Hereditary Fructose Intolerance Research Articles

Reply letter to “safety of SARS-Cov-2 vaccines administration for adult patients with hereditary fructose intolerance”

ABSTRACT In the letter, Urro et al. performed a search on the sucrose, fructose and sorbitol content in the approved Sars-Cov-2 vaccines and they concluded that these vaccines can be safely administered in adults affected by Hereditary fructose intolerance. The Pfizer-BioNTech COVID-19 Vaccine is currently approved for use in adolescents ≥ 12 years and the Moderna COVID-19 vaccine is close to approval for use in children over 12 years of age. Furthermore, both vaccines have initiated clinical trials that will include infant as young as 6 months. Therefore, we considerate important to analyze the safely administration of this two vaccines in children with Hereditary fructose intolerance.

The role of bioinformatic analysis in the early diagnosis of hereditary fructose intolerance

Abstract Introduction: The importance of early screening for congenital metabolic diseases is well illustrated by hereditary fructose intolerance (HFI), in which the enzyme aldolase B is not synthesized normally in the organism due to a mutation in the ALDOB (9q31.1) gene, and so the breakdown of fructose- 1-phosphate is inadequate. Early diagnosis is essential in the selection of appropriate treatment, as soon as possible. Otherwise, constant intake of fructose into the body can lead to worsening of symptoms and liver damage, which can finally lead to death. Objective: The aim of our research is to facilitate the screening of hereditary fructose intolerance, thus making possible the selection of the correct treatment as soon as possible. For this purpose, we used bioinformatics and the help of an application we made. Methods: Bioinformatic analysis is designed to facilitate the comparison of the patient’s gene obtained by chromosomal sequencing with the nucleotide sequence of the healthy gene. The program we created can recognize and compare the sequence of the patient’s ALDOB gene with the normal one. In a further step, the program can create the mRNA of the introduced gene, and from this, the structure of the protein encoded by the tested gene. Results: The program written in C# can recognize the ALDOB gene introduced in FASTA format, and in case of any differences, it determines the exact positions these can be found, and the type of nucleotides that differ from the normal ones in the introduced sequence. Conclusion: Bioinformatic processing provides a reliable and quick solution for early screening of HFI, since the necessary genetic sampling can be done even on the first week after birth, thus contributing to the establishment of correct treatment. This could also reduce the frequency of complications of patients with HFI and the number of deaths recorded mainly in infants.

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance.

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = −0.386, p = 0.024) and FSS (R = −0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

Molecular and clinical findings of Turkish patients with hereditary fructose intolerance.

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population. The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded. The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (ALDOB) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at aheterozygous, homozygous, or compound heterozygous level. This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.

Neonatal Hereditary Fructose Intolerance: Diagnostic Misconceptions and the Role of Genomic Sequencing

Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism due to deficiency of the enzyme aldolase B, preventing metabolism of fructose. Patients remain asymptomatic until exposed to fructose, sucrose, or sorbitol. HFI presenting as acute liver failure in the neonatal period is rare due to lack of exposure as breast milk and infant formulas are considered to be fructose free. Diagnosis can be delayed due to vague symptoms and lack of specific biomarkers. Recent advances in genetic testing have led to rapid diagnosis and favorable outcomes. We present the case of a formula-fed neonate who presented with acute liver failure where definitive diagnosis of HFI was made using expedited whole exome sequencing. Through this communication, we aim to bring attention to neonatal presentations of HFI from exposure to fructose in infant formulas and also highlight advances in rapid turnaround genomic testing in diagnosis.

I dentification of a novel small‐molecule allosteric inhibitor of glucose transporter type 5 for treating fructose‐induced diseases

