GLUD1 – Hyperinsulinism-Hyperammonemia Syndrome

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disorder caused by gain-of-function mutations in GLUD1, encoding mitochondrial glutamate dehydrogenase (GDH). Affected individuals present with fasting and protein-induced hypoglycemia, inappropriately elevated insulin levels, and persistent mild hyperammonemia. The loss of allosteric inhibition by GTP leads to constitutive activation of GDH, driving excess insulin secretion and ammonia overproduction.

Genetic evidence supports a strong association: screening of 48 unrelated HI/HA probands identified heterozygous missense mutations in exons 11–12 in 25 cases, 74% sporadic, with recurrent familial variants (e.g., c.1491A>G (p.Ile497Met)) and segregation in multiple pedigrees [PMID:10871207]. Additional series of 12 unrelated patients and 65 probands further delineated the mutation spectrum across exons 6–7 and 11–12, with dominant inheritance and recurrent founder alleles [PMID:11518822; PMID:11297618].

Inheritance is autosomal dominant with affected relatives documented in multiplex families (n=19) showing concordant segregation of activating GLUD1 variants [PMID:11297618]. Over 47 distinct missense substitutions have been reported, including hotspot residues Arg269, Ser445, Gly499, and Ile497. One representative variant is c.1491A>G (p.Ile497Met), confirmed de novo in multiple ethnicities [PMID:23295286].

Functional studies demonstrate that all HI/HA mutations impair GTP-mediated inhibition and enhance GDH activity. Recombinant GDH mutant enzymes exhibit 5–800-fold increases in GTP IC₅₀ and exaggerated insulin secretion in MIN6 and primary islet cells upon glutamine challenge [PMID:14532172; PMID:10871207]. Patient-derived lymphoblasts show elevated basal GDH activity and loss of negative regulation by GTP, confirming a consistent gain-of-function mechanism.

No substantive conflicting evidence has been reported; enzymatic analyses and clinical presentation are concordant across cohorts. Alternative genetic causes (e.g., SLC25A36) have been identified in GLUD1-negative HI/HA cases, but dominant GLUD1 mutations remain the primary etiology.

In summary, GLUD1 variants cause an autosomal dominant HI/HA syndrome through impaired GTP allosteric control, leading to constitutive GDH activation. Early genetic diagnosis enables prompt initiation of diazoxide and dietary management, preventing neuroglycopenic sequelae and optimizing long-term neurodevelopment.

References

• Diabetes • 2000 • Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene PMID:10871207
• Pediatric research • 2001 • Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients PMID:11518822
• The Journal of clinical endocrinology and metabolism • 2001 • Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase PMID:11297618
• American journal of physiology. Endocrinology and metabolism • 2004 • Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation PMID:14532172

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