Reduction in bone mineral density in glycogenosis type III may be due to a mixed muscle and bone deficit.

UNLABELLED: Glycogen storage disease type III (GSD III; OMIM 232400) is an autosomal recessive deficiency of the glycogen debrancher enzyme, amylo-1,6-glucosidase (EC 3.2.1.33). Patients with other hepatic glycogenoses are known to have reduced bone mineral content (BMC) and to be at consequent risk of fractures. They have key metabolic differences from GSD III patients, however. This study examines bone density and metabolism in 15 GSD III patients (6 female) from childhood to adulthood (aged 10-34 years). The results demonstrate that patients with GSD III have low bone mass at all skeletal sites compared with healthy individuals of the same age and sex, with a significant proportion (40-64%) having BMD > 2 standard deviations below the mean for whole body and lumbar spine. The deficiency seems to be attributable to a mixed muscle andbone deficit. Lower bone mass was found at all sites for GSD IIIa patients (combined liver and muscle defect) compared with GSD IIIb patients (liver only defect). CONCLUSION: Patients with GSD III have significantly abnormal bone mass, placing them at increased risk of potential fracture. The underlying mechanism is probably multifactorial with contributions from abnormal muscle physiology, abnormal metabolic milieu and altered nutrition affecting micronutrient intake. Therapies need to address all these factors to be successful.

Exercise capacity and biochemical profile during exercise in patients with glycogen storage disease type I.

Glycogen storage disease type I (GSD-I) is an inherited disorder of carbohydrate metabolism. Hepatic glucose-6-phosphatase is deficient, leading to impaired gluconeogenesis and glycogenolysis. Patients prevent fasting hypoglycemia by frequent feeds of low glycemic index foods. Normal muscle does not contain glucose-6-phosphatase, and GSD-I is usually classified as a hepatic glycogenosis. However, clinical experience has suggested that patients have decreased cardiovascular fitness, but this had not been formally investigated. This paper reports the results of maximal treadmill cardiopulmonary exercise testing in adult patients with GSD-I. It documents a major reduction in exercise capacity in these patients and demonstrates biochemical aspects of exercise that are different from those of normal controls. All patients showed a reduction in exercise capacity, but there was a wide range of exercise tolerance. Additional work needs to address whether improved adherence to or intensification of therapy in adulthood will ameliorate exercise intolerance.

Glycogenosis type I and diabetes mellitus: a common mechanism for renal dysfunction?

Diabetes mellitus and glycogen storage disease type I (GSDI) may initially appear disparate in metabolic profile: one characterized by uncontrolled hyperglycaemia due to disturbed insulin function and the other by fasting hypoglycaemia caused by impaired gluconeogenesis and glycogenolysis. However, they share a remarkably similar pattern and progression of renal dysfunction. This may be, we suggest, due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway. This pathway yields triose phosphate molecules, which are precursors of the lipid, diacylglycerol (DAG). DAG plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway. GSDI may be an interesting model which helps to unravel further the contributions of the many, varied nephropathic influences in diabetes. Conversely patients with this rare disorders would have much to gain from the innovative and vastly greater body of research carried out in diabetes.

The effect of L-alanine therapy in a patient with adult onset glycogen storage disease type II.

Adult-onset glycogen storage disease type II (GSD II) (McKusick 232300) is a progressive disabling myopathy. At present there is no treatment of proven clinical efficacy. Enzyme replacement therapy may in the future provide benefit but it will be costly and is not yet freely available. L-Alanine, a simple and relatively cheap therapy, has been shown to reduce protein degradation in GSD II patients but has not previously been assessed for clinical benefit in a controlled study. In this study L-alanine was assessed in a double blind, placebo-controlled, crossover n = 1 study. Assessments consisted of spirometry, cardiopulmonary exercise testing, quality of life measurements, biochemical markers and assessment by the criterion 4-component model of body composition. Alanine therapy was associated with a 15% gain in total body protein. However, the patient showed no functional improvement and reported feeling worse after treatment. Further controlled studies in a small group may be warranted, but not widespread use of this therapy.

A randomized controlled study of modified cobratoxin in adrenomyeloneuropathy.

Adrenomyeloneuropathy is a peroxisomal disorder that causes demyelination, with no proven therapy. Oral modified cobratoxin was assessed in a double-blind, randomized, crossover study of eight patients. Treatment was well tolerated. There were no significant improvements with therapy. The authors do not confirm previous anecdotal reports of dramatic improvement with modified cobratoxin.