Glycogen Storage Disease type IIIa and hypertrophic cardiomyopathy. A next-generation genotype phenotype study.

Hoogeveen, I.J. (2015) Glycogen Storage Disease type IIIa and hypertrophic cardiomyopathy. A next-generation genotype phenotype study. thesis, Medicine.

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Abstract

Background Glycogen Storage Disease type IIIa (GSD IIIa) is a rare inborn error of metabolism caused by mutations in the AGL gene. This results in a deficiency of the glycogen debrancher enzyme, and thus an impaired degradation of glycogen. GSD IIIa patients usually present during infancy or early childhood with hepatomegaly, hypoglycaemia and failure to thrive. GSD IIIa patients receive dietary treatment to compensate for their enzyme deficiency. Most patients display hypertrophic cardiomyopathy (HCM) at echocardiographic screening, although clinical HCM is rare. Besides a few case reports suggesting that dietary interventions can normalize HCM, not much is known about risk factors for the development of HCM in GSD IIIa patients. Research question Are there genetic factors associated with hypertrophic cardiomyopathy in GSD IIIa patients? Methods For this study we retrospectively studied echocardiographic, AGL and NGS data. AGL genotypes were dichotomized as either missense or non-missense. In a subset of patients we performed targeted next-generation sequencing (NGS) for a set of 60 genes known to be involved in the development of cardiomyopathies. The detected variants of NGS data were categorized into one of the five categories based on their expected clinical outcome. Results We included 17 GSD IIIa patients with available echocardiographic data. We detected 11 different AGL genotypes in 14 families. More patients carried non-missense AGL genotypes (n=13, 81%) compared to missense AGL genotypes (n=3, 19%). Seven patients (42%) displayed HCM at echocardiographic screening; all these patients had non-missense AGL genotypes. Only one patient presented with symptomatic HCM. For a subgroup of 8 patients we performed targeted-NGS. No (likely) pathogenic variants were detected. Discussion Our findings suggest that GSD IIIa patients with non-missense AGL genotypes are more likely to present HCM at echocardiographic screening, but that other cardiomyopathy-associated genes, currently available in the Cardiokit version 2.0, do not determine HCM in our study cohort. Future studies on AGL expression, analysis of dietary management in relation to echocardiographic outcome and other possible modifying genes involved in cardiac glycogen metabolism should provide more insight in risk factors for developing HCM in GSD IIIa patients. Conclusion We conclude that GSD IIIa patients with non-missense AGL genotypes seem to be more likely to develop HCM at echocardiographic screening compared to patients with missense AGL genotypes. However, NGS for cardiomyopathy-associated genes did not identify additional genetic risk factors in GSD IIIa patients with regard to HCM.

Item Type:	Thesis (Thesis)
Supervisor name:	Derks, dr. T.G.J. and Zwaag, dr. P.A. van der
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:45
Last Modified:	25 Jun 2020 10:45
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/687

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