Glucose transporter type 5 (GLUT5) is a major molecule that transports fructose in mammals. Fructose has become a major constituent of our modern diet and been implicated as an underlying cause of metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease. In addition, certain cancer cells have been found to utilize fructose via the GLUT5-dependent pathway for their survival. Moreover, mutations in the ALDOB gene cause hereditary fructose intolerance, a condition in which individuals experience hypoglycemia upon fructose intake. These results suggest that limiting fructose utilization by inhibiting GLUT5 may be a novel therapeutic strategy for treating fructose-induced diseases. In this study, we report the identification of a potent, selective, and orally available small-molecule inhibitor of GLUT5. Through high-throughput screening and subsequent compound optimization, we identified compound S-700. S-700 exhibited a potent inhibitory effect on fructose uptake in human GLUT5- and mouse GLUT5-overexpressed Chinese hamster ovary cells with IC50 values of 59 and 28 nM, respectively. The in vitro analysis showed that S-700 allosterically binds to GLUT5 independent of the fructose binding site. In contrast, S-700 did not inhibit human GLUT1; GLUT1 inhibition should be avoided as it impairs the brain function. Single oral administration of S-700 (0.03–1 mg/kg) potently inhibited GLUT5-mediated fructose uptake in the gut during an oral fructose tolerance test in rats. Notably, the predose of S-700 (1 mg/kg) up to 24 h before a fructose dose was highly effective in inducing this effect, indicating the durable effect of S-700. We further assessed the effects of chronic oral administration of S-700 (0.1–3 mg/kg/day) on liver triglyceride (TG) accumulation in Western Diet (D12079B)-fed rats. S-700 (0.3–3 mg/kg) potently suppressed TG levels in the liver and improved the abnormal liver weight of these animals. The therapeutic potential of S-700 (0.3–3 mg/kg/day) in decreasing liver TG levels was similar to or more potent than that of PF-06835919 (30 mg/kg/day), a ketohexokinase inhibitor blocking liver fructose metabolism. In addition, S-700 (0.3–3 mg/kg) increased glucagon-like peptide 1 secretion, reduced food intake, and decreased body weight in Western Diet-fed rats without causing abnormal changes during the study. Finally, S-700 (3 mg/kg) completely prevented fructose-induced hypoglycemia in Aldob knockout mice, a model of hereditary fructose intolerance. Taken together, these results suggest that S-700 is a novel drug candidate for treating fructose-induced diseases.

Hereditary fructose intolerance – two case reports and literature review

Hereditary fructose intolerance – two case reports and literature review

Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance

Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding. Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7gkg-1 glucose and 0.7gkg-1 fructose according to a cross-over design, once after a 7-day on a low fructose diet (LoFruD, <10g/d) and on another occasion after 7 days on a high fructose diet (HiFruD, 1.4gkg-1day-1 fructose+0.1gkg-1day-1 glucose). Uric acid, glucose, and insulin concentrations were monitored in fasting conditions and over 2h postprandial, and insulin resistance indexes were calculated. HiFruD increased fasting uric acid (p<0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p<0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p<0.05). Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.

Acquired Fanconi Syndrome from Ifosfamide

Fanconi syndrome is a renal proximal tubule defect that causes reabsorption defects of electrolytes. The clinical features of Fanconi syndrome are amino aciduria, proteinuria, hypophosphatemia, metabolic acidosis, and glycosuria. In children, it is usually resulting from a genetic defect, such as cystinosis, galactosemia, tyrosinemia, hereditary fructose intolerance, and Wilson disease [1]. However, in adults, it is usually resulting from medications, toxins, and kidney diseases such as light chain proximal tubulopathy and primary amyloidosis [1]. Ifosfamide is a chemotherapy agent that is well known in the literature to cause Fanconi syndrome. Herein, we present a case of a woman with cervical cancer who developed ifosfamide-induced Fanconi syndrome after her fifth cycle of chemotherapy.

Liver adenomatosis and NAFLD developed in the context of hereditary fructose intolerance.

A 36-year-old female patient without medical history was referred to our hospital after the incidental discovery of liver nodules. Liver MRI revealed a dozen of lesions, hyperintense on T1 and T2 weighted sequences with arterial enhancement persisting in portal and late phases. Macroscopic examination of right hepatectomy showed three well defined tumors with red brownish cut surface, the largest of which measured 7.5 cm in diameter.

Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten‐year experience in a Brazilian center

ObjectivesTo characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. MethodObservational, cross‐sectional, retrospective study. The laboratory records of 1,546 individuals (median age = 36 months, 25‐75 IQR = 10‐108; males = 810) submitted to the TfIEF test during the period were reviewed. ResultsFifty‐one individuals (3%) had an altered TfIEF pattern (5 ± 2.8 cases/year; median age = 24 months, 25‐75 IQR = 11‐57 months; males = 27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia = 4; hereditary fructose intolerance = 4; peroxisomal diseases = 2; PMM2‐CDG = 2; MPDU1‐CDG = 1; SLC35A2‐CDG = 1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. ConclusionsThe data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.

KHK inhibition for the treatment of hereditary fructose intolerance and nonalcoholic fatty liver disease: a double-edged sword.

KHK inhibition for the treatment of hereditary fructose intolerance and nonalcoholic fatty liver disease: a double-edged sword.

Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium.Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups.Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.

