Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD. The phenotype of GSD IV ranges from neonatal death to mild adult-onset disease with variable hepatic, muscular, neurologic, dermatologic, and cardiac involvement. There is a paucity of literature and clinical and dietary management in GSD IV, and liver transplantation (LT) is described to correct the primary hepatic enzyme defect. Objectives: We herein describe five cases of patients with GSD IV with different ages of onset and outcomes as well as a novel GBE1 variant. Methods: This is a descriptive case series of patients receiving care for GSD IV at Reference Centers for Rare Diseases in Brazil and in the United States of America. Patients were selected based on confirmatory GBE1 genotypes performed after strong clinical suspicion. Results: Pt #1 is a Latin male with the chief complaints of hepatosplenomegaly, failure to thrive, and elevated liver enzymes starting at the age of 5 months. Before LT at the age of two, empirical treatment with corn starch (CS) and high protein therapy was performed with subjective improvement in his overall disposition and liver size. Pt #2 is a 30-month-old Afro-American descent patient with the chief complaints of failure to gain adequate weight, hypotonia, and hepatosplenomegaly at the age of 15 months. Treatment with CS was initiated without overall improvement of the symptoms. Pt #3.1 is a female Latin patient, sister to pt #3.2, with onset of symptoms at the age of 3 months with bloody diarrhea, abdominal distention, and splenomegaly. There was no attempt of treatment with CS. Pt #4 is an 8-year-old male patient of European descent who had his initial evaluation at 12 months, which was remarkable for hepatosplenomegaly, elevated ALT and AST levels, and a moderate dilatation of the left ventricle with normal systolic function that improved after LT. Pt #1, #3.2 and #4 presented with high levels of chitotriosidase. Pt #2 was found to have the novel variant c.826G > C p.(Ala276Pro). Conclusions: GSD IV is a rare disease with different ages of presentation and different cardiac phenotypes, which is associated with high levels of chitotriosidase. Attempts of dietary intervention with CS did not show a clear improvement in our case series.

Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive lysosomal storage disease with heterogeneous clinical manifestations. Evidence on the disease burden of ASMD is limited in Brazil. Methods: This observational, multicenter, retrospective study assessed the characteristics and clinical data of patients with ASMD type B and type A/B. Patients’ demographic data were retrieved from Hospital de Clínicas de Porto Alegre between January 1, 1986 and May 31, 2021, and available medical records were collected from eight centers in Brazil. Results: The study included 124 patients (full cohort: ASMD type B [75.8%] and type A/B [24.2%]; median [interquartile range {IQR}] age: 10.0 [3.6–19.9] years at diagnosis, n = 94), while medical records were available for 24 patients (subset cohort: ASMD type B [87.5%] and type A/B [12.5%]; median [IQR] age: 6.7 [1.9–11.3] years at diagnosis). Hepatobiliary and splenic manifestations were the most common clinical findings at symptom onset/diagnosis (75.0% and 70.8%, respectively) and at the last follow-up/death (83.3% each), with the majority of patients showing abnormal liver function parameters at both time points. At least 50.0% of patients had comorbidities at symptom onset or diagnosis. The incidence of hospitalization was reported in 33.3% patients at symptom onset/diagnosis and in 45.9% at the last follow-up/death. During the follow-up period, two patients with ASMD type A/B died in the subset cohort. Conclusions: The study provides insights into the high burden of illness in patients with ASMD, highlighting the need for disease awareness and early diagnosis in Brazil.