29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype

Abstract

PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively collected the clinical, biological and radiological data of 29 French PMM2-CDG patients aged 15 years or more with a proven molecular diagnosis (16 females and 13 males). In addition, thirteen of these patients were reexamined at the time of the study to obtain detailed information. 27 of the 29 patients had a typical PMM2-CDG phenotype, with infantile hypotonia, strabismus, developmental delay followed by intellectual deficiency, epilepsy, retinitis pigmentosa and/or visceral manifestations. The main health problems for these patients as teenagers and in adulthood were primary ovarian insufficiency, growth retardation, coagulation anomalies and thrombotic events, skeletal deformities and osteopenia/osteoporosis, retinitis pigmentosa, as well as peripheral neuropathy. Three patients had never walked and three lost their ability to walk. The two remaining patients had a late-onset phenotype unreported to date. All patients (n = 29) had stable cerebellar atrophy. Our findings are in line with those of previous adult PMM2-CDG cohorts and points to the need for a multidisciplinary approach to the follow up of PMM2-CDG patients to prevent late complications. Additionally, our findings add weight to the view that PMM2-CDG may be diagnosed in teenage/adult patients with cerebellar atrophy, even in the absence of intellectual deficiency or non-neurological involvement.

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

“…Other hematological abnormalities like thrombocytopenia and neutropenia have rarely been reported. Thrombocytopenia has been described in only seven patients . Interestingly, three of them presented with severe congenital thrombocytopenia in the context of hydrops fetalis without evidence of bacterial or viral infection .…”

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

“…10 Later on, in surviving patients, other complications, such as thrombotic events, skeletal deformities, epilepsy, retinitis pigmentosa, hypogonadism and peripheral neuropathy become apparent. 11 None of our patients presented any evidence for such involvement, clearly distinguishing HIPKD from CDG1A.…”

Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect

“…Most CDGs are autosomal recessive diseases with multisystem manifestations . Thus, the diagnosis of CDG in children is usually based on severe clinical manifestations, although few adults with PMM2‐CDG have been reported with minimal manifestations and independent functioning in daily life . Our study has led to the diagnosis of three classical CDG cases with unexpected clinical signs that were not diagnosed in infancy.…”