Neurological Characteristics of Pediatric Glycogen Storage Disease

Abstract

Glycogen storage diseases (GSD) encompass a group of rare inherited diseases due dysfunction of glycogen metabolism. Hypoglycemia is the most common primary manifestation of GSD, and disturbances in glucose metabolism can cause neurological damage. The aims of this study were to first investigate the metabolic, genetic, and neurological profiles of children with GSD, and to test the hypothesis whether GSD type I would have greater neurological impact than GSD type IX. A cross-sectional study was conducted with 12 children diagnosed with GSD [Types: Ia (n=5); 1, Ib (n=1); 4, IXa (n=5); and 1, IXb (n=1)]. Genetic testing was conducted for the following genes using multigene panel analysis. The biochemical data and magnetic resonance imaging of the brain presented by the patients were evaluated. The criteria of adequate metabolic control were adopted based on the European Study on Glycogen Storage Disease type I consensus. Pathogenic mutations were identified using multigene panel analyses. The mutations and clinical chronology were related to the disease course and neuroimaging findings. Adequate metabolic control was achieved in 67% of patients (GSD I, 43%; GSD IX, 100%). Fourteen different mutations were detected, and only two co-occurring mutations were observed across families (G6PC c.247C>T and c.1039C>T). Six previously unreported variants were identified (5 PHKA2; 1 PHKB). The proportion of GSD IX was higher in our cohort compared to other studies. Brain imaging abnormalities were more frequent among patients with GSD I, early-symptom onset, longer hospitalization, and inadequate metabolic control. The frequency of mutations was similar to that observed among the North American and European populations. None of the mutations observed in PHKA2 have been described previously. Therefore, current study reports six GSD variants previously unknown, and neurological consequences of GSD I. The principal neurological impact of GSD appeared to be related to inadequate metabolic control, especially hypoglycemia.

Keywords: brain injury; central nervous system; glucose-6-phosphatase deficiency; glycogen storage disease; hypoglycemia; mutation; phosphorylase kinase deficiency.

Figure 1

Magnetic resonance imaging alterations in patients with GSD Ia. (A) (Patient #1). Extensive areas of gliosis and encephalomalacia are observed, particularly in the cortical and subcortical areas of the left occipital and parietal lobes, as well as along the frontoparietal transition with high convexity and compensatory ectasia of corresponding portions of the ipsilateral lateral ventricle. Moreover, lesion foci are observed, which are probably related to hemosiderin deposits, extending to the posterior aspects of the nucleocapsular region with signs of chronic Wallerian degeneration of the corresponding cortico-spinal tract. There is substantial left-sided cerebral atrophy. (B) (Patient #12) Retracted lesions affecting the cortex and subcortical white matter of the bilateral frontal regions and the left parieto-temporal transition are evident. These changes are suggestive of encephalomalacia and vascular sequelae. (C) (Patient #9) Oval foci showing high-intensity on T2-weighted sequences in the central white matter and projecting close to the peritrigonal regions. These nonspecific changes could represent gliosis around the perivascular spaces (terminal myelination areas). (D) (Patient #10) Small retracted lesions affecting the posterior occipital poles with loss of volume, especially on the right side, suggestive of lesions occuring secondary to hypoglycemia.