Social and health care needs in patients with hereditary fructose intolerance in Spain

IntroductionHereditary fructose intolerance is a metabolic disease due to an aldolase B deficiency. Our objective was to ascertain the social and health care needs of those with this deficiency. Material and methodsA prospective, observational study was performed. A survey of social and health care needs was conducted to hereditary fructose intolerance patients living in Spain. ResultsMost patients had been diagnosed, mainly by genetic analysis in children and based on fructose overload in adults. Population surveyed had no sequelae (72.34%) or disability (64%), and 83.33% of children and 52.38% of adults were taking drugs (p<.05) (2.06 drugs on average). Most patients had attended medical visits in the past two years, mainly in metabolic disease units (42.5%) and/or nutrition units (42.5%), but less than a half attended reference centers (mostly children [p<0.05]). Although 48% were satisfied with health care, they felt discriminated in recreational activities, school, health and/or daily activities. The most reliable sources of information were the specialized care physician (69.39%) and patients’ association (59.18%). Fifty-five percent reported no problem in any quality of life dimension, although some had problems in daily activities, pain, and anxiety. ConclusionsAlthough hereditary fructose intolerance is less disabling than other rare diseases, it is important to know the needs of those who suffer from it. Although time to diagnosis has shortened, the poorer health care and satisfaction with it perceived in adults makes it necessary to emphasize the needs of this population, and the critical need of training and information of health care professionals.

Hereditary fructose intolerance: a diagnostic trap in infants?

Hereditary fructose intolerance: a diagnostic trap in infants?

Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center

ObjectivesTo characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. MethodObservational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age=36 months, 25–75 IQR=10–108; males=810) submitted to the TfIEF test during the period were reviewed. ResultsFifty-one individuals (3%) had an altered TfIEF pattern (5±2.8 cases/year; median age=24 months, 25–75 IQR=11–57 months; males=27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia=4; hereditary fructose intolerance=4; peroxisomal diseases=2; PMM2-CDG=2; MPDU1-CDG=1; SLC35A2-CDG=1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. ConclusionsThe data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.

Daily Fructose Traces Intake and Liver Injury in Children with Hereditary Fructose Intolerance.

Background: Hereditary fructose intolerance (HFI) is a rare genetic disorder of fructose metabolism due to aldolase B enzyme deficiency. Treatment consists of fructose, sorbitol, and sucrose (FSS)-free diet. We explore possible correlations between daily fructose traces intake and liver injury biomarkers on a long-term period, in a cohort of young patients affected by HFI. Methods: Patients’ clinical data and fructose daily intake were retrospectively collected. Correlations among fructose intake, serum alanine aminotransferase (ALT) level, carbohydrate-deficient transferrin (CDT) percentage, liver ultrasonography, genotype were analyzed. Results: We included 48 patients whose mean follow-up was 10.3 ± 5.6 years and fructose intake 169 ± 145.4 mg/day. Eighteen patients had persistently high ALT level, nine had abnormal CDT profile, 45 had signs of liver steatosis. Fructose intake did not correlate with ALT level nor with steatosis severity, whereas it correlated with disialotransferrin percentage (R2 0.7, p < 0.0001) and tetrasialotransferrin/disialotransferrin ratio (R2 0.5, p = 0.0001). p.A150P homozygous patients had lower ALT values at diagnosis than p.A175D variant homozygotes cases (58 ± 55 IU/L vs. 143 ± 90 IU/L, p = 0.01). Conclusion: A group of HFI patients on FSS-free diet presented persistent mild hypertransaminasemia which did not correlate with fructose intake. Genotypes may influence serum liver enzyme levels. CDT profile represents a good marker to assess FSS intake.

Necesidades sociosanitarias en pacientes con intolerancia hereditaria a la fructosa en España

IntroductionHereditary fructose intolerance is a metabolic disease due to an aldolase B deficiency. Our objective was to ascertain the social and health care needs of those with this deficiency. Material and methodsA prospective, observational study was performed. A survey of social and health care needs was conducted to hereditary fructose intolerance patients living in Spain. ResultsMost patients had been diagnosed, mainly by genetic analysis in children and based on fructose overload in adults. Population surveyed had no sequelae (72.34%) or disability (64%), and 83.33% of children and 52.38% of adults were taking drugs (p <.05) (2.06 drugs on average). Most patients had attended medical visits in the past two years, mainly in metabolic disease units (42.5%) and/or nutrition units (42.5%), but less than a half attended reference centers (mostly children [p <0.05]). Although 48% were satisfied with health care, they felt discriminated in recreational activities, school, health and/or daily activities. The most reliable sources of information were the specialized care physician (69.39%) and patients’ association (59.18%). Fifty-five percent reported no problem in any quality of life dimension, although some had problems in daily activities, pain, and anxiety. ConclusionsAlthough hereditary fructose intolerance is less disabling than other rare diseases, it is important to know the needs of those who suffer from it. Although time to diagnosis has shortened, the poorer health care and satisfaction with it perceived in adults makes it necessary to emphasize the needs of this population, and the critical need of training and information of health care professionals.

Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content.

There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. To translate these experimental findings to the human situation. Case-control study. Outpatient clinic for inborn errors of metabolism. Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). IHTG content, assessed by proton magnetic resonance spectroscopy. IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.