Glycogen Storage Disease Type IV: A Rare Cause for Neuromuscular Disorders or Often Missed?

Authors

Schene IF1, Korenke CG2, Huidekoper HH3, van der Pol L4, Dooijes D5, Breur JMPJ6, Biskup S7, Fuchs SA1, Visser G8.
  1. Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands.
  2. Department of Neuropediatrics, Children’s Hospital Klinikum Oldenburg, Oldenburg, Germany.
  3. Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
  4. Department of Neurology, University Medical Centre Utrecht, Utrecht, The Netherlands.
  5. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  6. Department of Pediatric Cardiology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands.
  7. CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
  8. Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands. G.Visser-4@umcutrecht.nl.

Abstract

Advancements in genetic testing now allow early identification of previously unresolved neuromuscular phenotypes. To illustrate this, we here present diagnoses of glycogen storage disease IV (GSD IV) in two patients with hypotonia and delayed development of gross motor skills. Patient 1 was diagnosed with congenital myopathy based on a muscle biopsy at the age of 6 years. The genetic cause of his disorder (two compound heterozygous missense mutations in GBE1 (c.[760A>G] p.[Thr254Ala] and c.[1063C>T] p.[Arg355Cys])), however, was only identified at the age of 17, after panel sequencing of 314 genes associated with neuromuscular disorders. Thanks to the availability of next-generation sequencing, patient 2 was diagnosed before the age of 2 with two compound heterozygous mutations in GBE1 (c.[691+2T>C] (splice donor variant) and the same c.[760A>G] p.[Thr254Ala] mutation as patient 1). GSD IV is an autosomal recessive metabolic disorder with a broad and expanding clinical spectrum, which hampers targeted diagnostics. The current cases illustrate the value of novel genetic testing for rare genetic disorders with neuromuscular phenotypes, especially in case of clinical heterogeneity. We argue that genetic testing by gene panels or whole exome sequencing should be considered early in the diagnostic procedure of unresolved neuromuscular disorders.