab patients was relatively similar to that reported among other Caucasian patients. Apparently Arab ethnicity does not impact phenotypic expression in Gaucher disease in a unique manner. The predilection for type IIIc may be a result of consanguinity.

Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P).

BACKGROUND: Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA). We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P). The goal of this study was to clinically evaluate this assay. METHODS: Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. RESULTS: We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (PsiGBA) due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. CONCLUSION: Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that required amplification of a larger region for effective discrimination.

Homozygosity for the double D409H+H255Q allele in type II Gaucher disease.

Homozygosity for D409H has been associated with a unique type III subtype of the disease with a phenotype dominated by severe cardiovascular involvement, whereas neurological findings, if present, are restricted to oculomotor apraxia and features such as visceromegaly are either minimal or absent. Using PCR amplification followed by restriction enzyme analysis, 3 patients (1 Greek, 2 Albanians) were IDentified with the D409H/D409H genotype. All shared a very severe early-onset neurological phenotype that classified them as type II. Amplification and sequencing of the full coding region of the GBA gene revealed that all three patients were homozygous not only for D409H but also for H255Q. Both mutations were present on the same allele, as shown by analysis of the parental DNA. The double D409H+H255Q allele was found in heterozygosity in Greek, Bulgarian and Argentinian patients but was not IDentified in any Spanish patients carrying the D409H mutation.

Prenatal panel screening considerations for non-neuronopathic Gaucher disease in the Ashkenazi-Jewish population.

The Ashkenazi-Jewish population is at increased risk for several recessively inherited disorders. While some of the disorders have severe or fatal symptom manifestations, others, such as non-neuronopathic Gaucher disease, do not usually pose a serious, life-threatening illness. Many healthcare centers in Israel offer prenatal panel screening. Controversy exists over the inclusion of Gaucher disease in the panel screening, especially since Gaucher disease screening lacks prognostic reliability. Most screening participants do not discriminate between the specific tests in the panel and are unable to discern between severe, life-threatening diseases and those that are less severe and even treatable. By including screening for Gaucher in the panel screening program, there is risk of a "panel effect," leading to termination of a pregnancy positive for Gaucher disease, without sufficient knowledge and understanding of the disease. Increasing medical and public awareness and knowledge of the disease, its prognosis and treatment options may reduce the rate of under-informed abortions associated with prenatal screening for Gaucher disease.

Gaucher disease: multiple lessons from a single gene disorder.

UNLABELLED: Gaucher disease is the most common lysosomal storage disease. It is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a beta-glucosidase, which results in the accumulation of the lipid glucocerebroside in macrophages throughout the body. Gaucher disease is most common in the Ashkenazi Jewish population, and three mutations of the gene encoding glucocerebrosidase (GBA) have been shown to be prevalent in this population (c.1226 A > C [N370S], 84GG and IVS2[+1]). In non-Jewish patients, the most common mutation is c.1448 G > C (L444P). Until 15 years ago, treatment has been restricted to symptomatic interventions, such as splenectomy or hip replacement. However, there are now specific treatment options - enzyme replacement therapy and substrate reduction therapy. Future developments may include the use of chaperone therapy. CONCLUSION: The lessons that we have learned from Gaucher disease may well be applicable to the development of therapies for some of the other less common lysosomal storage diseases.

Characterization of neuronopathic Gaucher disease among ethnic Poles.

PURPOSE: Gaucher disease is a common lysosomal storage disease that results from inherited mutations in the gene (GBA) encoding acid beta-glucosidase (GCase). Here, the clinical and molecular findings of the subacute neuronopathic variant are delineated among ethnic Poles. METHODS: Longitudinal studies of visceral, bony, and central nervous system involvement are delineated clinically. Complete gene GBA sequencing was used to characterize the mutations and haplotypes in this population. RESULTS: A greater frequency of subacute neuronopathic Gaucher disease (type 3) is present among ethnic Poles compared with other European countries. Two type 3 phenotypes were found: The first was an early-onset variant with massive visceral disease, progressive kyphoscoliosis, mild cognitive deficits, and survival for three or more decades. This variant resembles the "Norrbottnian" Swedish phenotype. The other variant had more severe progressive central nervous system disease, milder visceral involvement, and absence of kyphoscoliosis. Myoclonus was present in some patients. Neither variant had bone crises and/or pain as major components. The L444P/L444P genotype was most common, but on several different haplotype backgrounds. Other alleles encoded D409H, V305L, and E326K/A446P on various haplotypes. CONCLUSIONS: These studies provide additional expansion of the type 3 genotypes with some commonalities with and differences from other reported variants. Also, such phenotypic expansion should be expected in the other variants of Gaucher disease as the spectrum of ethnic variation becomes more fully delineated.

