The diagnosis of hereditary fructose intolerance

Hereditary fructose intolerance (HFI) is a potentially life-threatening disorder and can be suspected from a detailed nutritional history. The usefulness of 2 diagnostic procedures, fructose tolerance test (FTT) and aldolase assay on biopsied liver, was studied. A standardized intravenous FTT with 200 mg/kg b.w. was done on 11 children with HFI, 17 age-matched contrast children, 6 adults with HFI and 6 adult controls. Blood glucose, phosphorus, urate, magnesium and fructose were followed for 2 hours. By the FTT, each HFI individual was reliably distinguished from controls and contrasts and even from those with acute liver disease other than HFI. Both children with non-HFI hepatopathy examined by both procedures had a normal FTT in spite of reduced liver fructaldolase activity. HFI children responded to the FTT by earlier and more pronounced hypoglycemia than adults, and one girl converted to an adult type response between the ages 12 and 181/2 years. Responses of two HFI sibling pairs and of one set of monozygotic twins were typical for age, but resemblance was no greater than within the unrelated HFI probands. The intravenous FTT is judged a reliable diagnostic tool, simple and harmless if done in hospital. Essential fructosuria is readily diagnosed by the FTT, but fructose-1,6-diphosphatase deficiency and HFI are not differentiated with certainty. Liver biopsies were obtained from 35 children with HFI, 14 contrast persons and 10 controls (of which 9 organ donors) and examined enzymatically. Deficiency of fructaldolase was observed in all HFI children but also in some contrast children suffering from acute liver disease other than HFI. In these, HFI could only be excluded when the reduced activity of reference enzymes such as fructose-1,6-diphosphatase and glucose-6-phosphatase and liver histology were included in the evaluation. In one deceased HFI infant, fructaldolase was deficient in both, liver and kidney cortex. Extent of antibody activation and of heat inactivation of residual fructaldolase varied between unrelated HFI patients but not within families. These results did not contribute to diagnosis but further documented genetic heterogeneity of HFI. For diagnosis of HFI we recommend 1. immediate elimination of fructose from the diet, 2. the intravenous FTT after several weeks of fructose withdrawal, and 3., should diagnosis still be uncertain, laparoscopic liver biopsy for assay of fructaldose and of reference enzymes and for histology.     

遗传性果糖不耐受1例及其父母常见基因突变检测

目的检测1例中国人的常染色体隐性遗传的遗传性果糖不耐受患儿及其父母的3种最常见致病基因。方法对2006年3月于吉林大学第二医院儿科就诊的疑患遗传性果糖不耐受的患儿进行了尿代谢产物分析,采集患儿及其父母外周血,提取全基因组DNA,使用等位基因特异性寡核苷酸分析法检测了A149P、A174D和N334K这3种最常见的基因突变。结果患儿临床诊断为遗传性果糖不耐受,进行PCR扩增,等位基因特异性寡核苷酸分析法显示患儿及其父母的A149P、A174D和N334K均为阴性。结论结合临床资料及尿中代谢产物分析,可以在临床上确诊遗传性果糖不耐受。PCR结合等位基因特异性寡核苷酸分析可用于遗传性果糖不耐受病例的基因诊断,中国人群中遗传性果糖不耐受的基因突变分型有待于进一步探索。     

ABNORMAL TYROSINE METABOLISM IN HEREDITARY FRUCTOSE INTOLERANCE

Elevated plasma tyrosine and methionine levels, together with excessive urinary excretion of p-hydroxypheny-acetic and -lactic acids were found in an infant with hereditary fructose intolerance (HFI). Such findings may be common in HFI and this diagnosis must be considered in any infant with biochemical abnormalities of tyrosine metabolism.     

Elevated carbohydrate-deficient transferrin (CDT) and its normalization on dietary treatment as a useful biochemical test for hereditary fructose intolerance and galactosemia

