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Clinical and Molecular Features of Patients with Congenital Disorders of Glycosylation in Brazil

Jaime Moritz Brum, Isabela Maria Pinto de Oliveira Rizzo, Daniel Rocha de Carvalho, Ana Luiza Villaça Coelho, Monica Magalhães Machado Navarro, Walquiria Domingues de Mello, Nilza do Carmo Fontes, Christiana Brenner, Luciano Farage, Anna Leticia Soares and Carlos Eduardo Speck-Martins

Introduction: Congenital Disorders of Glycosylation are a group of genetic disorders due to abnormal glycosylation of glycoproteins and glycolipids. Based on isoelectric focusing of plasma transferrin results, CDG are classified in two groups: CDG-I and CDG-II. While the diagnosis of PMM2-CDG (formerly CDG-Ia) and PMI-CDG (formerly CDG-Ib) is made by demonstration of the enzyme deficiency or by gene sequencing, the diagnosis of the other CDG is not easily performed. Psychomotor delay/mental retardation, hypotonia, seizures, ataxia, cerebellar atrophy, strabismus, inverted nipples, lipodystrophy, and stroke-like episodes characterize PMM2-CDG, by far the most common CDG. There is almost no information available in the literature on the frequency of CDG in patients with psychomotor delay/ mental retardation.

Patients and methods: We performed transferrin isoelectric focusing in 2619 patients who had psychomotor delay/mental retardation associated with other symptoms suggestive of CDG. Determination of leukocyte phosphomannomutase and phosphomannoseisomerase activities and PMM2 gene sequencing was performed in selected patients.

Results: We found 32 affected patients (26 CDG-I and 6-CDG-II). CDG-I group: The most prevalent PMM2- CDG clinical symptoms were those expected. We identified two novel mutations: p.G79V and p.R21W. Non-PMM2, non-PMI-CDG showed more frequently coagulopathy, hypotonia, cerebellar atrophy, and cryptorchidism/micropenis. Early deaths were found exclusively in this group. Ataxia, strabismus, elevated blood FSH and LH levels were more frequent in PMM2-CDG patients. CDG-II group: four out of six patients presented cutis laxa, seizures, large fontanel, facial dysmorphism, and non-lissencephalic cortical dysplasia. Hip luxation was present in three patients, and hydronephrosis in one. The other two patients had heterogeneous features.

Conclusions: We determined the frequency of CDG in a selected Brazilian cohort with symptoms suggestive of CDG as 1.2%(CDG-I ~ 1.0% and CDG-II ~ 0.2%), and identified two novel mutations in the PMM2 gene.