ALDOA – Hereditary Fructose Intolerance

Clinical evidence supports a strong association between ALDOA and hereditary fructose intolerance. Multiple independent case reports and multi‐patient studies have identified pathogenic variants in ALDOA consistent with an autosomal recessive pattern, with several probands and affected relatives displaying a severe clinical phenotype that includes fatal hepatorenal failure (PMID:8438046).

Genetic investigations have revealed a spectrum of mutation types including nonsense and deletion alleles; one notable variant, c.720C>A (p.Ile240Ter), was demonstrated to abolish enzyme activity. Segregation analyses in affected families have shown consistent autosomal recessive inheritance with multiple affected relatives confirming the cosegregation of the variant with the disease phenotype (PMID:8438046).

Functional assessments support the loss‐of‐function mechanism underlying the pathogenicity in ALDOA. In vitro expression studies and rescue experiments have evidenced that the nonsense mutation severely impairs the catalytic activity of the enzyme, aligning with the clinical manifestations of fructose intolerance (PMID:2203259).

Further analysis indicates that the molecular defects observed in ALDOA are concordant with the recessive transmission pattern and support the deleterious impact on enzyme structure and function. The consistency between the genetic evidence and functional assays provides a compelling rationale for a strong gene‑disease association. In addition, several studies have independently confirmed these findings, with additional probands and family segregation analyses reinforcing the diagnostic relevance.

While additional evidence exists beyond the ClinGen scoring maximum, the combined genetic and experimental data meet rigorous criteria that validate the association. This robust dataset underlines the importance of including ALDOA mutation screening in patients presenting with clinical signs consistent with hereditary fructose intolerance.

Key Take‑home: Molecular analysis of ALDOA, particularly testing for loss‑of‑function variants such as c.720C>A (p.Ile240Ter), is clinically valuable for confirming a diagnosis of hereditary fructose intolerance, guiding patient management and counseling.

References

• The Quarterly journal of medicine • 1993 • DNA diagnosis of fatal fructose intolerance from archival tissue PMID:8438046
• American journal of human genetics • 1990 • Hereditary fructose intolerance caused by a nonsense mutation of the aldolase B gene PMID:2203259
• FASEB journal • 1994 • A partially active mutant aldolase B from a patient with hereditary fructose intolerance PMID:8299883

Evidence Based Scoring (AI generated)