Objective: describe glycosylation type 1A PMM2 mutation presented as motor development regression and cognitive impairment proving to be a disease that should’ve been detected precociously.

Background: They’re one of the fastest growing groups of inborn errors of metabolism, CDG screening main relies on the analysis of serum transferrin or capillary electrophoresis. PMM2 deficiency is associated to human multi­system abnormal function.

Encodes an enzyme called phosphomannomutase 2, which catalyzes the conversion of mannose-1-phosphate that serves as a precursor for GDP-mannose. Himmelreich et al performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients.Lysosomal enzyme activity were decreased as citrate and pyruvate levels indicating mitochondrial dysfunction.

Method: Description’s: HVRS, 21yo, patient started having seizures until he was 2 months old, progressed with hypotonia, strabismus and delayed neuropsychomotor development, taking hi first steps at 8 years old. She’d cognitive regression after adolescence, moving to a special school (APAE).

Clinically, she’s axial and appendicular ataxia, dysmetria and dysdiadochokinesia, postural instability, ataxic gait not assuming tandem, use of a wheelchair for greater distances, Ataxic Scale of 16. Slowing of eye movement with slowed saccades and smooth pursuit. Flat feet. No ophthalmological findings for, OCT without changes, cerebellar atrophy on MRI, electroencephalogram with diffuse slowing. Female patient, with primary amenorrhea and diagnosed with ovarian hypoplasia with hypergonadotropic hypogonadism, discovered during gonadal development. Parents not consanguineous. She’s taking trehalose 30mg/d, Buspirone 5mg 12/12h, cloprimogyna 1cps/day. Started d-mannose 1g/day. Performs weekly physiotherapy.

Results: Patient got tested with Canvas negative results, and exoma PMM2:NM_000303.3:exon5:C367C>T:P.R123X rs 191295, as a pathogenic and also PMM2:NM_000303.3:exon6:c.484C>T:p.R162W, rs104894526, PMID: 21541725, 10386614 either pathogenic, as an compound heterozygote. Which remind us of the importance of performing exome in selected cases.

Conclusion: This present study had shown us a case of a regression development disorder with ataxic symptoms that are not seeing in other mutations feature discription’s on literature and a late diagnosis because of clinical presentation and limit resourcing for screening in Brazil. Neuropediatrics and pedriatians who treated the patient before, interpretaded as a cerebral palsy.

References: Raynor A, Bruneel A, Vermeersch P, Cholet S, Friedrich S, Eckenweiler M, Schumann A, Hengst S, Tuncel AT, Fenaille F, Thiel C, Rymen D. “Hide and seek”: Misleading transferrin variants in PMM2-CDG complicate diagnostics. Proteomics Clin Appl. 2024 Mar;18(2):e2300040. doi: 10.1002/prca.202300040. Epub 2023 Oct 24. PMID: 37876147.

Himmelreich N, Kikul F, Zdrazilova L, Honzik T, Hecker A, Poschet G, Lüchtenborg C, Brügger B, Strahl S, Bürger F, Okun JG, Hansikova H, Thiel C. Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches. Mol Genet Metab. 2023 Jul;139(3):107610. doi: 10.1016/j.ymgme.2023.107610. Epub 2023 May 16. PMID: 37245379.

Muthusamy K, Perez-Ortiz JM, Ligezka AN, Altassan R, Johnsen C, Schultz MJ, Patterson MC, Morava E. Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions. Genet Med. 2024 Feb;26(2):101027. doi: 10.1016/j.gim.2023.101027. Epub 2023 Nov 10. PMID: 37955240.

Zühlsdorf A, Park JH, Wada Y, Rust S, Reunert J, DuChesne I, Grüneberg M, Marquardt T. Transferrin variants: pitfalls in the diagnostics of Congenital disorders of glycosylation. Clin Biochem. 2015 Jan;48(1-2):11-3. doi: 10.1016/j.clinbiochem.2014.09.022. Epub 2014 Oct 8. PMID: 25305627.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pmm2-mutation/