Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots

Federica Conte,Eva Morava,Nurulamin Abu Bakar,Saskia B Wortmann,Anne Jonge Poerink,Stephanie Grunewald,Ellen Crushell,Lihadh Al-Gazali,Maaike C De Vries,Lars Mørkrid,Jozef Hertecant,Katja S Brocke Holmefjord,David Kronn,Annette Feigenbaum,Ralph Fingerhut,Sunnie Y Wong,Monique Van Scherpenzeel,Nicol C Voermans,Dirk J Lefeber

doi:10.1016/j.ymgme.2020.08.003

Abstract

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0–6 months of age).Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs).All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age.The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs.In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.

Highlights

Phosphoglucomutase 1 (PGM1) deficiency was initially described in 2009 as a Glycogen Storage Disease (GSD, or muscle glycogenosis, type XIV) in an adult patient with exercise intolerance, elevated creatine kinase levels, and episodes of rhabdomyolysis [1,2,3]
The Central Nervous System (CNS) was initially considered unaffected in PGM1-deficient patients8, recent studies suggest an association between PGM1 deficiency and neurological symptoms, including seizure and intellectual disability, which do not appear to be secondary to hypoglycemia [11,12]
The molecular mechanisms explaining how galactose can improve some of the symptoms are yet to be fully clarified, this case series show the beneficial effects of galactose supplementation on the clinical symptoms in infantile PGM1-Congenital Disorder of Glycosylation (CDG) patients

Summary

Introduction

Phosphoglucomutase 1 (PGM1) deficiency was initially described in 2009 as a Glycogen Storage Disease (GSD, or muscle glycogenosis, type XIV) in an adult patient with exercise intolerance, elevated creatine kinase levels, and episodes of rhabdomyolysis [1,2,3]. In 2014, several recessive PGM1 mutations were discovered in a larger cohort of patients showing a heterogeneous spectrum of symptoms including hypoglycemia, cleft uvula or palate, liver disease, growth delay, endocrine abnormalities, dilated cardiomyopathy, myopathy with or without rhabdomyolysis, and coagulation disturbance [4,5,6,7,8,9,10]. A number of articles describing the effects of oral D-galactose supplementation report evidence of liver dysfunction recovery, restoration of endocrine function with resolution of hypogonadotropic hypogonadism, amelioration of coagulation, and reduced occurrence of rhabdomyolytic and hypoglycemic episodes [4,6,15,16]. The treatment showed a clear enhancement of the glycosylation of glycoproteins by reducing both missing glycans and truncated glycans, without any evidence of glycogen accumulation [6]. Frequent feeding and a standard glucose infusion during the acute phase of hypoglycemia have been reported to be insufficient to treat hypoglycemia in several pediatric PGM1-CDG patients [12]

Results

Discussion

Conclusion