Abstract:
Hereditary Fructose Intolerance (HFI) is a rare autosomal recessive disorder resulting from defects in the Aldolase B (ALDOB) gene, leading to impaired fructose metabolism. ALDOB gene encodes the 364-amino acid fructose-1,6- bisphosphate aldolase, a glycolytic enzyme which is involved in the breakdown of fructose mostly found in fruits. This study focuses into the specific genetic characteristics of HFI patients shedding light on the prevalence and clinical implications of endemic variants in the Galician population. Genetic analyses revealed a high prevalence of the c.448G>C and c.360_363delCAAA variants in the ALDOB gene among all the Galician patients diagnosed with HFI, representing 45% (18/40) and 42.5% (17/40,) respectively. Additionally, two different CNVs deletions were identified: exons 2 to 6 in 3 patients and a novel deletion of the complete gene (E1_E9) in compound heterozygosity in one patient. In 2 patients the diagnosis was established by family study prior to the introduction of dietary fructose; and in 18 patients as a result of clinical symptoms (in 7/20 due to diarrhea related with sugar or fruit intake, in 6/20 due to recurrent hypoglycemia accompanied by ketoacidosis episodes in 3; due to hypoactivity episodes related to fruit intake (8/20) or to immunization with vaccine that includes sucrose (1/20) and in 2/20 due to liver dysfunction). Evolutionarily, 12 patients maintain intermittent gastrointestinal manifestations and 13 develop hepatic steatosis and one adult mild fibrosis despite good dietary adherence. All patients maintain normal values of transaminases after diagnosis. When comparing the two most frequent variants in homozygosity the frequency of hypoglycemia (80 vs 25%) and diarrhea at diagnosis (80% vs 0%, p:0.016) and evolutionarily hepatic steatosis (80% vs 50%) is higher in patients with c.448G>C variant in homozygosis. The prevalence of c.448G>C variant is high in Galician population, in accordance with previous European studies, although with a lower frequency (45%) than those reported (61 – 67.4%). Despite the lack of a clear genotypephenotype correlation, the homozygous variant c.448G>C seems to have greater hepatic developmental severity and is associated with higher frequency of diarrhea related to fructose consumption (pC and c.360_363delCAAA variants were associated with altered enzyme activity, providing mechanistic insights into its pathogenicity. Understanding the functional impact of these variants enhances our comprehension of HFI at a molecular level, facilitating the development of targeted therapeutic intervention. The homogeneity of the identified variants highlights the importance of region-specific genetic studies to tailor diagnosticapproaches effectively.
Audience Takeway
- This study represents a comprehensive understanding of HFI in the Galician population, emphasizing the prevalence and clinical implications of specific ALDOB gene variants, including c.448G>C and c.360_363delCAAA.
- This molecular knowledge highly contributes to the HFI accurate diagnosis, genetic counseling, and the development of targeted therapeutic strategies.
