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PubMed1971

Modulation of experimental renal dysfunction of hereditary fructose intolerance by circulating parathyroid hormone.

In a woman with hereditary fructose intolerance and intact parathyroid function, the experimental administration of fructose at different dosage schedules invariably induced the dose-dependent, complex dysfunction of the proximal renal tubule now recognized as characteristic. But in a woman with hereditary fructose intolerance and hypoparathyroidism given similar amounts of fructose, the experimental dysfunction was strikingly attenuated or nondemonstrable unless or until fructose and parathyroid hormone were administered in sustained combination. Thereupon, a renal dysfunction of characteristic type and severity occurred invariably and almost immediately. Thus, the concentration of circulating parathyroid hormone can modulate the functional expression of the experimental renal disorder. This effect of parathyroid hormone, which appears to involve more than simple physiologic summation, may have important clinical implications.

Adult↗

PubMedDate not supplied

[Clinical heterogeneity in fructose intolerance].

We observed eight infants with hereditary fructose intolerance which had been diagnosed by the fructose tolerance test and an aldolase assay on biopsied liver. None of these had been diagnosed before their admission to our department. The most frequent symptoms were vomiting and failure to thrive. All the patients had hepatomegaly. Laboratory findings were indicative of disturbed hepatic function. Hypoglycemia was found in only 3 out of 8 patients. The course was lethal in 2 patients; the 6 survivors are doing well following a fructose-free diet. The importance of practising paediatricians having the detailed nutritional history of the patient and precise knowledge of infant food formulae is stressed. The danger of using fructose continuing solutions for infusion therapy is pointed out. We also report a case of F-1,6-diphosphatase deficiency.

Carbohydrate Metabolism, Inborn Errors↗

PubMed1975

Fructose-induced hyperuricemia: observations in normal children and in patients with hereditary fructose intolerance and galactosemia.

After the infusion of fructose, 0.25 g/kg body wt, the mean peak plasma uric acid level was 5.4 +/- 0.7 (SEM) mg/100 ml in six normal children and was not significantly increased compared with that of the mean basal value of 4.1 +/- 0.5 mg/100 ml. The mean blood inorganic phosphate (Pi) levels were significantly less than the mean fasting value after fructose. Blood glucose, lactic acid, and fructose levels were significantly increased after fructose, but serum magnesium levels did not change. In two patients with hereditary fructose intolerance (HFI) the peak blood uric acid levels were 12.1 and 7.6 mg/100 ml, respectively, after fructose. In both patients the blood glucose concentrations decreased 69 and 26 mg/100 ml below the fasting levels after fructose. The serum Pi level decreased 2.3 and 1.2 mg/100 ml below fasting values, decrements greater than the mean decrement in serum Pi of 0.8 +/- 0.2 mg/100 ml which occurred in six normal children. The mean uric acid excretion, expressed as milligrams per mg urinary creatinine, was 0.6 +/- 0.1 (SEM) before fructose in the normal children and increased significantly to 1.0 +/- mg/mg creatinine after fructose. In two patients with HFI the uric acid excretion increased four- to fivefold after fructose administration; the increased uric acid excretion in HFI exceeded that of normal children. In three patients with galactosemia, increases in blood uric acid levels after galactose ingestion were similar to those in normal children after fructose, but less than those in patients with HFI after fructose. The serum Pi levels decreased less in galactosemic patients after galactose administration than in patients with HFI after fructose infusion. These studies support the hypothesis that fructose-induced hyperuricemia results from degradation of adenosine monophosphate. This effect appears to be specific for fructose. The lack of hyperruricemia in galactosemia patients after galactose ingestion may be explained by the observation that galactose is phosphorylated more slowly than fructose.

Adult↗

PubMed1983

Isolation and characterization of a mutant liver aldolase in adult hereditary fructose intolerance. Identification of the enzyme variant by radioassay in tissue biopsy specimens.

