GMPPA – Alacrima, Achalasia, and Intellectual Disability Syndrome

The GDP-mannose pyrophosphorylase A gene (GMPPA) encodes an enzyme critical for GDP-mannose synthesis in protein glycosylation. Biallelic loss-of-function variants in GMPPA cause an autosomal recessive congenital disorder of glycosylation known as Alacrima, Achalasia, and Intellectual Disability Syndrome. Affected individuals present a characteristic triad of absent tears, esophageal dysmotility, and intellectual disability.

Initial reports in 2013 described this syndrome in 18 patients, all displaying the core clinical triad and lacking the adrenal findings seen in Triple-A syndrome (PMID:31898852). Subsequent genetic analyses confirmed autosomal recessive inheritance with multi-family occurrence and experimental concordance.

A 2020 study reported three patients from two unrelated Guatemalan Maya-Mam families, all homozygous for a frameshift founder allele c.265dup (p.Leu89fs) (PMID:31898852). This work expanded the phenotype with novel dysmorphic features and underscored underdiagnosis in this population.

Functional assessment in siblings with a novel homozygous splice-donor variant c.853+1G>A revealed segregation in a nuclear family and complete loss of GMPPA protein on Western blot, accompanied by elevated GDP-mannose levels in patient lymphoblasts (PMID:28574218).

Mechanistic studies in Gmppa-knockout mice recapitulated cognitive and motor deficits, cortical layering defects, neuron loss, and myopathic alterations. GMPPA was shown to act as an allosteric inhibitor of GMPPB; its loss led to α-dystroglycan hyperglycosylation and increased turnover. Dietary mannose restriction rescued glycosylation and muscle pathology, although cognitive defects persisted (PMID:33755596).

The cumulative genetic and experimental evidence meets ClinGen criteria for a Strong gene–disease association. GMPPA sequencing should be incorporated into diagnostic panels for patients with alacrima, achalasia, and intellectual disability, especially in populations at risk for the p.Leu89fs founder variant. Key take-home: Biallelic GMPPA mutations define a clinically recognizable autosomal recessive glycosylation disorder with implications for targeted genetic testing and metabolic intervention.

References

• American Journal of Medical Genetics. Part A | 2020 | Evidence of GMPPA founder mutation in indigenous Guatemalan population associated with alacrima, achalasia, and mental retardation syndrome. PMID:31898852
• American Journal of Medical Genetics. Part A | 2017 | A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction. PMID:28574218
• The Journal of Clinical Investigation | 2021 | GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation. PMID:33755596

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