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Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score. An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values. Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27years, age range: 4-67years). The median GD-DS3 score was 4 (range: 1-10.1) and median MRE value was 2.43kPa (range: 1.30-5.20kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r=0.47, p

A Caucasian male with Gaucher disease type 3, treated with continuous enzyme therapy (ET) for 11 years, experienced progressive mesenteric and retroperitoneal lymphadenopathy, lung disease, and neurological involvement leading to death at an age of 12.5 years. Autopsy showed significant pathology of the brain, lymph nodes, and lungs. Liver and spleen glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels were nearly normal and storage cells were cleared. Clusters of macrophages and very elevated GluCer and GluS levels were in the lungs, and brain parenchymal and perivascular regions. Compared to normal brain GluCer (GC 18:0), GluCer species with long fatty acid acyl chains were increased in the patient's brain. This profile was similar to that in the patient's lungs, suggesting that these lipids were present in brain perivascular macrophages. In the patient's brain, generalized astrogliosis, and enhanced LC3, ubiquitin, and Tau signals were identified in the regions surrounding macrophage clusters, indicating proinflammation, altered autophagy, and neurodegeneration. These findings highlight the altered phenotypes resulting from increased longevity due to ET, as well as those in poorly accessible compartments of brain and lung, which manifested progressive disease involvement despite ET.

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal disorder caused by deficiency of iduronate 2-sulfatase resulting in progressive accumulation of dermatan and heparan sulfate with multisystem involvement including neurological, respiratory, cardiac and skeletal. Long-term enzyme replacement therapy for MPS II has demonstrable benefits in walking ability, endurance and organomegaly and possibly life expectancy and is usually delivered by a central venous port system. Intravenous catheter use is a major risk factor for development of deep vein thrombosis (DVT) which isassociated with significant morbidity, including debilitating extremity pain and swelling, pulmonary embolism, superior vena cava syndrome as well as increased overall mortality. Data from patients who require long-term central venous access show a prevalence of catheter related DVT with obstruction of 3-5%, with higher rates of asymptomatic non-occlusive thrombi. Here we report a series of six individuals with MPS II that presented acutely with severe symptomatic DVT. Of our cohort of 18 MPS II patients, six (33.3 %) ages 12 to 27 years presented with symptomatic DVT, five of which coinciding with site of catheter placement. Veins affected included subclavian, jugular, axillary, common femoral, and brachial veins. All patients were admitted to the ICU and underwent chest CT angiogram, four of which revealed the presence of remarkable diffuse tortuous collateral veins. Coagulation profile and thrombophilia workup were unremarkable in all cases. In conclusion, symptomatic DVT in Hunter patients appears to be at a higher rate than those with long-term central access for other indications. Interestingly, the majority of patients with DVT showed evidence of extensive formation of tortuous collateral vessels. The pathogenesis of these findings remains unclear. This highlights the importance of further understanding mechanisms and clinical implications of DVT and vasculopathy as well as of adopting measures for screening and prevention of these findings in MPS II patients.

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, progressive, X-linked genetic disorder that is caused by mutations in the human IDS gene and is characterized by deficient activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). Without functional IDS activity, the glycosaminoglycans (GAG), dermatan sulfate and heparan sulfate, accumulate in the body and lead to widespread tissue and organ damage. Patients with MPS II develop progressive respiratory and cardiac disease, skeletal abnormalities and in the severe form, cognitive decline and early death, despite treatment with enzyme replacement therapy. SB-913 is a new type of investigational treatment for MPS II. SB-913 uses zinc finger nuclease (ZFN)-mediated in vivo genome editing to insert a normal copy of the IDS transgene into liver cells, delivered via AAV2/6 vectors. The precision and specificity of SB-913 allows for integration at a targeted genomic location and is intended to reduce GAG accumulation with lifelong continuous endogenous production of IDS. CHAMPIONS is an ongoing Phase 1/2 clinical trial to determine if dose escalation of SB-913 is safe and tolerable in patients with MPS II, and is the first trial to attempt in vivo genome editing in humans. CHAMPIONS is a multicenter, open-label, dose escalation study with one-time peripheral intravenous infusion of SB-913, followed by three years of observation. Six adult subjects with attenuated MPS II have received SB-913, with two subjects in each of three dose cohorts (5e12 vg/kg, 1e13 vg/kg, and 5e13 vg/kg). The infusions were generally well-tolerated and no serious adverse events related to the study drug were reported at any dose with up to 10 months of exposure. No persistent transaminitis was observed. Additional analysis of the trial data is ongoing and will be presented as available. These results support further development of SB-913 for the treatment of MPS II.