Hereditary fructose intolerance (HFI) is a metabolic disorder caused by enzymic deficiency of aldolase B, a genetically distinct cytosolic isoenzyme expressed exclusively in liver, kidney, and intestine. The molecular basis of this enzyme defect has been investigated in three affected individuals from a nonconsanguineous kindred, in whom fructose-l-phosphate aldolase activities in liver or intestinal biopsy samples were reduced to 2-6% of mean control values. To identify a putative enzyme mutant in tissue extracts, aldolase B was purified from human liver by affinity chromatography and monospecific antibodies were prepared from antiserum raised in sheep. Immunodiffusion gels showed a single precipitin line common to pure enzyme and extracts of normal liver and intestine, but no reaction with extracts of brain, muscle, or HFI liver. However, weak positive staining for aldolase in hepatocyte and enterocyte cytosol was demonstrated by indirect immunofluorescence of HFI tissues. This was abolished by pretreatment with pure enzyme protein. Accordingly, a specific radioimmunoassay (detection limit 7.5 ng) was established to quantify immunoreactive aldolase B in human biopsy specimens. Extracts of tissue from affected patients gave 10-25% immunoreactive enzyme in control samples; immunoreactive aldolase in intestinal extracts from four heterozygotes was reduced (to 55%) when compared with seven samples from normal control subjects (P < 0.05). In extracts of HFI tissues, there was a sevenfold reduction in apparent absolute specific activity (1.02 vs. 8.82 U/mg) of immunoreactive fructose-l-phosphate aldolase B, but the apparent specific activity in heterozygotes (7.71 U/mg) was only slightly impaired. Displacement radioimmunotitration of aldolase B in liver supernatants showed a significant (P < 0.005) decrease in antibody avidity for immunoreactive protein in HFI tissue when compared with the pure enzyme or extract of normal control liver. Immunoaffinity chromatography on antialdolase B-Sepharose facilitated isolation and purification of enzyme from liver biopsy specimens. Active aldolase in normal liver, with substrate activity ratios and Michaelis constants identical to biochemically purified human enzyme, could be recovered from antibody columns. Chromatography on monospecific Fab' antialdolase B enabled pure enzyme protein to be retrieved quantitatively from normal control and HFI liver: direct chemical assay showed 1.88 and 1.15 mg aldolase protein/g of tissue, respectively. This confirmed that the catalytic properties of the HFI aldolase were profoundly impaired with specific activities of fructose-l-phosphate cleavage of 7.21 and 0.07 U/mg, respectively. Radioimmunoassay gave estimates of 7.66 and 1.18 U/mg, respectively. Sodium dodecyl sulfate-polyacrylamide electrophoresis indicated that immunopurified aldolase from HFI liver possessed a single subunit size similar to material from control liver extracts: M(r) 39,100 vs. 37,900+/-700 (SD) D, respectively. Electrofocusing under denaturing conditions of aldolase isolated in parallel from control and HFI liver revealed the same complement of subunits and, despite qualitative differences in distribution of bands during degradation, no additional charged species. Fructose phosphate aldolase deficiency in hereditary fructose intolerance is attended by the synthesis of an immunoreactive, but functionally and structurally modified enzyme variant that results from a restricted genetic mutation.

Adolescent↗

PubMed1990

Determination of fructose metabolic pathways in normal and fructose-intolerant children: a 13C NMR study using [U-13C]fructose.

