A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III.

INTRODUCTION: A deficiency of glycogen debrancher enzyme in patients with glycogen storage disease type III (GSD III) manifests with hepatic, cardiac, and muscle involvement in the most common subtype (type a), or with only hepatic involvement in patients with GSD IIIb. OBJECTIVE AND METHODS: To describe longitudinal biochemical, radiological, muscle strength and ambulation, liver histopathological findings, and clinical outcomes in adults (≥18 years) with glycogen storage disease type III, by a retrospective review of medical records. RESULTS: Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19-68) and 16 years (0-41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc4) was significantly associated with AST, ALT and CK. CONCLUSION: GSD III is a multisystem disorder in which a multidisciplinary approach with regular clinical, biochemical, radiological and functional (physical therapy assessment) follow-up is required. Despite dietary modification, hepatic and myopathic disease progression is evident in adults, with muscle weakness as the major cause of morbidity. Consequently, definitive therapies that address the underlying cause of the disease to correct both liver and muscle are needed.

Physical therapy assessment and whole-body magnetic resonance imaging findings in children with glycogen storage disease type IIIa: A clinical study and review of the literature.

INTRODUCTION: Early recognized manifestations of GSD III include hypoglycemia, hepatomegaly, and elevated liver enzymes. Motor symptoms such as fatigue, muscle weakness, functional impairments, and muscle wasting are typically reported in the 3rd to 4th decade of life. OBJECTIVE: In this study, we investigated the early musculoskeletal findings in children with GSD IIIa, compared to a cohort of adults with GSD IIIa. METHODS: We utilized a comprehensive number of physical therapy outcome measures to cross-sectionally assess strength and gross motor function including the modified Medical Research Council (mMRC) scale, grip and lateral/key pinch, Gross Motor Function Measure (GMFM), Gait, Stairs, Gowers, Chair (GSGC) test, 6 Minute Walk Test (6MWT), and Bruininks-Oseretsky Test of Motor Proficiency Ed. 2 (BOT-2). We also assessed laboratory biomarkers (AST, ALT, CK and urine Glc4) and conducted whole-body magnetic resonance imaging (WBMRI) to evaluate for proton density fat fraction (PDFF) in children with GSD IIIa. Nerve Conduction Studies and Electromyography results were analyzed where available and a thorough literature review was conducted. RESULTS: There were a total of 22 individuals with GSD IIIa evaluated in our study, 17 pediatric patients and 5 adult patients. These pediatric patients demonstrated weakness on manual muscle testing, decreased grip and lateral/key pinch strength, and decreased functional ability compared to non-disease peers on the GMFM, 6MWT, BOT-2, and GSGC. Additionally, all laboratory biomarkers analyzed and PDFF obtained from WBMRI were increased in comparison to non-diseased peers. In comparison to the pediatric cohort, adults demonstrated worse overall performance on functional assessments demonstrating the expected progression of disease phenotype with age. CONCLUSION: These results demonstrate the presence of early musculoskeletal involvement in children with GSD IIIa, most evident on physical therapy assessments, in addition to the more commonly reported hepatic symptoms. Muscular weakness in both children and adults was most significant in proximal and trunk musculature, and intrinsic musculature of the hands. These findings indicate the importance of early assessment of patients with GSD IIIa for detection of muscular weakness and development of treatment approaches that target both the liver and muscle.

Diurnal variability of glucose tetrasaccharide (Glc4) excretion in patients with glycogen storage disease type III.

AIM: The urinary glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc4), is a glycogen limit dextrin that is elevated in patients with glycogen storage disease (GSD) type III. We evaluated the potential of uncooked cornstarch therapy to interfere with Glc4 monitoring, by measuring the diurnal variability of Glc4 excretion in patients with GSD III. METHODS: Voids were collected at home over 24 hours, stored at 4°C and frozen within 48 hours. Glc4 was analyzed using liquid chromatography-tandem mass spectrometry and normalized to creatinine. RESULTS: Subjects with GSD III (median age: 13.5 years, range: 3.7-62; n = 18) completed one or more 24-hour urine collection, and 28/36 collections were accepted for analysis. Glc4 was elevated in 16/18 subjects (median: 13 mmol/mol creatinine, range: 2-75, reference range: <3). In collections with elevated Glc4 (23/28), two-thirds (15/23) had low diurnal variability in Glc4 excretion (coefficient of variation [CV%] <25). The diurnal variability was significantly correlated with the Glc4 concentration (Pearson R = .644, P < .05), but not with the dose of uncooked cornstarch. High intraday variability (>25%) was not consistently observed in repeat collections by the same subject. CONCLUSIONS: The extent and variability of Glc4 excretion relative to creatinine was not correlated with cornstarch dose. A majority of collections showed low variability over 24 hours. These findings support the use of single time-point collections to evaluate Glc4 in patients with GSD III treated with cornstarch. However, repeat sampling over short time-periods will provide the most accurate assessment of Glc4 excretion, as intraday variability may be increased in patients with high Glc4 excretion.

Use of waxy maize heat modified starch in the treatment of children between 2 and 5 years with glycogen storage disease type I: A retrospective study.

BACKGROUND: Glycogen storage disease type I (GSDI) is caused by deficiency of the enzyme glucose-6-phosphatase or glucose-6-phosphate transporter. Mainstay of treatment is provision of uncooked cornstarch (and/or continuous nocturnal pump feed (CNPF) to maintain normoglycemia). Waxy maize heat modified starch (WMHMS) is another treatment option to maintain normoglycemia overnight. Our objective was to describe our experience treating children 2-5 years of age with GSDI using WMHMS overnight. METHOD: This is a retrospective case series review (n = 5) comparing the overnight feeding regimen and biochemical control one year before and after nocturnal WMHMS therapy. The WMHMS trial, in which blood glucose and lactate levels were monitored hourly, is reported in detail. RESULTS: Most patients successfully transitioned to nocturnal WMHMS feeds. These patients had stable glucose and lactate throughout the overnight period, permitting a fasting period of 6.5-8 h overnight. Within the time period studied, WMHMS appeared to have improved overnight control of blood glucose levels with fewer reported episodes of hypoglycemia compared to CNPF. CONCLUSION: WMHMS can be an effective substitute treatment to achieve stable nocturnal glucose control in children younger than five years of age. A larger multicenter prospective study is recommended to establish stronger evidence of the efficacy and safety of using WMHMS in treatment of young children with GSDI.