MPI – MPI-congenital disorder of glycosylation

Phosphomannose isomerase (MPI) deficiency underlies MPI-congenital disorder of glycosylation, a multisystem disorder characterized by protein-losing enteropathy, abnormal coagulation, and liver dysfunction. Several independent case reports (PMID:10586187) and multi-patient studies (PMID:10980531) have documented probands presenting with severe hypoglycemia and gastrointestinal as well as hepatic manifestations. The constellation of clinical findings, including hepatic fibrosis and coagulopathy as noted in both pediatric and adult patients (PMID:32963965), emphasizes the broad phenotypic spectrum associated with MPI deficiency.

Genetic evidence for this disorder is robust with reported cases from multiple unrelated families. Multiple studies have reported a total of over 12 probands (PMID:10586187, PMID:10980531) in which variants in MPI segregated with the disorder. Notably, the recurrent missense variant c.656G>A (p.Arg219Gln) has emerged as a pathogenic allele, and its detection in several independent studies underscores the strength of the association.

Segregation analysis in affected families further supports the causal role of MPI mutations. In one study, an affected sibling provided additional segregation evidence, reinforcing the autosomal recessive inheritance pattern. Although extensive segregation data are limited, the presence of segregating variants in even a small number of relatives is consistent with the genetic model observed in glycosylation disorders.

The genetic variant spectrum in MPI includes several mutation types, predominantly missense alleles. Of these, the c.656G>A (p.Arg219Gln) variant was identified in one of the key reports and is instrumental in diagnostic evaluations. This variant meets the full coding change criteria and has been consistently reported across independent studies, enabling its use in clinical genetic testing.

Functional studies have demonstrated a reduction in enzyme activity consistent with MPI deficiency. In vitro assays and animal models reveal that the pathogenic mechanism is likely related to haploinsufficiency, as reduced phosphomannose isomerase activity impairs proper glycosylation. These functional findings support the genetic data by providing a mechanistic explanation for the observed clinical phenotypes, further substantiating the role of MPI in the disorder (PMID:9525984).

In summary, the integration of genetic, segregation, and functional evidence establishes a strong association between MPI (HGNC:7216) and MPI-congenital disorder of glycosylation (MONDO_0011257). Although additional evidence exists that exceeds the ClinGen scoring maximum, the current data provide critical support for a definitive research and diagnostic framework. Key take‑home: Robust genetic and experimental evidence make MPI deficiency a clinically actionable target for early diagnosis and therapeutic intervention.

References

• The Journal of pediatrics • 1999 • Severe hypoglycemia as a presenting symptom of carbohydrate‐deficient glycoprotein syndrome PMID:10586187
• Molecular genetics and metabolism reports • 2020 • Clinical outcomes in an adult patient with mannose phosphate isomerase‐congenital disorder of glycosylation who discontinued mannose therapy PMID:32963965
• The Journal of clinical investigation • 1998 • Carbohydrate‐deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy PMID:9525984
• Human mutation • 2000 • Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG‐Ib) PMID:10980531

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