An inborn deficiency in the ability of aldolase B to split fructose 1-phosphate is found in humans with hereditary fructose intolerance (HFI). A stable isotope procedure to elucidate the mechanism of conversion of fructose to glucose in normal children and in HFI children has been developed. A constant infusion of D-[U-13C]fructose was given nasogastrically to control and to HFI children. Hepatic fructose conversion to glucose was estimated by examination of 13C NMR spectra of plasma glucose. The conversion parameters in the control and HFI children were estimated on the basis of doublet/singlet values of the plasma beta-glucose C-1 splitting pattern as a function of the rate of fructose infusion (0.26-0.5 mg/kg per min). Significantly lower values (approximately 3-fold) for fructose conversion to glucose were obtained for the HFI patients as compared to the controls. A quantitative determination of the metabolic pathways of fructose conversion to glucose was derived from 13C NMR measurement of plasma [13C]glucose isotopomer populations. The finding of isotopomer populations of three adjacent 13C atoms at glucose C-4 (13C3-13C4-13C5) suggests that there is a direct pathway from fructose, by-passing fructose-1-phosphate aldolase, to fructose 1,6-bisphosphate. The metabolism of fructose by fructose-1-phosphate aldolase activity accounts for only approximately 50% of the total amount of hepatic fructose conversion to glucose. It is suggested that phosphorylation of fructose 1-phosphate to fructose 1,6-bisphosphate by 1-phosphofructokinase occurs in human liver (and intestine) when fructose is administered nasogastrically; 47% and 27% of the total fructose conversion to glucose in controls and in HFI children, respectively, takes place by way of this pathway. In view of the marked decline by 67% in synthesis of glucose from fructose in HFI subjects found in this study, the extent of [13C]glucose formation from a "trace" amount (approximately 20 mg/kg) of [U-13C]fructose infused into the patient can be used as a safe and noninvasive diagnostic test for inherent faulty fructose metabolism.

Blood Glucose↗

PubMed1977

[Diagnostic procedures in hereditary fructose intolerance (author's transl)].

In order to diagnose hereditary fructose intolerance up to now, there were only the dangerous fructose-load and the biochemical evidence of this metabolic defect from biopsies of liver, intestine or kidney. Since there are no screening tests nor tests for heterocygote carriers or prenatal diagnostic procedures, we tested a simple method to determine serum activities of the two enzymes concerned in this defect (fructose-1-phosphate aldolase, fructose-1,6-diphosphate aldolase). Even in completely healthy children we could measure both activities in a good range. Children with known liver lesion caused other than HFI had significantly increased activities of both enzymes. In 4 cases with HFI we could not measure any activity of fructose-1-phosphate aldolase and a decreased activity of fructose-1,6-di-phosphate aldolase in serum, despite an apparently damaged liver. We propose to define those two serum activities in any case of an obscure liver lesion, frequent vomiting and postprandial hypoglycemia in early childhood, in order to exclude HFI or to demonstrate its possible presence.

Aldehyde-Lyases↗

PubMed1987

[Acute liver and kidney failure following sorbitol infusion in a 28-year-old patient with undiagnosed fructose intolerance].

In connection with nephrectomy fatal liver and renal failure occurred after infusion of 50 g sorbitol in a 28 years old patient with undiagnosed fructose intolerance. A marked hypoglycemia and lactacidosis, an increase in uric acid, an acute liver failure with breakdown of excretory and synthetic function and disorder of hemostasis were typical of fructose/sorbitol infusion in hereditary fructose intolerance. Under adequate diet, as indicated in our case, HFI could be undiagnosed up to adult age. Therefore, fructose intolerance should be excluded by anamnesis before infusion of fructose/sorbitol. In unknown anamnesis (unconsciousness) fructose/sorbitol containing infusions should not be used. Fructose/sorbitol containing infusions should not be given routinely, but only with certain indication.

Abscess↗

PubMed1983

Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. A cause of growth retardation.

In two unrelated boys, 5.3 and 3.8 years of age with hereditary fructose intolerance, apparently isolated growth retardation (-2.71 S.D. and -2.40 S.D.) occurred after infancy, even though acute symptomatic fructose intoxication was prevented by restriction of dietary fructose. When more stringent restriction of dietary fructose was instituted (approximately 40 mg per kilogram of body weight per day), growth velocity increased from the 25th to the 97th percentile in one child and from well below the 3d to above the 75th percentile in the other. When restriction of dietary fructose was experimentally relaxed (from 10 to 250 mg per kilogram per day), neither boy had symptoms, hypoglycemia, or evidence of hepatic or renal dysfunction, but both had sustained hyperuricemia and hyperuricosuria and increases in the plasma concentration and urinary excretion of magnesium. We conclude that in patients with hereditary fructose intolerance, clinically important chronic fructose intoxication can occur after infancy without causing symptoms of acute fructose intoxication and can be expressed as an apparently isolated, reversible retardation of somatic growth with a continuing disorder of adenine nucleotide metabolism, characterized in part by recurrently increased rates of degradation of adenine nucleotides.