A comprehensive assessment of renal function in patients with Gaucher disease.

BACKGROUND: Gaucher disease (GD) is caused by deficiency of acid beta-glucocerebrosidase and is the most common lysosomal storage disease. Patients may have massive hepatosplenomegaly, severe bone disease, and, occasionally, pulmonary or neurological involvement. Although other storage diseases, such as Fabry disease, frequently affect the kidneys, reports of renal abnormalities in patients with GD are limited to case reports. Our aim was to perform a comprehensive evaluation of renal function in patients with GD. METHODS: Evaluation was performed at routine clinic visits and included blood pressure recording and renal ultrasound. Serum chemistries, urinalysis, urine electrolytes, total protein, and tubular proteinuria were assessed, and estimated glomerular filtration rate (GFR) was calculated. RESULTS: One hundred sixty-one patients underwent evaluation, including 26 children. GFR was significantly greater in patients with GD than in age- and sex-matched healthy controls (P = 0.01 in men, P < 0.001 in women, P = 0.003 in children). Subgroups of patients with markers of more severe disease had a greater GFR than other patients. No patient had decreased renal function. Significant proteinuria was found only in patients with such comorbidities as diabetes mellitus or multiple myeloma. No evidence of renal tubular abnormalities was found, and kidney sonographic appearance and size were normal. CONCLUSION: Despite the multiorgan nature of the disease, a systematic evaluation did not find renal abnormalities in patients with GD. Glomerular hyperfiltration was observed in a proportion of patients, particularly those with markers of more severe disease. This phenomenon does not seem to be associated with a subsequent decline in renal function.

Ashkenazi Jewish genetic disorders.

The frequency of several genes responsible for 'single-gene' disorders and disease predispositions is higher among Ashkenazi Jews than among Sephardi Jews and non-Jews. The disparity is most likely the result of founder effect and genetic drift, rather than heterozygote advantage. The more common Mendelian Ashkenazi Jewish genetic disorders are summarized, and examples of variable expressivity and penetrance, inconsistent genotype-phenotype correlation, and potential modifiers are presented. The importance of genetic counseling in both the pre- and post-test phases of population screening is emphasized.

The 1604A (R496H) mutation in Gaucher disease: genotype/phenotype correlation.

Gaucher disease is the most common sphingolipid storage disease but genotype only broadly predicts phenotype. The 1604G-->A (1604A;R496H) mutation has been described as having a low incidence among Ashkenazi Jews. The purpose of this study was to ascertain phenotypic expression and prevalence of this mutation among patients with Gaucher disease and among healthy Ashkenazi Jews. Patients in two Gaucher clinics (in the United States and Israel) and from an international Gaucher registry were assessed for frequency and phenotype expression; 200 healthy Ashkenazi Jews were screened as well. Molecular analysis was performed by standard methods. In the Gaucher clinic with mostly Jewish patients, the gene frequency was 1.68% compared with 0.38% in the international registry with mostly non-Jewish patients. Among Ashkenazi Jewish controls, no alleles with 1604A were identified. There was a marked overrepresentation of severe alleles in patients carrying the 1604A mutation, suggesting that many patients who are compound heterozygotes for 1604A are not diagnosed as having Gaucher disease because their disease is presumably so mild as to evade detection. In view of its rarity and mild expression, the inclusion of the 1604A mutation in the standard kit for screening for Gaucher disease is unnecessary.