Abnormalities in protein glycosylation are reported in fructosemia (HFI) and galactosemia, although, particularly in HFI, the published data are limited to single cases. The purpose was to investigate the usefulness of the carbohydrate-deficient transferrin (CDT) profile for identification and monitoring of these disorders. First we analyzed CDT values before and shortly after the diagnosis in 10 cases of HFI and 17 cases of galactosemia. In all patients, elevated CDT levels were found that significantly (p < 0.0001) decreased with the therapeutic diet (27.3 +/- 11.5% versus 9.3 +/- 5.1% for HFI and 43.8 +/- 14.1% versus 11.2 +/- 4.0% for galactosemia). To evaluate the use of CDT test in monitoring compliance, the test was performed in 25 HFI patients on fructose-restricted diet. We found an elevated CDT level on 104 from 134 tests (mean 11.3 +/- 5.5%, control 1.5%-6.2%). The fructose intake was found to be 90 +/- 70 mg/kg/d, and the diet was unbalanced. A number of patients presented lower height, elevated urinary uric acid excretion, and hypercalciuria. In conclusion, abnormal percentage of CDT (%CDT) values may allow prompt detection of HFI (or galactosemia). Persistence of some abnormalities in HFI on treatment may be caused by trace amounts of fructose ingestion and/or a deficient diet. Regular %CDT measurements are suggested for HFI treatment monitoring.     

Understanding the double burden of malnutrition in food insecure households in Brazil

Household food insecurity (HFI) has been associated with both obesity among mothers and undernutrition among children. However, this association has not been well investigated in mother/child pairs living in the same household. The objective of this study was to examine the relationship of coexistence of maternal overweight and child stunting with HFI in Brazil. We conducted secondary data analyses of the 2006 Brazilian National Demographic and Health Survey. We analyzed the nutritional status of 4299 pairs of 15–49‐year‐olds mothers and their children under 5 years of age. The double burden of malnutrition (DBM) was defined as the presence of an overweight mother and a stunted child in the same household. HFI was measured with the Brazilian HFI Measurement Scale. The association between DBM and HFI was examined with hierarchical multivariable logistic regression analyses. Severe HFI was associated with DBM after adjusting for macroeconomic and household level socio‐economic and demographic variables (Adjusted OR: 2.65 – CI: 1.17–8.53). Findings suggest that policies and programmes targeting HFI are needed to prevent the coexistence of child chronic undernutrition and maternal overweight/obesity in the same household. These investments are likely to be highly cost‐effective as stunting has been identified as one of the major risk factors for poor child development and adult overweight/obesity and a strong risk factor for the development of costly chronic diseases including type 2 diabetes and cardiovascular disease.     

Household food insecurity and early childhood development: Systematic review and meta‐analysis

Household food insecurity (HFI) is a powerful stressor negatively associated with early childhood development (ECD). However, no comprehensive review has examined the association of HFI and ECD. Therefore, this systematic review and meta‐analysis investigated the association between HFI and ECD domains and subdomains in children under 5 years old. Peer‐reviewed and grey literature were systematically searched in electronic databases with no year or language restrictions. Studies were eligible if they assessed the association between HFI and one or more ECD domains. Data were extracted using a standard predefined protocol. Meta‐analysis was performed, and the heterogeneity across studies was explored. Nineteen studies were included in the systematic review and 14 in the meta‐analysis. Of the studies, 15 were from high income countries (HICs) and four from low–middle income countries (LMICs). For developmental risk and the cognitive/math and cognitive/school readiness and reading subdomains, the only studies available were conducted in HICs. The meta‐analysis showed that HFI was associated with developmental risk (OR 1.28; 95% CI [1.14, 1.45]), cognitive/vocabulary (OR 0.94; 95% CI [0.90, 0.98]), and cognitive/math (OR 0.84; 95% CI [0.73, 0.96]). HFI was marginally associated with cognitive/school readiness and reading (OR 0.91; 95% CI [0.82, 1.00]) and motor development (OR; 0.91, 95% CI [0.80, 1.04]). HFI was associated with poor ECD in children under 5 years old. Specifically, HFI was associated with developmental risk and poor math skills in studies conducted in HICs and with poor vocabulary skills in studies conducted in both HICs and LMICs. Prospective studies examining HFI and ECD are needed in LMICs.     

