Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series

Abstract Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, 1,4‐alpha‐glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin‐like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.