News on Clinical Details and Treatment in PGM1-CDG

Abstract

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

SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy

“…20,22 In PGM1-CDG (MIM 614921), a disorder with characteristics of both glycogenosis and CDG, galactose supplementation was shown to improve glycosylation as well as clinical presentation. 23,24 Galactose substitution is also a treatment option for SLC35A2-CDG. This disorder resembles clinically SLC39A8 deficiency with encephalopathy (epilepsy, severe psychomotor disability, blindness, cerebral atrophy) and dysmorphism.…”

Nutritional Therapies in Congenital Disorders of Glycosylation (CDG)

“…Interestingly, in some unknown way, galactose supports the ER related glycosylation as well in PGM1 deficiency, where it has been shown that lipid linked oligosaccharide synthesis is arrested, but recovers on in vitro galactose treatment [ 24 , 25 , 26 ]. Galactose might offer extra energy substrate for patients, since some of the adults with PGM1 deficiency also show an improvement of their muscle disease [ 39 ].…”

The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism

“…It is proposed that the PGM1 mutations cause HH due to the decreased threshold for glucose-mediated insulin release from the pancreatic cells (131). A later report (132) on two of the patients from the publication by Tegtmeyer (128) has shown more pronounced hypoglycosylation in childhood than in adults with a total PGM1-mRNA level reduced to 0.25% of that of normal controls. The study has also reported that hypoglycaemia might occur in PGM1 deficient patients by starving and would be exaggerated by strong exercise (132).…”