RESUMO
PMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype-phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients' phenotype. The phenotypic effects of patients' genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base.
Assuntos
Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/patologia , Estudos de Associação Genética , Fosfotransferases (Fosfomutases)/deficiência , Adolescente , Adulto , Bélgica/epidemiologia , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/epidemiologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Fenótipo , Fosfotransferases (Fosfomutases)/química , Fosfotransferases (Fosfomutases)/genética , Estrutura Secundária de Proteína/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. CASE PRESENTATION: Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. CONCLUSION: Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.