Abstract
Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases with the phosphomannomutase 2 (PMM2)-CDG being the most common form of CDG. Most of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly psychomotor retardation, facial dysmorphisms, characteristic distribution of the fat pads, and variable coagulation abnormalities. The association of fetal hydrops with CDG has been reported, and pericardial effusion was also rarely observed in patients with PMM2-CDG. Here we describe an infant boy with PMM2-CDG. The diagnosis was suspected based on inverted nipples, fat pads, and combined coagulopathy. However, the primary symptom was progressive pericardial effusion leading to patient death at the age of 3 months. Screening for CDG performed by the use of isoelectric focusing of serum transferrin showed a typical PMM2-CDG pattern. Exome sequencing revealed one common pathogenic variant (c.691G > A/p.Val231Met) and one novel variant (c.447 + 3dupA) in the PMM2 gene. Both PMM2 variants were further confirmed by Sanger sequencing in both the proband and the parents’ DNA. The novel variant was predicted to result in loss of donor splice site, and the analysis at mRNA level confirmed that it leads to exon five skipping (r.348_447del) and causes premature termination of translation to the protein (p.G117Kfs∗4), therefore is classified as likely pathogenic. Although there is no curative therapy for the PMM2-CDG at the moment, the other supportive care options are available to be offered. The definite diagnosis of PMM2-CDG can also assist in the process of genetic counseling, family planning, and preimplantation genetic diagnosis.
Highlights
Congenital disorders of glycosylation (CDG) are a genetically and clinically heterogeneous group of > 130 disorders characterized by genetic defects in the synthesis and attachment of glycoprotein and glycolipid glycans (Chang et al, 2018)
From the pathophysiological point of view, phosphomannomutase 2 (PMM2)-CDG is a disorder of protein N-glycosylation characterized by genetic defects leading to deficiency/dysfunction of PMM2, the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate (Matthijs et al, 2000)
The patient’s non-specific but uncommon findings of pericardial effusion, inverted nipples, fat pads, and combined coagulopathy pointed us toward an early clinical suspicion of a PMM2-CDG disease
Summary
Congenital disorders of glycosylation (CDG) are a genetically and clinically heterogeneous group of > 130 disorders characterized by genetic defects in the synthesis and attachment of glycoprotein and glycolipid glycans (Chang et al, 2018). Deficiency of GDP-Man and Dol-P-Man causes hypoglycosylation of numerous glycoproteins, including serum glycoproteins (lysosomal enzymes and transport proteins) and membrane glycoproteins This results in multi-organ involvement, whereas the variability of disease severity and course are not fully understood (Altassan et al, 2019). We describe a novel splicing mutation in a case of PMM2-CDG, presented with pericardial effusion, with typical dysmorphic facial features, inverted nipples, failure to thrive, and psychomotor retardation. At the age of 3 months, the patient was admitted to the intensive care unit for low food intake and clinical deterioration He presented significant failure to thrive with weight being 3060 g (below 0.1 percentile, SD −5.15), length of 52 cm (below 0.1 percentile, SD −5.31), and frontooccipital circumference 38.5 cm (below 0.1 percentile, SD −3.93). The patient died due to obstructive cardiogenic shock at the age of 3 months
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