Dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG)
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(2020) 15:258
RESEARCH
Open Access
Dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) Roman Taday, Marianne Grüneberg, Ingrid DuChesne, Janine Reunert and Thorsten Marquardt*
Abstract Background: PMM2-CDG (CDG-Ia) is the most frequent N-glycosylation disorder. While supplying mannose to PMM2-deficient fibroblasts corrects the altered N-glycosylation in vitro, short term therapeutic approaches with mannose supplementation in PMM2-CDG patients have been unsuccessful. Mannose found no further mention in the design of a potential therapy for PMM2-CDG in the past years, as it applies to be ineffective. This retrospective study analyzes the first long term mannose supplementation in 20 PMM2-CDG patients. Mannose was given at a total of 1–2 g mannose/kg b.w./d divided into 5 single doses over a mean time of 57,75 ± 25,85 months. Protein glycosylation, blood mannose concentration and clinical presentation were monitored in everyday clinical practice. Results: After a mean time period of more than 1 year the majority of patients showed significant improvements in protein glycosylation. Conclusion: Dietary mannose supplementation shows biological effects in PMM2-CDG patients improving glycosylation in the majority of patients. A double-blind randomized study is needed to examine the role of mannose in the design of a therapy for children with PMM2-CDG in more detail. Keywords: PMM2, Congenital disorder of glycosylation (CDG), Glycoprotein profile, Mannose, Therapy
Background Congenital disorders of glycosylation (CDG) are a steadily growing group of inherited disorders caused by an impaired glycoprotein and -lipid production [1]. The most common type is the N-glycosylation defect caused by phosphomannomutase 2 deficiency (EC 5.4.2.8; PMM2CDG or CDG-Ia; OMIM 601785) [2]. Patients with PMM2-CDG have a broad and variable spectrum of clinical presentations with psychomotor retardation, muscular hypotonia, failure to thrive, ataxia, epilepsy, strabismus, cerebellar hypoplasia, liver dysfunction, coagulopathy, variable development delay, dysmorphic features, and inverted mammilles; in later stages there may be stroke* Correspondence: [email protected] Department of General Pediatrics, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
like episodes and retinitis pigmentosa, while nerve conduction velocity and tendon reflexes decrease with age [3, 4] Patients suffering from MPI-deficiency (EC 5.3.1.8; CDG-Ib, mannosephosphate isomerase deficiency; OMIM 154550) benefit from a dietary supplementation of mannose, a monosaccharide that bypasses the reduced endogenous Man-6-P (mannose-6-phosphate) production caused by the MPI defect [5] (Fig. S1). In PMM2-CDG utilization of exogenous mannose or endogenous Man-6P originating from Frc-6-P (fructose-6-phosphate) is impaired, due to the enzyme PMM2 being located downstream their entrance [5–8]. Mannose supplementation in PMM2-CDG should be less or not effective (Fig. S1). However, adding mannose to a culture of P
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