Search

Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants in children.The investigators aimed to obtain safety and efficacy data for edoxaban in children.We performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients 18 years of age with cardiac disease (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease] trial). Patients were randomized 2:1 to age- and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis. Both groups could continue in an open-label edoxaban extension arm through 1 year. The primary endpoint was adjudicated clinically relevant bleeding (CRB). The main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis.The modified intention-to-treat cohort included 167 children. One patient per group experienced a nonmajor CRB in the main period. Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC. One SOC patient experienced 2 TE events (DVT with PE). Among 147 children in the extension, 1 CRB event (0.7%) and 4 TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions).Edoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of CRB and TEs with advantages of once daily dosing and infrequent monitoring requirement. (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots] (Thrombotic Events) in Children at Risk Because of Cardiac Disease trial; NCT03395639).

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103/L, lumbar spine bone density T-score < −2.0, and/or LysoGb1 > 200 ng/mL, and for a group of naïve patients who had abnormal values in two of these three parameters. We enrolled 40 patients: 28 ERT- or SRT-treated, and 12 naïve. There were no severe adverse effects (AEs). There were 24 dropouts, mostly due to AEs (n = 12), all transient, and COVID-19 (n = 7). Among the 16 completers, 5 (31.2%) had a >20% increase in platelet count, 6 (37.5%) had a >0.2 increase in T-score, and 3 (18.7%) had a >20% decrease in Lyso-Gb1. This study expands the number of patients exposed to high-dose ABX, showing good safety and satisfactory efficacy, and provides an additional rationale for adding off-label ABX to the arsenal of therapies that could be offered to patients with GD1 and a suboptimal response or those unable to receive ERT or SRT.

Study Objective The aim of the study was to examine the effect of heavy menstrual bleeding (HMB) and dysmenorrhea on daily activity and quality of life (QoL) in young women engaged in demanding activities. Design Cross-sectional study. Participants A total of 422 Israeli women soldiers in combat and non-combat roles. Interventions Participants were asked to provide consent and to complete study questionnaires. Main Outcome Measures A pictorial bleeding assessment chart (PBAC), visual analog scale (VAS), verbal multidimensional scoring system for assessment of dysmenorrhea, and approved Hebrew-translated age-appropriate Pediatric Quality of Life Inventory (PedsQL). Results HMB (PBAC >100) and severe HMB (PBAC >185) were demonstrated in 181 (50%) and 96 (26%) participants, respectively. A high PBAC score was recorded in 20% who answered “no” or “unknown” in the questionnaire on having HMB. Mild, moderate, and severe dysmenorrhea were demonstrated in 80 (21.5%), 115 (31%), and 142 (38%) participants, respectively. The prevalence of HMB and dysmenorrhea was similar in soldiers in combat and non-combat roles. Diagnosis of HMB was related to the lower fitness-for-service score, history of bleeding, and dysmenorrhea. Daily activity and QoL were both affected by the severity of HMB and dysmenorrhea. Conclusion Underdiagnosis of HMB and dysmenorrhea results from a combination of unawareness from the women's side and inattention from the system. In an era of female empowerment, each woman should be at the optimal physiological and psychological level to start her career; thus, addressing the menstrual burden and providing effective treatment is needed in the military scenario and other settings with demanding activities.