Carbohydrate Metabolism, Inborn Errors↗

PubMed1992

Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans.

The diagnosis of hereditary fructose intolerance (HFI) presents a difficult challenge that often involves procedures of high risk to the patient. A relatively noninvasive method that involves molecular analysis of common alleles would offer a decided advantage. The molecular defects in the aldolase B gene were studied in 31 HFI subjects (23 pedigrees, 47 apparently independent alleles) from the United States and Canada. We screened for the three most common European alleles by direct hybridization of allele-specific oligodeoxyribonucleotides (ASOs) to portions of the aldolase B gene that were amplified by PCR. Fifty-five percent of mutant North American alleles were A149P (ala149----pro), the most common mutation in the European population. The other two alleles, A174D (ala174----asp) and N334K (asn334----lys), represent 11 and 2% of North American alleles, respectively. Nine patients, representing 32% of independent alleles studied, had an HFI allele that was not of this common missense class. This North American allele distribution is significantly different from that in Europe, where 13% of HFI alleles are not of this type. Preliminary screening of amplified DNA with this set of ASOs indicated that 80% of symptomatic HFI patients can be identified in the American population by this simple genetic test.

Alleles↗

PubMed1991

[Etiology, pathophysiology and clinical significance of hereditary fructose intolerance].

Due to repeatedly described incidents in patients with undiscovered hereditary fructose intolerance, the application of fructose and sorbit-containing parenteral solutions is a topic vehemently discussed. This paper presents a survey of the literature dealing with the inborn defect of fructose-1-phosphate aldolase. The physiology and pathophysiology of fructose metabolism are described as well as the clinical appearance and diagnostic possibilities. The acute course of a fructose incompatibility is determined by a threatening decrease in the blood glucose level, which is attributed to the inhibition of several enzymes of glycolysis and gluconeogenesis by an intracellular accumulation of fructose-1-phosphate. Within hours a global functional breakdown of organs, which normally have the enzyme, occurs. The impairment of the liver function finds expression in a severe coagulopathy, the damage of the kidney leads to anuria. In chronic oral fructose supply, damage of the liver and small intestinal mucosa with corresponding gastrointestinal symptoms determine the clinical course. Concerning diagnosis, contrary to the liver biopsy and the fructose tolerance test, the mucosal biopsy with determination of fructose-1-phosphate aldolase activity has the advantage of greater specificity and is better tolerated by the patient. A total abstinence to fructose and sorbitol-containing solutions is not considered to be necessary when the rarity of the illness is taken into account and certain precautions are taken. These include a specific anamnesis of nutrition as well as a total abstinence from fructose and sorbitol in infants and in the unconscious patient. For clinical routine a simple fructose tolerance test is suggested.

Chromosome Aberrations↗

PubMed1980

Microflora and chemical composition of dental plaque from subjects with hereditary fructose intolerance.

We compared the microbiological and chemical composition of dental plaque from subjects with hereditary fructose intolerance who restrict their dietary sugar intake with that of control subjects who do not. The two groups showed no significant differences in chemical composition of plaque: the mean protein, carbohydrate, calcium, magnesium, and phosphate contents were similar. Dental plaque from both groups contained similar numbers of total colony-forming units per microgram of plaque protein, and Streptococcus sanguis, an indigenous nonpathogen, was isolated with equal frequency from plaque samples of both groups. However, potentially odontopathic Streptococcus mutans and Lactobacillus were isolated three to four times more frequently from plaque samples of control subjects than from plaque samples of subjects with hereditary fructose intolerance. Clearly, diet (sucrose in particular) influences the colonization and multiplication of specific cariogenic organisms in dental plaque.

