Hereditary fructose intolerance

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ALDOB (HGNC:417)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 04/13/2023
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ALDOB	hereditary fructose intolerance (0009249)	229600	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion of limited for adults, despite having strong actionability in the pediatric setting. Although it is likely that hereditary fructose intolerance is actionable when identified within the adult setting, the scorers agreed with an assertion of limited based on the limited understanding of adult-diagnosed hereditary fructose intolerance, and the unknown effectiveness of treatment in the context of secondary findings.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity associated with hereditary fructose intolerance including organ failure / Avoidance of dietary, iatrogenic, or acute exposure to fructose, sucrose, and sorbitol	2	0D	3D	2	7DD

Severity of Outcome

Prevalence of the Genetic Condition

Hereditary fructose intolerance (HFI) is rare, making precise prevalence estimates challenging. A recent epidemiological review suggests the prevalence of HFI may have a wider distribution, with an estimated total prevalence between 1:10,000 and 1:52,300, depending on how the carrier frequency is calculated.

Clinical Features (Signs / symptoms)

HFI is associated with an inability to metabolize fructose completely in the liver, intestine, and kidneys and is characterized by metabolic disturbances (lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia, hyperalaninemia, and hypoglycemia that may be fatal). Clinical symptoms of HFI include gastrointestinal distress (nausea, vomiting, diarrhea, pain), hepatic dysfunction (hepatomegaly, distention, jaundice), bleeding tendency, and renal tubular dysfunction following dietary exposure to fructose, sucrose, or sorbitol. If large quantities of fructose are ingested, the patient may acutely develop lethargy, seizures and/or progressive coma. Persistent fructose exposure can result in chronic growth restriction, failure to thrive, renal and hepatic failure, seizures, coma, and risk of death.

Natural History (Important subgroups & survival / recovery)

HFI is a benign condition when treated, but is life-threatening and potentially fatal if left untreated. It can onset at any age, however symptoms of untreated HFI typically first manifest during infancy at the time of weaning, when fructose or sucrose is introduced into the diet. HCI may onset earlier than 5-6 months of age due to the addition of fructose-containing nutrients in infant formulas. If identified and treated before permanent organ injury occurs, individuals with HFI can expect normal neurocognitive development, health, quality of life, and life expectancy. Conversely, when individuals with HFI do not adhere to recommended dietary restrictions, chronic liver and/or renal disease are expected. Hepatomegaly may remain a persistent complication despite fructose restriction and resolution of initial hepatic fibrosis. Some individuals are not diagnosed and do not manifest symptoms until adulthood due to aversion to fructose-containing foods and a self-imposed fructose-free diet refined through trial and error. All patients achieve adulthood but develop a natural aversion to fruits/sweets and report a lifelong history of vomiting and hypoglycemia following fructose ingestion.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

1-2 in 500

In a large carrier screening study of multiple disorders in an ethnically diverse population in the United States, overall carrier frequency for an ALDOB pathogenic variant was 1:122 (~0.8%). Carrier frequency in persons self-identifying as Middle Eastern (n=388) was 1:97 (~1.0%) while the frequency for self-identifying African American population (n=678) was 1:226 (~0.4%), although these data may underestimate the prevalence in persons of non-European ancestry based on the variants examined. Carrier frequencies estimates in European countries have ranged from 0.8-1.3%.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on penetrance among individuals identified molecularly was found.

Tier Not provided

>= 40 %

The following clinical features were found at presentation in a case series of 50 children with symptomatic HFI:

• Vomiting - 50/50 (100%)

• Hepatomegaly - 50/50 (100%)

• Anorexia - 27/50 (54%)

• Delayed growth (weight) - 23/49 (47%)

• Bleeding tendency - 23/50 (46%)

• Jaundice - 19/50 (38%)

• Edema and/or ascites - 15/50 (30%)

• Delayed growth (height) - 15/49 (31%)

• Aversion to sweet foods - 13/50 (26%)

• Postprandial pallor/shock/seizures - 8/50 (16%)

Tier 5

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on the relative risk was identified.

Expressivity

No genotype-phenotype correlations have been identified for HFI; clinical severity and extent of organ damage appear to depend on an individual's nutritional environment. However, it has been suggested that tolerance of dietary fructose probably depends on an individual's residual enzyme activity.

Tier 4

Intrafamilial clinical variability has been observed in siblings who inherited biallelic ALDOB pathogenic variants. Heterozygotes are not at increased risk of developing HFI. While carriers are generally asymptomatic, case reports indicate that heterozygous ALDOB pathogenic variants may result in symptoms in some patients, including hypoglycemia, ketosis, recurrent febrile episodes, liver dysfunction. A recent case control study reported that heterozygous individuals showed a postprandial increase in plasma uric acid concentration in response to fructose ingestion, suggesting that heterozygosity for HFI may predispose to hyperuricemia.

Tier 3

Intervention Effectiveness

Patient Management

Management by multidisciplinary specialists, including gastroenterology, nephrology, ophthalmology, and clinical/metabolic nutrition, is recommended.

