Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction.

[triple a syndrome]

In guanosine diphosphate (GDP )-mannose pyrophosphorylase A (GMPPA ), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima , delayed developmental milestones , and gait abnormalities in a consanguineous Pakistani pedigree . Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia , alacrima , and neurological deficits . This autosomal-recessive disorder shows many similarities with triple A syndrome , which is characterized by achalasia , alacrima , and variable neurological deficits in combination with adrenal insufficiency . GMPPA is a largely uncharacterized homolog of GMPPB . GMPPB catalyzes the formation of GDP-mannose , which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb -girdle muscular dystrophies with hypoglycosylation of α-dystroglycan . Surprisingly , GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations . This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself . Thus , a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation , in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism .

Diseases
Validation

Diseases presenting "congenital" symptom

triple a syndrome

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