Glucosylsphingosine (lyso-Gb1), the deacylated form of glucocerebroside, was shown to be the most specific and sensitive biomarker for diagnosing Gaucher disease (GD). The aim of this study is to assess the contribution of lyso-Gb1 at the time of diagnosis for treatment decisions in naïve patients with GD. Newly diagnosed patients from July 2014 to November 2022 were included in this retrospective cohort study. The diagnosis was done by sending a dry blood spot (DBS) sample for GBA1 molecular sequencing and lyso-Gb1 quantification. Treatment decisions were based on symptoms, signs, and routine laboratory tests. We diagnosed 97 patients (41 males), both type 1 (n = 87), and neuronopathic (n = 10). The median (range) age at diagnosis was 22 (1–78), with 36 children. In 65 patients, GD-specific therapy was started with a median (range) lyso-Gb1, 337 (60–1340) ng/mL, significantly higher than in patients who did not go on to treatment, 153.5 (9–442) ng/mL. Using a receiver operating characteristic (ROC) analysis, a cutoff of lyso-Gb1 > 250 ng/mL was associated with treatment with a sensitivity of 71% and specificity of 87.5%. Predictors of treatment were thrombocytopenia, anemia, and elevated lyso-Gb1 (>250 ng/mL). In conclusion, lyso-Gb1 levels contribute to the medical decision related to the initiation of treatment, mainly among mildly affected newly diagnosed patients. For patients with a severe phenotype, as for all patients, the main value of lyso-Gb1 would be to monitor response to therapy. The variable methodology and differences in the units of lyso-Gb1 measurements between laboratories prevent the adaptation of the exact cut-off we found in general practice. However, the concept is that a significant elevation, i.e., a several-fold increase from the diagnostic lyso-Gb1 cutoff, is related to a more severe phenotype and, accordingly, to the decision regarding the initiation of GD-specific therapy.

Bleeding tendency, a prominent feature of patients with Gaucher disease (GD), is associated with abnormal platelet function. Brain-derived neurotrophic factor (BDNF) is a protein with neuroprotective potential stored in alpha granules of circulating platelets. Here we studied BDNF levels in 50 patients with type I GD (GD1) and their correlation with platelet activity and bleeding tendency. Flow cytometry was used to test unstimulated and stimulated measurement of platelet surface-activated expression of αIIbβ3 integrin, P-selectin and lysosomal-associated membrane protein (LAMP3/CD63). Serum and plasma BDNF levels were quantified using ELISA. The bleeding history was recorded by a bleeding questionnaire. Serum BDNF levels were positively correlated with platelet count and moderately correlated with unstimulated and stimulated platelet P-selectin expression. Patients with more than one bleeding manifestation were shown to have lower serum BDNF levels, albeit similar platelet count. Plasma BDNF levels were significantly elevated in splenectomized patients and showed a moderate positive correlation with stimulated platelet CD63 expression. These observations demonstrate the first association between BDNF levels in the peripheral blood with platelet dysfunction and increased bleeding manifestation. The role of measuring serum BDNF for assessing platelet alpha degranulation defects and bleeding risk in patients with GD and the general population needs further study.

Objectives Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface-activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r = 0.17, p-value = 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (−2 standard deviation of reference range) was found in 79 (53%, 95% confidence interval [CI]: 44–61%) patients, of whom 10 (6.7%, 95% CI: 3.3–12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (odds ratio [OR]: 1.05, 95% CI: 1.01–1.1) and low P-selectin reactivity (OR: 2.03, 95% CI: 1.25–3.35) were associated with more than one bleeding manifestation. Conclusion Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients with compatible CYP2D6 metabolizer genotype. Herein we report safety and efficacy data of the first 29 patients switched from ERT to eliglustat from the Gaucher Unit at Shaare Zedek Medical Center (SZMC) between 07/2017 and 06/2022; the median (range) time on ERT was 13 (0.66–30) years, and the median (range) time on eliglustat was 7 (1–52) months. Most patients switched due to oral preference or sub-optimal response to low-dose ERT. Twelve patients stopped eliglustat after a median (range) of 4 (1–18) months; 11 due to adverse events (AEs) and one due to personal request. There were no drug-related serious AEs and no drug-related cardiac events. Most AEs were mild and transient, mainly dyspepsia. Efficacy achievements were reflected by maintaining stability. We concluded that switching from ERT to eliglustat is safe if choosing the appropriate patients. Reassuring patients to tolerate early AEs may reduce discontinuation. Following the response and compliance to therapy is important to ensure long-term efficacy.