Tier 4

To establish the extent of disease and needs in an individual diagnosed with HFI, evaluation by the following specialists is recommended:

• Biochemical geneticist or pediatrician with an interest in metabolic conditions

• Dietician with experience in managing inherited metabolic conditions

• Ophthalmologist

• Hepatologist

• Nephrologist

Tier 4

Dietary restriction of fructose, sucrose, and sorbitol is the cornerstone of HFI treatment and should be strictly followed and maintained, especially during infancy. Currently, there are no specific guidelines regarding dietary fructose limits in any age group. Evidence from 50 children presenting with confirmed and symptomatic HFI shows that upon dietary restriction of fructose, the improvement observed is dramatic. Vomiting and gastrointestinal symptoms resolved nearly immediately, bleeding tendency resolves in approximately 24 hours, renal tubular dysfunction can resolve in as little as 3 days. Clinical and biological findings, with the exception of hepatomegaly, resolved within a few weeks. Normal growth occurred in 2-3 years. In the 50 symptomatic patients and 5 patients who received treatment from birth, liver enlargement persisted despite treatment and resolution of fibrosis.

Tier 3

Given that reduced fruit and vegetable intake is a daily requirement, daily supplementation with a “sugar-free” multivitamin is recommended to prevent micronutrient deficiencies, specifically water-soluble vitamins.

Tier 4

Acute presentations should be managed symptomatically in a hospital setting, including intravenous glucose (dextrose) administration, supportive treatment of hepatic insufficiency (including fresh frozen plasma or exchange transfusion), and treatment of metabolic acidosis, if present. Acute episodes of intoxication should be managed in a hospital setting with immediate and complete elimination of fructose and may require intensive care.

Tier 4

During any hospitalization, great care should be taken to avoid enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate. Of note, a 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures) should not be given to neonates known to have HFI. This recommendation is supported by case reports of reported accidental and iatrogenic fructose infusion-related serious organ failure events and/or deaths. Alerts should be placed in the patient's chart or medical record to notify practitioners to the HFI diagnosis and to the medical risks associated with exposures to fructose and related metabolites. The patient is advised to wear at all times a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI. Hospital pharmacists should be utilized or parenteral medications, which should be cleared for use on a case-by-case basis

Tier 4

Surveillance

No formal guidelines for surveillance were identified. Once the diagnosis of HFI has been made, periodic evaluation of liver function, renal function, and growth is reasonable, particularly if compliance with dietary restrictions is not absolute. Suggested surveillance evaluations and intervals are as follows:

• Diet/nutrition – every 3-4 months in first year of life; every 6-12 months thereafter.

• Liver dysfunction/non-alcoholic fatty liver disease– every 6-12 months.

• Renal dysfunction – every 6-12 months

• Hypoglycemia – as needed for findings such as lethargy, seizures, jitteriness, diaphoresis.

• Chronic excess fructose ingestion – every 6-12 months.

Tier 4

Circumstances to Avoid

Fructose tolerance testing (“fructose challenge”) in the diagnosis of HFI should be avoided because it is dangerous and, evidenced by past use, could result in death.

Tier 4

Carbohydrate ingredients in infant formulas that are contraindicated in HFI and can trigger onset of symptoms in undiagnosed individuals include fructose, high-fructose corn syrup, sucrose, inulin, and fructooligosaccharides.

Tier 3

Enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate including fructose, fructose-containing oligosaccharides, high-fructose corn syrup, honey, agave syrup, inverted sugar, maple flavored syrup, molasses, palm or coconut sugar, and sorghum, should be avoided. HFI patients should also avoid medicines and formulas in which fructose/sucrose may not be listed as a primary component but may be present (high risk concoctions include syrups, enema solutions, some immunoglobulin solutions, and many infant and pediatric nutritional drinks).

Tier 4

Although vaccinations are generally safe in children with HFI, two potentially harmful vaccines are the sucrose-containing rotavirus vaccines, Rotarix pre-established oral suspension and RotaTeq, the only rotavirus vaccines approved for use in the US. Additional vaccines with high sucrose content should not be administered to children under a specified weight.

Tier 4

Nature of Intervention

Nature of Intervention

The primary intervention for HFI is lifelong avoidance of enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate. This dietary restriction may lead to deficiencies in water-soluble vitamins (e.g., vitamin C and folates). Compliance may not be absolute. Despite fructose restriction and resolution of initial fibrosis, hepatomegaly may remain a persistent complication, including in individuals ascertained by family history and treated from birth.

Context: Adult Pediatric

Chance to Escape Clinical Detection

The diagnosis of HFI may be made in an older individual who has, through a natural aversion to fruits and sweets, avoided fructose-containing food since childhood. Several reported accidental and iatrogenic fructose infusion-related deaths have been reported in patients with undiagnosed or inadequately disclosed HFI.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ALDOB			229600	0009249

References List

ALDOLASE B, FRUCTOSE-BISPHOSPHATE; ALDOB. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 612724, (2020) World Wide Web URL: http://omim.org/

FRUCTOSE INTOLERANCE, HEREDITARY. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 229600, (2016) World Wide Web URL: http://omim.org/

Hereditary fructose intolerance. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=469

Odievre M, Gentil C, Gautier M, Alagille D. (1978) Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients. American journal of diseases of children (1960). 132(6):605-8.

P Baker, L Ayres, S Gaughan, J Weisfeld-Adams. Hereditary Fructose Intolerance. (2015) . In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK333439/

Pinheiro FC, Sperb-Ludwig F, Schwartz IVD. (2021) Epidemiological aspects of hereditary fructose intolerance: A database study. Human mutation. 42(1098-1004):1548-1566.