Comparison of Comorbidities between Adults and Children with Glycogen Storage Disease Type Ia (GSDIA)

Objectives: Glycogen Storage Disease Type Ia (GSDIa) is a rare inherited disorder resulting in acute hypoglycemia due to impaired release of glucose from glycogen. Despite dietary management practices to prevent hypoglycemia in patients with GSDIa, complications still occur in children and throughout adulthood. This retrospective cohort study compared the prevalence of complications in adults and children with GSDIa. Method(s): Using ICD-10 diagnosis codes, the IQVIA Pharmetrics Plus database was searched for patients with >=2 GSDI claims (E74.01) from January 2016 through February 2020, with >=12 months continuous enrollment beginning prior to March 2019 (for one year of follow-up before COVID-19), and no inflammatory bowel disease diagnoses (indicative of GSDIb). Complication prevalence in adults and children with GSDIa was summarized descriptively. Result(s): In total, 557 patients with GSDIa were identified (adults, 67%;male, 63%), including 372 adults (median age, 41 years) and 185 children (median age, 7 years). Complications occurring only in adults were atherosclerotic heart disease (8.6%), pulmonary hypertension (3.0%), primary liver cancer (1.9%), dialysis (0.8%), and focal segmental glomerulosclerosis (0.3%). Other complications with the greatest prevalence in adults/children included gout (11.8%/0.5%), insomnia (10.0%/1.1%), osteoarthritis (22.0%/2.7%), severe chronic kidney disease (4.3%/0.5%), malignant neoplasm (10.8%/1.6%), hypertension (49.7%/8.7%), acute kidney failure (15.3%/2.7%), pancreatitis (3.0%/0.5%), gallstones (7.8%/1.6%), benign neoplasm (37.4%/8.1%), hepatocellular adenoma (7.0%/1.6%), neoplasm (41.1%/9.7%), and hyperlipidemia (45.2%/10.8%). Complications with the greatest prevalence in children/adults included poor growth (22.2%/1.9%), gastrostomy (29.7%/3.2%), kidney hypertrophy (2.7%/0.8%), seizure (1.6%/0.5%), hypoglycemia (27.0%/11.3%), hepatomegaly (28.7%/15.9%), kidney transplant (1.6%/1.1%), diarrhea (26.5%/18.6%), nausea and/or vomiting (43.8%/35.8%), acidosis (20.0%/17.2%), and anemia due to enzyme disorders (43.8%/40.6%). Conclusion(s): GSDIa is associated with numerous, potentially serious complications. Compared with children, adults with GSDIa had a greater prevalence of chronic complications, potentially indicating the progressive nature of disease. Children with GSDIa had more acute complications related to suboptimal metabolic control.Copyright © 2023

Vaccination strategies for people living with inborn errors of metabolism in Brazil.

OBJECTIVE: Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. SOURCE OF DATA: The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. SYNTHESIS OF DATA: A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended CONCLUSIONS: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them.

Developmental Risk Factors of Young Children with Inherited Metabolic Disorders During the COVID-19 Pandemic

Objective: Coronavirus disease 2019 (COVID-19) pandemic has led to emergence of new developmental risk factors. Developmental risk factors for young children with inherited metabolic disorders have not been studied based on a comprehensive framework. We aimed to determine the developmental risk factors of young children with inherited metabolic disorders during COVID-19 pandemic based on bioecological theory. Material(s) and Method(s): In a cross-sectional design, children aged 0-42 months that who had appointments at Ankara University School of Medicine Department of Pediatrics (AUDP) Pediatric Metabolism Division with the diagnoses of inherited metabolic disorders were recruited between October 1st, 2020 to January 1st, 2021. Developmental risk factors were assessed with a semi-structured interview based on questions of the Expanded Guide for Monitoring Child Development revised for the pandemic at AUDP Developmental Pediatrics Division. Result(s): The sample consisted of 95 children with inherited metabolic disorders (median age:25, IQR: 17-35 months, 57.9% boys). Most children (54 children, 56.8%) had amino-acid metabolism disorders. Child-related developmental risk factors included new behavioral problems in most of the sample (53 children, 55.8%) and increased screen time in 26 children (27.3%). As family-related developmental risk factors, 40 children (42.1%) were living with a family member diagnosed with major depression. In environment-related developmental risk factors;41 families (43.2%) experienced a decrease in their household income and 21 (22.1%) loss of job during the pandemic, 17 (17.9%) delay in health care follow up visits, 8 of 28 (28.6%) discontinuity of intervention and rehabilitation services. Participation in life was severely limited in 42 (44.2%) children with inherited metabolic disorders. Conclusion(s): Apart from life threatening medical problems, children and their families in Turkey and potentially in other low- and middle-income countries face multiple developmental risk factors. Preventable or reducible risk factors should be addressed to support these children's development in this pandemic and beyond. Copyright © 2022 Ankara Pediatric Hematology Oncology Training and Research Hospital. All rights reserved.

