Hereditary fructose intolerance

Actionability Pediatric Summary Report

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

• Gene: ALDOB (HGNC:417)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 11/01/2018
• Curation Status: Released (1.2.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ALDOB	N/A (MONDO:0009249)	229600	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity associated with hereditary fructose intolerance / Dietary restriction of fructose, sucrose, and sorbitol	2	3N	3C	2	10NC
Organ failure from acute exposure to fructose, sucrose, and sorbitol / Avoidance of iatrogenic or acute exposure to fructose, sucrose, and sorbitol	2	0N	3C	3	8NC

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of hereditary fructose intolerance (HFI) has been extrapolated based on carrier frequencies of pathogenic variants to be approximately 1:18,000 – 1:34,000 in Europe and in multiple populations in the United States (All – 1:60,000; self-identified Middle Eastern – 1:38,000; self-identified African American – 1:205,000).

Clinical Features (Signs / symptoms)

HFI is associated with an inability to metabolize fructose completely in the liver, intestine and kidneys. Clinical symptoms of HFI include gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain, anorexia), jaundice, bleeding tendency, renal tubular dysfunction and metabolic disturbances 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, and risk of death.

Natural History (Important subgroups & survival / recovery)

Symptoms of HFI become apparent during infancy at the time of weaning, when fructose or sucrose is introduced into the diet. Of note, some individuals have survived and been diagnosed in adulthood due to aversion to fructose-containing foods and a self-imposed fructose-free diet refined through trial and error. If identified and treated before permanent organ injury occurs, individuals with HFI have a normal life expectancy. Hepatomegaly may remain a persistent complication despite fructose restriction and resolution of initial hepatic fibrosis.

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 patients with symptomatic HFI in childhood:

• Vomiting - 50/50 (100%)

• Hepatomegaly - 50/50 (100%)

• Anorexia - 27/50 (54%)

• Weight retardation - 23/49 (47%)

• Bleeding tendency - 23/50 (46%)

• Jaundice - 19/50 (38%)

• Edema and /or ascites - 15/50 (30%)

• Height retardation - 15/49 (31%)

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

• 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

Intervention Effectiveness

Patient Management

Dietary restriction of fructose, sucrose, and sorbitol is the cornerstone of HFI treatment (see circumstances to avoid).

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 disorders

• Dietician with experience in managing inherited metabolic diseases

• Hepatologist

• Nephrologist

Tier 4

Daily supplementation with a sugar-free multivitamin is recommended to prevent micronutrient deficiencies, specifically the water-soluble vitamins such as vitamin C and folates, in the setting of reduced fruit and vegetable intake.

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.

Tier 4

During any hospitalization, great care should be taken to avoid enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate. Of particular 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.

Tier 3

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 information on surveillance was identified.

Circumstances to Avoid

Dietary restriction of fructose, sucrose, and sorbitol is necessary for the management of HFI, and should be strictly followed and maintained, especially during infancy. Currently, there are no specific guidelines regarding dietary fructose limits in any age group. In addition, HFI patients should 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). Evidence from 50 patients 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 ~24 hours, renal tubular dysfunction can resolve in as little as 3 days, and 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 in spite of treatment and resolution of fibrosis.

Tier 3

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.

Context: 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. A number of reported accidental and iatrogenic fructose infusion-related deaths have been reported in patients with undiagnosed or inadequately disclosed HFI.

Context: Pediatric

Tier 3

Gene Condition Association

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

References List

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/