Moderate and severe household food insecurity predicts stunting and severe stunting among Rwanda children aged 6–59 months residing in Gicumbi district

Household food insecurity (HFI) plays an important role in child malnutrition in many low‐income countries. We determined the association between HFI and stunting and severe stunting among Rwandan children from the Gicumbi district, aged 6–59 months using a cross‐sectional study of 2,222 children. HFI factor was calculated by summing all seven HFI (access) frequency questions and was categorised into food security, mildly food insecurity, moderately food insecurity, and severe food insecurity. The association between stunting, severe stunting, and HFI was determined using the multiple logistic regression analyses that adjust for clustering and sampling weights. The odds of moderate and severe HFI were significantly higher among stunted children aged 6–59 months than those who were not stunted (adjusted odds ratio [AOR] = 1.43; 95% confidence interval [CI] [1.11, 1.84] and AOR = 1.35; 95% CI [1.08, 1.69], respectively). Children from households with moderate food insecurity were 2.47 times more likely to be severely stunted (AOR = 2.47; 95% CI [1.77, 3.46]), and those from households with severe food insecurity were more likely to be severely stunted (AOR = 1.82; 95% CI [1.34, 2.48]), compared with children aged 6–59 months from households with food security. Other factors included male children and children who did not attend monthly growth monitoring sessions. This study showed that moderate and severe HFI correlated with stunting and severe stunting. Interventions to improve stunting in Gicumbi children should also focus on male children, children who did not attend monthly growth monitoring sessions, and households with moderate and severe food insecurity.     

Hereditary fructose intolerance in a patient with phenylketonuria.

Classical phenylketonuria (PKU) and hereditary fructose intolerance (HFI) are two inborn errors of metabolism that have an autosomal recessive mode of inheritance. In this paper, we described a 3-year-old girl with PKU and HFI. The occurrence of these two defects in the same patient is thought to be fortuitous and not genetically related since this is the first reported case and the statistical probability of such an occurrence is very low.     

Seasonal variation in the association between household food insecurity and child undernutrition in Bangladesh: Mediating role of child dietary diversity

Household food insecurity (HFI) and child dietary diversity (CDD) are variable across seasons. We examined seasonal variation in HFI and child undernutrition association and tested how CDD mediates this association. We analyzed data for 26,353 children aged 6–59 months drawn from nationally representative cross-sectional Food Security and Nutrition Surveillance Project data collected during 2012–2014 in Bangladesh across three seasons annually: Post-Aman harvest (January–April); Monsoon (May–August); and Post-Aus harvest (September–December). Multivariable logistic regression analysis adjusted for individual, maternal, household and geographical characteristics reveals that children of food-insecure households were more likely than food-secure households to be stunted (adjusted odds ratio, AOR: 1.12; 95% confidence interval, CI: 1.02–1.23; p < 0.05), wasted (AOR: 1.21; 95% CI: 1.05–1.39; p < 0.01) and underweight (AOR: 1.16; 95% CI: 1.04–1.3; p < 0.01). CDD mediated 6.1% of the total effect of HFI on underweight. These findings varied across seasons. HFI was associated with greater odds of underweight during Monsoon (AOR: 1.32; 95% CI: 1.08–1.62; p < 0.01) and Post-Aus (AOR: 1.21; 95% CI: 1.06–1.37; p < 0.01) while wasting during Post-Aus (AOR: 1.65; 95% CI: 1.35–2.01; p < 0.001). CDD largely mediated the total effect of HFI on underweight during the Post-Aman in 2012–2014 (23.2%). CDD largely mediated the total effect of HFI on wasting (39.7%) during Post-Aman season in 2014 and on underweight (13.7%) during the same season in 2012. These findings demonstrate that HFI is seasonally associated with child undernutrition and mediated by CDD as well in Bangladesh and seasonality and diversity should be considered while designing appropriate population-level food-based interventions to resolve child undernutrition.     

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.     

Hereditary fructose intolerance and alpha(1) antitrypsin deficiency.

A patient with coexisting hereditary fructose intolerance (HFI) and alpha(1) antitrypsin deficiency (alpha(1)ATD) is described. Protease inhibitor typing was not conclusive, presumably because of impaired N-glycosylation secondary to HFI. The case underlines the diagnostic role of molecular genetic techniques in inborn errors of metabolism.     

Hereditary fructose intolerance and alpha(1) antitrypsin deficiency

A patient with coexisting hereditary fructose intolerance (HFI) and alpha(1) antitrypsin deficiency (alpha(1)ATD) is described. Protease inhibitor typing was not conclusive, presumably because of impaired N-glycosylation secondary to HFI. The case underlines the diagnostic role of molecular genetic techniques in inborn errors of metabolism.     