The clinical dilemma of sick neonates with positive COVID antibodies-A case series from India

In the face of the emergence of COVID-19, the multisystem inflammatory syndrome in neonates, which is associated with severe acute respiratory syndrome-related coronavirus, has increasingly been reported. The clinical presentation and evolution of multisystem inflammatory syndrome (MIS) mimics neonatal diseases such as sepsis. Because of the similarities, these cases present clinical and laboratory peculiarities that necessitate distinguishing them from more common neonatal illnesses to reach a consensus on this new disease in the future. Here, we present two cases from India in which neonates had MIS-like manifestations but were later diagnosed with sepsis and metabolic disorder, posing a management dilemma.

Opportunities for fellowship education: the first year of the Medical Biochemical Genetics Clinical Core Seminar Series

Background: The Medical Biochemical Genetics (MBG) Fellowship is an Accreditation Council of Graduate Medical Education (ACGME) subspecialty,one-year training program designed to prepare ClinicalMedical Genetics and Genomics graduates for practice in the diagnosis and treatment of inborn errors of metabolism (IEM). The ACGMErequires each program to provide “structured education, includingformal coursework in the basic sciences and clinical areas pertinent tobiochemical genetics”. There are currently 19 programs around theUnited States (US). Most have only one fellow per year. An average of18 MBG fellows every two years sit for the board examination. Eachprogram has a separate, individual curriculum. This puts a potentiallylarge burden on faculty to generate and teach didactic lectures for asingle fellow per year, and limits the fellow to learn in isolation,without interaction with the greater US IEM community. In 2020,amidst the COVID-19 pandemic, faculty at the University of Coloradoapproached the program directors of the individual MBG programsacross the US to establish a unified MBG curriculum to meet the“formal coursework” requirement. Twelve MBG programs opted totake part.Methods: A curriculum, designated as the MBG Clinical Core SeminarSeries (CCSS),was established to included 13 lectures covering contentfrom the American Board of Medical Genetics and GenomicsBiochemical Genetics Blueprint. Sessions were held weekly fromAugust through November of 2020 using a virtual platform (https://zoom.us/). Each session was designated to be 90 minutes: 75 min fordidactic teaching and 15 min for questions/interaction with the facultyspeaker and one another. Lectures were taught by expert faculty,boarded in Medical/Clinical Biochemical Genetics and well-known inthe field for the lecture subject matter. Invitations were sent out toMBG programs nationwide, and responding participants were addedto an email listserv that was kept through the MBG program at theUniversity of Colorado. Attendance was not limited to MBG fellows,but faculty were instructed to focus on MBG fellows as the primaryaudience. After each lecture, opportunity was given to all participantsto engage in a brief survey to evaluate the class using 3 generalquestions (see below) and response both by free text and using a Likertscale (5 = Strongly Agree to 1 = Strongly Disagree). Lectures wererecorded on ZOOM, and recordings with accompanying referencematerialwere distributed to the entire listserv using a Dropbox link, aswell as uploaded and stored on the Society for Inherited MetabolicDisease website.Results: The number of participants on the listservwas 217 by the endof the lecture series. Synchronous participation included an average of75 participants per session. In total, there were 98 responses to thethree questions in the survey. Respondents include both MBG andClinical Biochemical Genetics (CBG) fellows (22 responses), as well asattending physicians, genetics/pediatrics residents, genetic counselors,advanced practice providers, and nurses. Participants scored thethree questions as follows: “This session will improve my ability todiagnose and manage metabolic patients” (4.60 ± 0.59);“This sessionmade me feel more connected to the larger metabolic community”(4.62 ± 0.65);and “This session was high-yield given breadth anddepth of content and time allotted” (4.61 ± 0.65). Of note, MBG andCBG fellow responses to the three questions were 4.73 ± 0.54,4.36 ± 0.83, and 4.77 ± 0.41, respectively. Free text comments weregenerally positive, with the major critiques being the large amount ofcontent for time allotted and the desire for board-related practicequestions.Conclusions: The MBG-CCSS endeavored to create a unique opportunityfor trainees to network, facilitate teaching by nationallyrecognized experts, and minimize duplication of effort in individualtraining programs. These goals were all achieved with great success.An unexpected finding was the level of interest from a much largernumber of individuals than expected, far more than th US cohort ofMBG fellows. This points to a significant unmet demand for IEMfocusededucation at all levels around the country. Evaluation scoresfrom fellows, as well as comments, indicate several areas forimprovement including 1) less content per session 2) more participantinteraction 3) incorporated board practice questions and 4) formalassessment of knowledge using a written final exam. We will alsostrive to improve fellow-fellow and fellow-faculty dialogue through interactive questions and smaller fellow-faculty-only discussions.Moving forward, we will continue to build on the success of the firstyear, to prepare and inspire IEM providers for independent clinicalpractice