Adolescent↗

PubMed1993

The molecular basis of hereditary fructose intolerance in Italian children.

We investigated the molecular defects of the aldolase B gene in five unrelated patients affected by hereditary fructose intolerance. The techniques used were DNA amplification, direct sequencing and allele-specific oligonucleotide (ASO) hybridization. The most frequent substitutions found in the hereditary fructose intolerance alleles analysed were the A174D and the A149P mutations, which account for 50% and 30% of the alleles, respectively. In two unrelated families, we found a rare mutation, the MD delta 4 previously described only in one British family, which may be an important cause of the disease in Italy.

Base Sequence↗

PubMed1983

Comparative study of Streptococcus mutans laboratory strains and fresh isolates from carious and caries-free tooth surfaces and from subjects with hereditary fructose intolerance.

This study was undertaken to investigate and compare some biochemical and physiological properties related to sugar metabolism of 4 laboratory strains and 13 freshly isolated strains of Streptococcus mutans from carious and caries-free tooth surfaces and from subjects with hereditary fructose intolerance. Growth in Trypticase (BBL Microbiology Systems)-yeast extract in the presence of various sugars was almost the same for all of the fresh isolates, which grew generally better than the laboratory strains. This was especially noticeable on sucrose where the fresh isolates (including those isolated from hereditary-fructose-intolerant patients) grew two to four times more rapidly than the laboratory strains. The rate of acid production by the fresh isolates, measured with resting cells in the presence of glucose, was quite comparable to the rate of the laboratory strains. The glucose analog, 2-deoxyglucose, inhibited the acid production from glucose by two laboratory strains (6715 and ATCC 27352), but none of the fresh isolates was affected by its presence. The antibiotic, gramicidin D, which allows free diffusion of H(+) across the cell membrane, inhibited the acid production of all of the strains. Phosphoenolpyruvate phosphotransferase activity toward alpha-methylglucoside was found in all of the laboratory and freshly isolated strains. 2-Deoxyglucose phosphotransferase activity was detected in all of the laboratory strains, but many clinical strains, especially those from hereditary-fructose-intolerant patients, contained very low or almost undetectable 2-deoxyglucose phosphotransferase activity. In one strain, the activity was restored after repeated culturing in Trypticase-yeast extract medium supplemented with glucose. Glucokinase and lactate dehydrogenase activities were detected in all of the strains tested. No marked differences were observed for these two enzymes between the fresh isolates and the laboratory strains except for three clinical strains which possessed low levels of glucokinase. The growth of all of the strains in a broth containing 4 mM glucose and 4 mM lactose was studied. Various patterns were observed: diauxie, glucose utilized before lactose but without diauxie, both sugars consumed concurrently, and lactose consumed more rapidly than glucose.

Carbohydrate Metabolism, Inborn Errors↗

PubMed1989

Molecular analysis of aldolase B genes in the diagnosis of hereditary fructose intolerance in the United Kingdom.

To investigate the molecular basis of hereditary fructose intolerance, we have studied 12 British patients, all of whom were found to carry a single mutation in the gene coding for aldolase B. We have estimated the frequency of this lesion, termed A149P, amongst affected individuals in the population and predict that a diagnosis may be made non-invasively in more than 83 per cent of cases by demonstrating the presence of this allele. Genetic diagnosis and detection of asymptomatic carriers of the disease may be achieved by the specific amplification of DNA derived from mouthwash samples followed by hybridization to allele-specific oligonucleotides.

Adolescent↗

PubMed1993

A possible case of transient hereditary fructose intolerance.

A patient is described who presented with the signs and symptoms of hereditary fructose intolerance a few hours after her first fructose challenge. The diagnosis was confirmed by the demonstration of reduced activity of hepatic aldolase B towards fructose-1-phosphate. A second liver biopsy 10 months later had normal aldolase B activity towards fructose-1-phosphate and a fructose tolerance test was also normal. A possible explanation for these findings is proposed.