Household food insecurity in Mexico is associated with the co‐occurrence of overweight and anemia among women of reproductive age,but not female adolescents

We aimed to determine the association between household food insecurity (HFI) and the co‐occurrence of overweight and anemia among women of reproductive age in the Mexican population. We analyzed data on 4,039 nonpregnant female adolescents (15–19 years) and 10,760 nonpregnant adult women of reproductive age (20–49 years) from the 2012 National Health and Nutrition Survey of Mexico. The survey uses a two‐stage sampling design, stratified by rural and urban regions. The Latin American and Caribbean Food Security Scale was used to assess HFI. We assessed overweight and obesity in women based on World Health Organization classifications for body mass index, and BMI‐for‐age Z‐scores for female adolescents, and defined anemia as an altitude‐adjusted hemoglobin (Hb) concentration < 120 g/L based on measurement of capillary Hb concentrations. In multiple logistic regression models adjusting for potential confounding covariates, HFI was not associated with the co‐occurrence of anemia and overweight among female adolescents. The adjusted odds of women of reproductive age from mildly and moderately food‐insecure households, respectively, experiencing concurrent anemia and overweight were 48% (OR: 1.48; 95% CI: 1.15, 1.91) and 49% (OR: 1.49; 95% CI: 1.08, 2.06) higher than among women from food‐secure households. Severe HFI was not associated with concurrent overweight and anemia among female adolescents or women. HFI may be a shared mechanism for dual forms of malnutrition within the same individual, simultaneously contributing to overconsumption and dietary inadequacy.     

Hereditary fructose intolerance: A comprehensive review

Hereditary fructose intolerance (HFI) is a rare autosomal recessive inherited disorder that occurs due to the mutation of enzyme aldolase B located on chromosome 9q22.3. A fructose load leads to the rapid accumulation of fructose 1-phosphate and manifests with its downstream effects. Most commonly children are affected with gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycemia. Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure. Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency. For confirmation, a genetic test is favored over the measurement of aldolase B activity in the liver biopsy specimen. The crux of HFI management lies in the absolute avoidance of foods containing fructose, sucrose, and sorbitol (FSS). There are many dilemmas regarding tolerance, dietary restriction and occurrence of steatohepatitis. Patients with HFI who adhere strictly to FSS free diet have an excellent prognosis with a normal lifespan. This review attempts to increase awareness and provide a comprehensive review of this rare but treatable disorder.     

Increased concentrations of HbAlab in hereditary fructose intolerance and galactosemia

In patients with diabetes mellitus nonenzymatic glycosylation of hemo-globin is a result of increased blood glucose concentrations. In analogy glycosylated hemo-globin fractions were determined in 23 patients with hereditary fructose intolerance (HFI) and 8 patients with galactosemia (G) by means of hemoglobin chromatography on a column packed with Bio-Rex 70 resin. The concentrations were compared to those of 14 control patients and 43 patients with type 1 diabetes mellitus. Compared to controls, in HFI- and G-patients HbAlab was significantly increased. In contrast diabetic patients presented with a marked and significant increase of the HbAlc fraction. When purified hemoglobin was incubated with different monosaccharides respectively monosaccharide phosphates, an increase of HbAlab resulted mainly after galactose and fructose-1-phosphate. The determination of HbAlab in patients with HFI and G is considered a possible means of metabolic control.     

Clinical Course of Hereditary Fructose Intolerance in 56 Patients

The clinical course of hereditary fructose intolerance (HFI) was investigated retrospectively in 56 patients. The most frequently observed features were hepatomegaly, vomiting, diarrhea and failure to thrive. Fructose containing formulae given in the neonatal period lead in about one third of patients to cirrhosis of the liver — regardless of the amount ingested. Among patients receiving small amounts of fructose a mild clinical course was observed five times as often as a severe course. Two out of 12 patients who had developed cirrhosis of the liver, died soon after diagnosis in the early months of life. This stresses the danger of infants receiving fructose very early. Good dietary control brought serum transaminase activity to normal in half the time required with poor control. There was no correlation between dietary control and the duration of hepatomegaly.     