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Four decades ago, Hal Broxmeyer demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al reported the first successful cord blood transplant (CBT) of a child with Fanconi Anemia using matched sibling CB. This patient survives and 35 years later still has durable hematopoiesis from the CB donor graft. In 1991, Rubinstein et al established an unrelated donor (UD) CB bank and in 1993 the first UD CBT was using a unit from this bank. Since that time, >40,000 CBTs have been performed worldwide. We hypothesized that changes in cord blood banking (increased size, diversity, and quality of banked units enabling selection of units with higher cell doses and closer HLA matching) and in transplantation (less use of steroids, availability of newer therapies for prophylaxis and treatment of graft versus host disease [GVHD], improved antifungal and antiviral detection and therapeutics) have improved outcomes of CBT today. To address this hypothesis, we performed a retrospective study combining data from Eurocord and Duke University in a large cohort of children transplanted with a single UD CB unit (CBU) from 1993-2019. Standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic GVHD, treatment related mortality [TRM], and relapse) and changes in outcomes over 3 time periods (1:<2005, n=1297;2:2005-2010, n=1735;and 3:>2010, n=1802) were studied. Relative contributions of cell dose and HLA matching to transplant outcomes over time were assessed. A total of 4834 patients (4015 from Eurocord and 819 from Duke) were analyzed. The majority of patients, (59%, n=2839) had malignant diagnoses including 1422 with ALL, 887 with AML and 167 with MDS. Of the 1995 with non-malignant diagnoses, 761 had inborn errors of metabolism, 644 had primary immunodeficiency, 325 had a bone marrow failure syndrome and 206 had a histiocytic disorder. Half of the patients had positive serologies for CMV prior to transplant. The median age of the cohort fell from 5.2 to 3.25 years over time. In patients with malignancies, use of total body irradiation decreased over time. The median total nucleated cell (TNC) and CD34+ cell doses administered were 8.07x10e7 and 6.17x10e5 cells/kg and increased over time. HLA matching and transplantation of patients in earlier disease states also increased over time, p<0.001 for both. The probability of 5-year OS in the entire cohort was 53.48% and improved over time: 42%;57.4%;and 60.4%, in periods 1,2,3 respectively (p<0.0001). OS improved with closer HLA matching, higher cell dose, myeloablative conditioning, and negative pre-transplant CMV serologies. For patients with malignancies, DFS increased and TRM and acute GVHD decreased over time. In contrast, leukemic relapse did not change throughout the years. OS was higher in patients with inborn errors of metabolism and also improved over time with 57.8% surviving before 2005, 69.4% from 2005-2010, and 71% after 2010 (p=0.0141). Similar results were seen in the cohort with immune deficiencies. In the entire cohort, the median time to neutrophil engraftment decreased from 25 days (period 1) to 19 days (period 3). In multivariate analysis for engraftment, a higher TNC dose (p=0.001) up to but not beyond the median cell dose (8.07x10e7 cells/kg), total body irradiation, and the use of ATG improved engraftment. Acute GVHD decreased from 35% before 2005 to 27.1% after 2010 (p=0.0556) while the incidence of chronic GvHD was stable. The use of ATG reduced the risk of acute GVHD and closer HLA matching reduced the risk of both acute and chronic GVHD. In this population of patients receiving high cell doses, outcomes were predominantly influenced by HLA matching and increasing cell dose did not abrogate HLA mismatching. In conclusion, we analyzed the largest cohort of pediatric patients undergoing CBT over the past 3 decades. OS, DFS and engraftment have improved over time accompanied b decreases in TRM and acute GVHD. Relapse and chronic GVHD were stable and remain low. These improvements are explained by the increased availability of high quality banked CBUs enabling selection of closer HLA matching and units with higher cell doses. The numbers of CBTs have decreased in the past decade, but these results support the ongoing use of CBT in children lacking matched related or unrelated donors. [Formula presented] Disclosures: Kurtzberg: Neurogene: Consultancy;CryoCell: Patents & Royalties: Duke licensed IP, and data and regulatory packages for manufacturing and use of cord blood and cord tissue MSCs in the treatment of patients with hypoxic ischemic encephalopathy, cerebral palsy, autism, acute ischemic stroke, COVID-ARDS, and COVID-MIS-C.;Sinocell: Patents & Royalties: Duke licensed IP, data, and regulatory packages for use of autologous and sibling cord blood to treat children with cerebral palsy.;Celularity: Current holder of stock options in a privately-held company. Troy: SinoCell: Patents & Royalties;CryoCell: Patents & Royalties;Bristol Myers Squibb: Research Funding;Synthetic Biologics: Honoraria;Gamida Cell: Consultancy;The EMMES Corporation: Consultancy;The Community Data Roundtable: Consultancy;AegisCN: Consultancy.