Female↗

PubMed1988

[Fatal consequences of fructose infusion in undiagnosed fructose intolerance].

A 13-year-old girl with previously undiagnosed fructose intolerance was operated on for acute appendicitis. Postoperatively she received several infusions containing fructose or sorbitol. Haematemesis occurred on the fourth postoperative day, as well as tarry stools and jaundice. Blood sugar was 2 mg/100 ml, Quick test 3%, liver enzymes were markedly elevated, serum bilirubin was over 9 mg/100 ml, and there was a metabolic acidosis. Despite intensive treatment, including haemodialysis and plasmapheresis, she died on the 11th postoperative day.

Adolescent↗

PubMed1983

Allelic heterogeneity in adult hereditary fructose intolerance. Detection of structural mutations in the aldolase B molecule.

Hereditary fructose intolerance (HFI) is a disorder of visceral carbohydrate metabolism which is transmitted as a recessive character of moderate to high gene prevalence. The condition is caused by enzymic deficiency of aldolase B and is associated with the synthesis of inactive enzyme protein. The molecular structure of aldolase B was examined in tissue samples from four adult patients who were the offspring of non-consanguineous unions. Titration of aldolase protein, by radioimmunoassay, showed that antibody recognition of the inactive enzyme was attenuated differently in two unrelated HFI patients. The existence of separate structural lesions was confirmed by protein blotting and immunodetection of enzyme subunits after sodium dodecyl sulphate/polyacrylamide electrophoresis. In one patient the subunit size was identical to wild type (Mr 38,000) and in the other, a single faint band (Mr 39,000) was identified. Radioimmunotitration studies, in two affected offspring of this latter patient by a proven HFI carrier, also revealed differences in antibody recognition. Segregation of different mutant alleles within this kindred demonstrates heterogeneity in HFI occurring at the same genetic locus. Variations in apparent immunoreactivity of aldolase B in HFI are thus related to overt modification of enzyme subunits and indicate that the disorder results principally from structural rather than regulatory mutations in the aldolase B gene.

Adolescent↗

PubMed1993

Association of the widespread A149P hereditary fructose intolerance mutation with newly identified sequence polymorphisms in the aldolase B gene.

Hereditary fructose intolerance (HFI) is a potentially fatal autosomal recessive disease resulting from the catalytic deficiency of fructose 1-phosphate aldolase (aldolase B) in fructose-metabolizing tissues. The A149P mutation in exon 5 of the aldolase B gene, located on chromosome 9q21.3-q22.2, is widespread and the most common HFI mutation, accounting for 57% of HFI chromosomes. The possible origin of this mutation was studied by linkage to polymorphisms within the aldolase B gene. DNA fragments of the aldolase B gene containing the polymorphic marker loci from HFI patients homozygous for the A149P allele were amplified by PCR. Absolute linkage to a common PvuII RFLP allele was observed in 10 A149P homozygotes. In a more informative study, highly heterozygous polymorphisms were detected by direct sequence determination of a PCR-amplified aldolase B gene fragment. Two two-allele, single-base-pair polymorphisms, themselves in absolute linkage disequilibrium, in intron 8 (C at nucleotide 84 and A at nucleotide 105, or T at 84 and G at 105) of the aldolase B gene were identified. Mendelian segregation of these polymorphisms was confirmed in three families. Allele-specific oligonucleotide (ASO) hybridizations with probes for both sequence polymorphisms showed that 47% of 32 unrelated individuals were heterozygous at these loci; the calculated PIC value was .37. Finally, ASO hybridizations of PCR-amplified DNA from 15 HFI patients homozygous for the A149P allele with probes for these sequence polymorphisms revealed absolute linkage disequilibrium between the A149P mutation and the 84T/105G allele. These results are consistent with a single origin of the A149P allele and subsequent spread by genetic drift.

Autoradiography↗