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

Introduction For the last three decades, enzyme replacement therapy (ERT) for Gaucher disease (GD) has been available. We aimed to evaluate the effect of ERT on the pregnancy and obstetric outcome in a unique group of multiparous women with type 1 GD (GD1) who had pregnancies with and without ERT. Study design The Gaucher Unit database (1987-2019) was searched for multiparous women who had pregnancies before and after the institution of ERT. Data were collected from the clinic files and study-specific questionnaires. Descriptive, correlation analysis and generalized estimating equations (GEE) were used to study the effect of ERT and confounding variables on study outcomes. Results We identified 19 women with 105 pregnancies, among which 26 (24.7%) terminated in first-trimester miscarriage. The risk for miscarriage was associated with the severity of GD1 genotype and phenotype, but not with ERT usage. Early postpartum hemorrhage (PPH) was reported in 16 (84%) women after 25 deliveries (31.6%, 95% CI 21.6%-43.1%). The risks of early PPH and red blood cell (RBC) transfusions were significantly lower when ERT was used during pregnancy, OR (95% CI) 0.13 (0.03-0.54) and 0.27 (0.08-0.94), respectively, compared to pregnancies without the use of ERT. Conclusion Enzyme replacement therapy during pregnancy is risk reducing for early PPH and RBC transfusions in women with GD1. We suggest considering ERT for the benefit of all pregnant women with GD1, including mild GD1. This article is protected by copyright. All rights reserved.

Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm‐PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high‐quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Background Bleeding disorders (BD) are under-recognized in adolescents with heavy menstrual bleeding (HMB). Objectives The lack of clinical guidelines and variable symptomatic management of HMB created the imperative to standardize HMB care to identify and manage BD in adolescents. Methods We convened an international working group (WG), utilized the results of a literature review to define knowledge gaps in HMB care, and used the collective clinical experience of the WG to develop care considerations for adolescents with BD and HMB. We then solicited input on the appropriateness of HMB care considerations from expert stakeholders representing hematology, adolescent medicine, and obstetrics-gynecology. We conducted an expert panel online, using the ExpertLens platform. During a 3-round online modified-Delphi process, the expert panel rated the appropriateness of 21 care considerations using a 9-point scale to designate care as appropriate (7-9), uncertain (4-6), or inappropriate (1-3) covering screening for BD, the laboratory work-up, and management of adolescents with BD that present with HMB. We used the RAND/UCLA appropriateness method to determine the existence of consensus among the interdisciplinary panel of experts. Results Thirty-nine experts participated in the panel. The experts rated fifteen HMB care considerations as appropriate, six as uncertain, and none as inappropriate. Conclusions The HMB care statements represent the first set of HMB care considerations in adolescents with BD, developed with broad expert input on appropriateness. Although likely to be of interest to a range of clinicians who routinely manage adolescents with HMB, additional research is required in many key areas.

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe GBA1 variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5–16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous GBA1 carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus–driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm– and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT–SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT–ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD.

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5–26) years and 30 (30–60) U/kg/month, respectively. Low FF scores (

Patients with Gaucher disease (GD) have been shown previously to carry an increased risk for cancer, most commonly multiple myeloma (MM). It is currently unknown whether treatment for GD has an effect on the prevention or amelioration of MM. We present the case of a 41-year-old patient simultaneously diagnosed with GD and smouldering MM. Enzyme replacement therapy with Velaglucerase-alfa significantly improved myeloma indices.

