BACKGROUND Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.)

IntroductionPhosphoglucomutase 1 deficiency (PGM1 deficiency) has been identified as both, glycogenosis and congenital disorder of glycosylation (CDG). The phenotype includes hepatopathy, myopathy, oropharyngeal malformations, heart disease and growth retardation. Oral galactose supplementation at a dosage of 1 g per kg body weight per day is regarded as the therapy of choice.ResultsWe report on a patient with a novel disease causing mutation, who was treated for 1.5 years with oral galactose supplementation. Initially, elevated transaminases were reduced and protein glycosylation of serum transferrin improved rapidly. Long-term surveillance however indicated limitations of galactose supplementation at the standard dose: 1 g per kg body weight per day did not achieve permanent correction of protein glycosylation. Even increased doses of up to 2.5 g per kg body weight did not result in complete normalization.Furthermore, we described for the first time heart rhythm abnormalities, i.e. long QT Syndrome associated with a glycosylation disorder.Mass spectrometry of IGFBP3, which was assumed to play a major role in growth retardation associated with PGM1 deficiency, revealed no glycosylation abnormalities. Growth rate did not improve under galactose supplementation.ConclusionsThe results of our study indicate that the current standard dose of galactose might be too low to achieve normal glycosylation in all patients. In addition, growth retardation in PGM1 deficiency is complex and multifactorial. Furthermore, heart rhythm abnormalities must be considered when treating patients with PGM1 deficiency.

Phosphoglucomutase 1 deficiency has recently been reported as a novel disease that belongs to two different classes of metabolic disorders, congenital disorders of glycosylation (CDG) and glycogen storage diseases.This paper focuses on previously reported siblings with short stature, hypothyroidism, increased transaminases, and, in one of them, dilated cardiomyopathy (DCM). An intronic point mutation in the PGM1-gene (c.1145-222 G>T) leads to a complex alternative splicing pattern and to almost complete absence of PGM1 activity.Exercise-induced muscle fatigue, chest pain, and rhabdomyolysis persisted into adulthood. Fainting occurred during the first minutes of strong exercise due to glucose depletion and serum heart troponin was increased. A second wind phenomenon with an improvement in exercise capacity after some minutes of training was observed. Regular aerobic training improved fitness and helped to avoid acute damage. DCM improved during therapy.Glycosylation deficiency was most prominent in childhood. Glycosylation improved with age and further improved with oral galactose supplementation even in adulthood. Optimal improvement of glycosylation-dependent phenotypes should be achieved by early and permanent galactose treatment.However, in case of mutations in ZASP, DCM can develop as a consequence of impaired binding of PGM1 to the heart-specific isoform of ZASP, independently of overall glycosylation efficiency. Thus, even if mutations in PGM1 impair the function of the ZASP-PGM1 complex, supplementation of galactose cannot be expected to restore that function. Therefore, knowledge of PGM1 deficiency in a patient should prompt surveillance of early signs of DCM and specific treatment if necessary. Abbreviations