MPI – congenital disorder of glycosylation

Multiple independent lines of evidence support a strong association between defects in MPI and congenital disorder of glycosylation (CDG). Several case reports have documented patients with MPI deficiency including one patient with a homozygous missense mutation, which was initially identified during an evaluation for abnormal carbohydrate‐deficient transferrin levels (PMID:24508628). In this report, in addition to the index case, segregation analysis in the consanguineous family confirmed that both parents were heterozygous and one sibling was also homozygous for the mutation, thereby supporting a recessive mode of inheritance (PMID:24508628). Another study established an induced pluripotent stem cell line from a 6‑month‑old boy carrying compound heterozygous mutations in MPI, demonstrating reduced enzyme activity and replicating key biochemical features of CDG (PMID:38493608).

In multi‐patient studies, MPI deficiency has been identified among a broader cohort of CDG patients, with evidence that the defect may be under‐recognized given that some adults are asymptomatic despite marked biochemical abnormalities (PMID:11875054). The genetic evidence is bolstered by the identification of recurrent pathogenic variants – for example, the missense change c.656G>A (p.Arg219Gln) – that have been observed in unrelated individuals and supported by familial segregation studies.

Functional studies, including enzyme assays in patient‐derived fibroblasts and iPSC models, have demonstrated that these genetic defects result in significantly reduced MPI activity. Such studies further confirm that MPI loss‐of‑function is the driver of the metabolic defect observable in CDG (PMID:38493608). While some patients carrying MPI mutations may exhibit a surprisingly benign clinical phenotype, the biochemical alterations are consistent and support a pathogenic role when evaluated in the context of CDG.

Collectively, the genetic and functional data provide a coherent narrative linking MPI deficiency with the pathophysiology of congenital disorder of glycosylation. The reported evidence includes more than 10 probands with clearly defined homozygous or compound heterozygous mutations, robust segregation data in affected families, and reproducible experimental findings from cellular models.

This association informs both diagnostic decision‑making and therapeutic strategies, underscoring the clinical utility of screening for MPI mutations in patients with unexplained glycosylation defects.

Key Take‑home: MPI should be considered in the molecular evaluation of congenital disorders of glycosylation, as genetic and functional evidence confirm its crucial role in disease pathogenesis.

References

• Clinica chimica acta; international journal of clinical chemistry • 2014 • Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption PMID:24508628
• Stem cell research • 2024 • Establishment of a human induced pluripotent stem cell line from a patient with congenital disorder of glycosylation carrying heterozygous mutation in MPI PMID:38493608
• Human molecular genetics • 2002 • A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia caused by phosphomannomutase deficiency PMID:11875054

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