Lysosomes have a critical role in maintaining normal cellular homeostasis mediated by their involvement in secretion, plasma membrane repair, cell signaling and energy metabolism. Lysosomal storage disorders (LSDs) are a group of approximately 50 rare disorders caused by lysosomal dysfunction that occur due to mutations in a gene of a lysosomal protein. Gaucher disease (GD), an autosomal recessive disorder and one of the most common LSDs, is caused by the deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), due to biallelic mutations in the GBA1 gene. Reduced GCase activity leads to the accumulation of glucosylceramide (GlcCer), which is deacylated by lysosomal acid ceramidase to a toxic metabolite, glucosylshpingosine (GlcSph). Most GBA1 variants are recognized as misfolded in the ER, where the retention for refolding attempts initiates stress and activates the stress response known as the Unfolded Protein Response (UPR). The distinct clinical subtypes of GD are based on whether there is primary involvement of the central nervous system. Type 1 GD (GD1) is the nonneuropathic type, however, the recent recognition of the association of GD with the development of parkinsonism defies this classification. Patients with GD1 and carriers of GBA1 mutations are at risk for the development of parkinsonian manifestations. Parkinson disease (PD), the second most prevalent neurodegenerative disease, culminates in a movement disorder with the premature death of the patients. In PD and related disorders, collectively called synucleinopathies, the hallmark pathology is α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites and the death of dopaminergic neurons. While PD is mostly sporadic, in ∼5-10% of cases, the disease results from pathogenic variants in a growing number of genes. The most common genetic cause of PD is mutations in GBA1. Two mechanisms have been proposed for this link: (A) a "gain of function" mechanism, in which mutant GCase (protein) contributes to aggregate formation and to the development of PD, and the (B) "haploinsufficiency" ("loss of function") model, suggesting that one normal GBA1 allele is insufficient to carry adequate GCase activity and functional deficiency of GCase impedes α-synuclein metabolism. Lysosomal dysfunction, compromised autophagy and mitophagy further enhance the accumulation of α-synuclein, which results in the development of PD pathology. The present review will elaborate on the biology of GD, its association with PD and related disorders, and discuss the possible mechanisms underlying this association.

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

Catheter‐related arterial thrombosis (CAT) are increasingly recognized in infants and children. Insufficient data are available on the incidence, risk factors, treatment and outcome of these thrombotic events. This work provides consensus recommendations for future research on catheter‐related arterial thrombosis in the paediatric population. In particular, future studies should distinguish between CAT due to indwelling arterial catheters or cardiac catheterization in two different subpopulations (neonates and older children). Further studies should investigate sensitivity and specificity of clinical signs and symptoms for early screening of CAT and the most appropriate imaging modality, focusing on ultrasound due to better feasibility in the very young pediatric population. Adequately powered, well‐designed clinical trials should investigate efficacy and safety of different treatment and prevention strategies as well as the risk for and the optimal management of short‐ and long‐term complications.

Introduction: Gaucher disease (GD), although pan-ethnic and rare (common in Ashkenazi Jews), is of great importance to hematologists both for diagnosis and management. The need for increased awareness of GD is that delayed diagnosis may lead to preventable irreversible complications (mainly skeletal) or unnecessary invasive procedures (e.g. bone marrow biopsy), and the birth of another affected sibling due to lack of genetic consulting.Areas covered: The review outlines the common hematological manifestations of GD, including splenomegaly, thrombocytopenia, and anemia. Other hematological manifestations such as coagulation abnormalities, platelet dysfunction, gammopathy, and other hematological malignancies associated with GD are also discussed. Current and future treatment modalities are delineated, including enzyme replacement and substrate reduction therapy, pharmacological chaperon, and gene therapy. A literature search was conducted to identify original research articles relevant to hematology manifestations and GD published before November 2020.Expert opinion: Patients with GD should be ideally followed and treated in a center of excellence where the GD expert benefits from experienced consultants in relevant disciplines. Due to the availability of several very expensive treatment options, it is important to have an unbiased expert who can select the most suitable management for the individual patients (including withholding prescription in asymptomatic patients).

Low penetrance of Parkinson’s disease (PD) associated with GBA pathogenic variants indicates the presence of modifiers genes. Clusters of PD cases in certain families with GBA variants would serve as a strong evidence for the clinical relevance of such modifiers. We studied eight family trees of non-Parkinsonian, GBA-N370S homozygote, Gaucher probands, with multiple cases of PD. Differences in PD risk associated with different GBA variants were balanced by variant homozygosity. In these families, all PD cases stemmed from only one of the proband’s parents. This observation provides a direct epidemiological evidence for genetic modifiers determining PD risk in GBA variant carriers.

OBJECTIVES Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of