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

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.

Appendices

Synopsis

Our recent diagnoses of GSD IV in two patients with hypotonia and delayed development of gross motor skills further expand the clinical phenotype of GSD IV and demonstrate the value of early genetic testing in the diagnostic procedure of unresolved neuromuscular disorders.

Details of the Contributions of Individual Authors

IFS and GV drafted the manuscript and designed the figures with support of SF GV is the metabolic pediatrician of patient 1. GCK is the pediatric neurologist of patient 2. HHH interpreted the stable isotope fasting test in patient 1. LP is the clinical neurologist of patient 1. DD executed the genetic diagnostics in patient 1. JMPJB is the pediatric cardiologist who interpreted the echocardiography and MRI-angiography in patient 1. SB executed the genetic diagnostics in patient 2. All authors revised the manuscript.

Competing Interest Statement

The authors declare they have no conflicts of interest.

Ethics Approval and Patient Consent Statement

No ethics approval or patient consent was required for the presented findings.