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.
Bibliographical noteFunding Information:
We thank the patient described in this case report for allowing us to share her details, and we thank C. Pérez-Cerdá of the Center of Molecular Biology-Severo Ochoa, Madrid, for her contribution. This work is funded by the grant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute of Neurological Diseases and Stroke (NINDS) and the National Center for Advancing Translational Sciences (NCATS), and the Rare Disorders Consortium Disease Network (E.M. and S.K.)
National Institutes of Health, Grant/ Award Number: 1U54NS115198-01 grant; Rare Disorders Consortium Disease Network; National Center for Advancing Translational Sciences; National Institute of Neurological Diseases and Stroke; Frontiers in Congenital Disorders of Glycosylation
© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
- chromosome 16
- congenital disorders of glycosylation
- uniparental isodisomy
- whole exome sequencing