A self‐applied valid scale for rapid tracking of household food insecurity among pregnant women in Sri Lanka

Rapid household food insecurity (HFI) tracking has been identified as a priority in the context of the COVID‐19 pandemic and its aftermath. We report the validation of the Latin American and Caribbean Food Security Scale (Escala Latinoamericana y Caribena de Seguridad Alimentaria [ELCSA]) among pregnant women in Sri Lanka. The eight‐item adult version of the ELCSA was translated from English to Sinhala and Tamil. Cognitive testing (on 10 pregnant women and five local experts) and psychometric validation of the self‐administered HFI tool were conducted among pregnant women (n = 269) attending the special clinics of the Rajarata Pregnancy Cohort (RaPCo) in Anuradhapura in February 2020. We assessed the psychometric properties and fit using a one parameter logistic model (Rasch model analysis) using STATA Version 14 and WINSTEP software Version 4.3.4. Concurrent validity was tested using psychological distress. The scale was internally consistent (Cronbach''s alpha = 0.79) and had a good model fit (Rasch items infit statistic range: 0.85 to 1.07). Item 8 (‘did not eat for the whole day’) was removed from the model fit analysis, as it was not affirmed by respondent. Item severity scores ranged from −2.15 for ‘not eating a diverse diet’ to 4.43 for ‘not eating during the whole day’. Concurrent validity between HFI and psychological distress was confirmed (r = 0.15, p < 0.05). The self‐applied version of ELCSA‐pregnancy in Sri Lanka (ELCSA‐P‐SL) is a valid and feasible valid tool. We recommend it to track HFI among pregnant women in lower income countries during the COVID‐19 pandemic.     

ALDOB基因复合杂合变异致遗传性果糖不耐受饮食控制30年1例报告并文献复习

目的 总结1例ALDOB基因复合杂合变异致遗传性果糖不耐受（HFI）患者饮食控制30年的远期随访结局和饮食控制经验。方法 回顾性总结1例ALDOB基因复合杂合变异致HFI初诊时的临床资料、30年饮食控制经历、基因检查结果和远期随访结局,系统筛选和记录能引起患者症状的食谱。复习文献,总结HGMD数据库收录为ALDOB致病变异、同时有详细临床信息的HFI患者的临床资料,分析饮食控制与未控制的随访结局。结果 女,4岁,因“不明原因低热,呕吐后症状缓解”就诊。生后20 d开始添加奶粉,喂养后立即呕吐,改为米粥喂养,呕吐症状缓解。儿童期食西瓜、蛋糕等后出现呕吐症状,开始停止摄入含糖类食物。7岁时曾以“吃甜食后低热、饥饿感、呕吐后可缓解”就诊,曾诊断“生长发育不良,遗传代谢性疾病待查”,家属开始系统筛选和记录能引起患儿呕吐症状的水果、蔬菜等食物。目前随访至30岁,身高174.6 cm,体重57.6 kg,智力发育正常,心、肺、甲状腺、肝、肾功能未见异常。WGS检测及家系Sanger验证,发现ALDOB基因复合杂合变异［NM_000035, exon4:c.360_363delCAAA(p.N120Kfs*32); exon9:c.1013C>T (p.A338V)］ ,A338V来自父亲,N120Kfs*32来自母亲。HGMD数据库收录为ALDOB基因致病变异、同时有临床信息的HFI患者33例,未控制饮食患者预后不良比例 ［75%（6/8）］ 高于饮食控制患者［50%（9/18）］。控制饮食但仍出现预后不良的患者中,移码变异占556%,高于控制饮食后未出现预后不良的患者（27.8%）。结论 饮食控制对HFI的改善预后具有重要意义,但携带移码变异的患者在控制饮食的情况下仍可能有不良预后,需要更为严格的饮食控制并密切随访。     

HEREDITARY FRUCTOSE INTOLERANCE IN FOUR SWEDISH FAMILIES

A brief review is given of hereditary fructose intolerance. Seven adult cases of the disease from four families, two of which are distantly related, are reported. Among their relations at least two more persons have shown symptoms of fructose intolerance. The first symptoms appeared in infancy on weaning, when sweetened formulas or fruit juice supplements were given, and consisted of retching, vomiting, and sweating. All the subjects quickly developed strong aversion to foods containing fructose. None had dental caries. All were physically and mentally normal. The characteristic hypoglycaemia and hypophosphataemia were observed in all cases in intravenous fructose tolerance tests. The plasma FFA showed an initial fall after injection of fructose, followed by a sharp rise. The initial fall probably supports the view that fructose is readily metabolized in adipose tissue in subjects with HFI. The subsequent rise may be due to lipolysis. The urinary excretion of adrenaline was examined in one case, and raised values were recorded during the fructose tolerance tests; the significance of this is discussed.