A Broad Characterization of Glycogen Storage Disease IV Patients: A Clinical, Genetic, and Histopathological Study

Author:

Wilke Matheus Vernet Machado Bressan12ORCID,de Oliveira Bibiana Mello13ORCID,Starosta Rodrigo Tzovenos4ORCID,Shinawi Marwan4,Lu Liang5,He Mai5,Ma Yamin5,Stoll Janis6,de Souza Carolina Fischinger Moura17,de Siqueira Ana Cecilia Menezes8,Vieira Sandra Maria Gonçalves9,Cerski Carlos Thadeu10,Refosco Lilia Farret1,Schwartz Ida Vanessa Doederlein1231112

Affiliation:

1. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos St., 2350, 3rd Floor, Porto Alegre 90035-903, Brazil

2. Post Graduation Program Ciências da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Brazil

3. Post Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Brazil

4. Division of Medical Genetics and Genomics, Washington University in Saint Louis, Saint Louis, MO 63130, USA

5. Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO 63130, USA

6. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Washington University in Saint Louis, Saint Louis, MO 63130, USA

7. Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Brazil

8. Treatment Center of Inborn Errors of Metabolism, Instituto de Medicina Integral Professor Fernando Figueira, Recife 50070-902, Brazil

9. Pediatrics Gastroenterology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil

10. Pathology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil

11. Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Brazil

12. BRAIN Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil

Abstract

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.

Funder

Fundo de Incentivo à Pesquisa e Eventos (FIPE) of the HCPA

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

Reference20 articles.

1. Liver Transplantation for Glycogen Storage Disease Type IV;Liu;Front. Pediatr.,2021

2. Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., Everman, D.B., and Mirzaa, G.M. (2022, February 22). Glycogen Storage Disease Type IV, GeneReviews®, Available online: http://www.ncbi.nlm.nih.gov/books/NBK115333/.

3. The potential of dietary treatment in patients with glycogen storage disease type IV;Derks;J. Inherit. Metab. Dis.,2021

4. Adult Polyglucosan Body Disease: Natural History and Key Magnetic Resonance Imaging Findings;Mochel;Ann. Neurol.,2012

5. Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy;Yi;Hum. Gene Ther.,2017

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