GMPPA – Triple-A Syndrome (Association Refuted)

Patients with classic Triple-A syndrome (alacrima, achalasia, adrenal insufficiency) harbor biallelic AAAS variants; no adrenal dysfunction‐causing GMPPA mutations have been reported (PMID:35607266). A 22-month-old with alacrima and achalasia but normal adrenal function carried compound heterozygous GMPPA variants, defining AAMR syndrome rather than Triple-A syndrome (PMID:35607266). Literature review confirms all AAMR cases lack adrenal involvement, distinguishing them from MONDO:0009279.

Functional studies in GMPPA-knockout mice and patient cells reveal increased GDP-mannose and α-dystroglycan hyperglycosylation, with cognitive and motor defects but no adrenal pathology (PMID:33755596). Thus, GMPPA loss-of-function impacts glycosylation pathways but does not recapitulate the adrenal insufficiency hallmark of Triple-A syndrome.

Key Take-home: GMPPA testing should be reserved for alacrima with achalasia and neurologic features when adrenal function is intact, as it defines AAMR syndrome distinct from Triple-A syndrome.

References

• Ophthalmic Genetics • 2022 • AAMR syndrome in a 22-month-old and literature review. PMID:35607266
• The Journal of Clinical Investigation • 2021 • GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation PMID:33755596

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