ALDOB – Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disorder caused by deficiency of fructose-1-phosphate aldolase B encoded by ALDOB. Affected individuals typically present in infancy with hypoglycemia, hepatomegaly, seizures and impaired liver function following fructose exposure. Genetic confirmation is achieved by identification of biallelic pathogenic ALDOB variants. Clinical validity is definitive based on over 300 probands across more than 92 families, extensive segregation and consistent functional data (PMID:1967768; PMID:18541450).

Genetic evidence includes at least 160 unrelated HFI patients in a French cohort (PMID:18541450) and 153 American HFI patients (PMID:20033295), all harboring ALDOB variants in a recessive inheritance pattern. Segregation analysis in 41 pedigrees further supports causality (PMID:1967768). The variant spectrum comprises missense changes (e.g., p.Ala150Pro), nonsense alleles (e.g., p.Arg60Ter), frameshifts, splice defects and large deletions.

A recurrent pathogenic variant, c.448G>C (p.Ala150Pro), has been observed in homozygous form in multiple neonatal acute liver failure cases and in compound heterozygotes worldwide. Loss-of-function variants, including nonsense and frameshift alleles, account for the majority of pathogenic alleles.

Functional studies demonstrate that HFI-associated ALDOB missense mutants exhibit reduced catalytic activity, altered substrate specificity and decreased protein stability when expressed in bacterial or mammalian systems (PMID:10229688; PMID:12417303). Animal or cellular models corroborate the enzyme deficiency and metabolic block at fructose-1-phosphate.

No credible conflicting evidence disputing the ALDOB–HFI association has been reported.

In summary, robust genetic and experimental data conclusively establish ALDOB deficiency as the cause of HFI. Early molecular diagnosis enables dietary management to prevent life-threatening metabolic crises.

Key take-home: ALDOB mutation screening provides a definitive, non-invasive diagnostic route for HFI, guiding lifesaving dietary interventions.

References

• Lancet • 1990 • Molecular analysis of aldolase B genes in hereditary fructose intolerance PMID:1967768
• Molecular Genetics and Metabolism • 2008 • Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations PMID:18541450
• Journal of Inherited Metabolic Disease • 2010 • Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population PMID:20033295
• The Biochemical Journal • 1999 • Alteration of substrate specificity by a naturally-occurring aldolase B mutation (Ala337-->Val) in fructose intolerance PMID:10229688
• FEBS Letters • 2002 • Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance PMID:12417303

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