Gaucher disease (GD) is a lysosomal storage disease characterized by deficiency of glucocerebrosidase within lysosomes, altering degradation of glycosphingolipids, which causes accumulation of glycosylceramide. Patients with GD type 1 (GD1) have an increased incidence of gammopathy (i.e., hypergammaglobulinemia, monoclonal gammopathy of undetermined significance [MGUS]), and multiple myeloma (MM) when compared to the general population. No formal evaluation of gammopathy screening has been reported in the literature. We conducted an IRB approved retrospective analysis of clinical and laboratory data, including screening for MM, in adults with GD at Cincinnati Children’s Hospital Medical Center between 2010 and 2018. During the 8-year study period, 20 adults with GD (11 females/9 males) ages 19 to 71 (mean = 51.95 years) were screened for MM using serum protein electrophoresis (SPE) and immunofixation (IFE). Of those, 10 were treated with substrate reduction therapy (SRT) and 9 with enzyme therapy (ET). We identified no patients with MM, 2 with MGUS, and 1 with persistent polyclonal gammopathy. The 2 MGUS patients were 48 and 61 years-old, female and male respectively, with intact spleens. SPE and IFE follow-up has been stable without progression. The polyclonal gammopathy patient was a 54-year-old splenectomized male. All patients with abnormal SPE or IFE were on therapy (2 ET/ 1 SRT). Only one abnormal patient’s GBA genotype was known (p.Asn409Ser, p.Leu483Pro). Other SPE abnormalities included slight increases/decreases in albumin, protein, and beta globulin, or slight decreases in alpha 2 or gamma globulin without clinical significance. Family history of cancer was documented in 10 individuals, with no MM or blood-related malignancies reported. Our data show that as in the general population and previous GD studies, gammopathies are more common in patients greater than 50 years. These data support screening in GD1 for gammopathy greater than age 40 years.

Gaucher Disease (GD) is a lysosomal storage disease characterized by hepatosplenomegaly, pulmonary disease, fatigue, and bone pain and crises. While most physicians show primary concern with visceral and hematologic symptoms, patients report interest in decreasing fatigue and pain, which has an effect on quality of life. Generalized joint hypermobility (GJH) is characterized by joint laxity and increased joint range, and affect levels of both pain and fatigue. The relationship in patients with GD between chronic pain, residual fatigue, and GJH was investigated. Participants with GD Type 1 performed a Beighton Score and five-part questionnaire to meet diagnostic criteria for GJH. The Brief Pain Inventory (BPI) and Fatigue Severity Scale (FSS) were used to assess pain and fatigue. Therapeutic goals and the Disease Severity Scoring System (DS3) evaluated treatment goals and disease involvement. 33% of our population (4/12) met GJH criteria. Of those with GJH, 50% expressed moderate pain severity and 25% reported moderate pain interference, compared to 12.5% and 0% without GJH. 50% of both groups reported severe fatigue. There was a strong positive correlation between reported values of pain severity, pain interference, and fatigue. Participants met a median of 96.3% of Gaucher-related therapeutic goals. In those with GJH versus those without GJH, 50% and 57.1%, respectively, had “mild disease” involvement. We did not see significant changes in the levels of pain and fatigue between the two groups of participants, but the study did reinforce those who report higher levels of pain severity and interference also report high levels of fatigue, regardless of a GJH diagnosis. Someone with high levels of pain may need anticipatory management for fatigue. Our patients were well-managed and met many therapeutic goals, which may account for the levels of pain and fatigue reported. Future studies recommended include larger, more generalizable studies for GD and GJH.

Thomas Burrow, DavidWitte, Laurie Bailey, Carlos Prada, Ying Sun, Mitchell Cohen, Steve Wu, Gregory Grabowski, Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA, Department of Pathology, Cincinnati Children's Hospital Medical Center, and University Of Cincinnati, Cincinnati, Ohio, USA, Centro de Medicina Genomica y Metabolismo, Fundacion Cardiovascular de Colombia, Floridablanca, Colombia, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA, Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center and Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA