Bulbar muscle weakness and fatty lingual infiltration in glycogen storage disorder type IIIa

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Abstract

Glycogen storage disorder type III (GSD III) is a rare autosomal recessive disorder resulting from a deficiency of glycogen debranching enzyme, critical in cytosolic glycogen degradation. GSD IIIa, the most common form of GSD III, primarily affects the liver, cardiac muscle, and skeletal muscle. Although skeletal muscle weakness occurs commonly in GSD IIIa, bulbar muscle involvement has not been previously reported. Here we present three GSD IIIa patients with clinical evidence of bulbar weakness based on instrumental assessment of lingual strength. Dysarthria and/or dysphagia, generally mild in severity, were evident in all three individuals. One patient also underwent correlative magnetic resonance imaging (MRI) which was remarkable for fatty infiltration at the base of the intrinsic tongue musculature, as well as abnormal expansion of the fibro-fatty lingual septum. Additionally, we provide supportive evidence of diffuse glycogen infiltration of the tongue at necropsy in a naturally occurring canine model of GSD IIIa. While further investigation in a larger group of patients with GSD III is needed to determine the incidence of bulbar muscle involvement in this condition and whether it occurs in GSD IIIb, clinical surveillance of lingual strength is recommended.

Highlights

► We provide the first report of bulbar muscle involvement in glycogen storage disorder (GSD) IIIa. ► Three GSD IIIa patients had lingual weakness by instrumental assessment. ► One patient had correlative abnormal fatty infiltration of the tongue on MRI. ► Supportive abnormal glycogen infiltration on histopathology is seen in a canine model of GSD IIIa.

Introduction

Glycogen storage disorder type III (GSD III) is a rare autosomal recessive disorder that results from a deficiency of glycogen debranching enzyme (GDE), a critical enzyme in glycogen degradation [1]. There are 2 major GSD III subtypes, with GSD IIIa accounting for about 85% of affected individuals and GSD IIIb comprising approximately 15%. Patients with GSD IIIa have involvement of skeletal muscle, cardiac muscle, and liver, while GSD IIIb results primarily in hepatic disease [2]. GSD IIIa typically presents in early childhood with hepatomegaly, ketotic hypoglycemia, hypertriglycemia, and elevated liver transaminases. Myopathy is usually slowly progressive, with early weakness, hypermobility, and increased abdominal girth from hepatomegaly leading to delay in the achievement of gross motor skills in infancy [3]. These findings are generally followed by more pronounced muscle weakness in the third and fourth decades [4], [5] which may be exacerbated by underlying peripheral polyneuropathy [6], [7]. The proximal musculature is primarily affected, but distal muscle involvement may also be present in the calves, peroneal muscles [8], and hands [5], [9]. Cardiac involvement in the form of hypertrophy and cardiac rhythm disturbances has also been noted and usually emerges during childhood [10], [11]. Other disease features may include impaired growth, osteoporosis and osteopenia [12], and polycystic ovary disease [13].

Although skeletal muscle involvement occurs commonly in GSD IIIa, involvement of the bulbar muscles has not, to our knowledge, been previously reported. We have recently encountered bulbar disease in the form of lingual weakness in three patients with GSD IIIa. A proband patient led to the evaluation of lingual disease in two additional consecutive clinic patients with GSD IIIa, and we performed further correlation with lingual pathology from necropsy in a naturally-occurring canine model of GSD IIIa (detailed in a recent publication by Yi et al. [14]). We will describe the clinical findings in these three patients and the animal model.

Section snippets

Materials and methods

The three patients with GSD III were encountered via the GSD program at the Metabolic Clinic at Duke University Medical Center during routine clinical care. These data are presented as part of a larger Institutional Review Board-approved GSD III natural history study. GSD IIIa was confirmed with gene mutation analysis and/or enzymatic assay in all patients.

Standard physical examinations were performed which included manual muscle strength testing and assessment of gross motor function. Patients

Results

Table 1 summarizes the clinical characteristics of the 3 human patients presented in this study.

Discussion

While cardiac and skeletal muscle disease have been clearly established in GSD IIIa, bulbar muscle involvement has not been previously reported. We have provided the first description of bulbar muscle involvement in GSD IIIa, detailing three consecutive patients with instrumentally confirmed lingual weakness. Further supportive evidence was provided by MRI findings which revealed fatty infiltration at the base of the intrinsic tongue musculature and abnormal expansion of the fibro-fatty lingual

Acknowledgments

We thank Dr. Beth L. Thurberg at Genzyme Corporation for her contribution of the canine histopathology for this report. We also thank Dr. Baodong Sun at Duke University for his guidance and assistance with the GSD IIIa canine model.

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