👪

Inheritance

1

Autosomal recessive HP:0000007

HFI is inherited in an autosomal recessive pattern due to biallelic ALDOB pathogenic variants.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:34524712 SUPPORT Human Clinical

"of autosomal recessive inheritance caused by pathogenic variants in the ALDOB"

This directly supports autosomal recessive inheritance and identifies ALDOB as the causal gene.

⚙

Pathophysiology

3

Aldolase B deficiency

Biallelic ALDOB pathogenic variants reduce aldolase B activity in the liver, kidneys, and intestine, blocking normal fructose metabolism after exposure to fructose-containing sugars.

Hepatocyte link epithelial cell of proximal tubule link

fructose catabolic process link ↓ DECREASED

fructose-bisphosphate aldolase activity link ↓ DECREASED

Downstream

Fructose-1-phosphate accumulation and ATP depletion Loss of aldolase B causes fructose-1-phosphate accumulation with downstream ATP depletion after fructose ingestion.

Show evidence (2 references)

PMID:31713637 SUPPORT Other

"a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules."

This supports decreased aldolase B catalytic activity as the proximal fructose-catabolic lesion in HFI.

PMID:34524712 SUPPORT Human Clinical

"gene that lead to aldolase B deficiency in the liver, kidneys, and intestine."

This supports ALDOB deficiency in liver, kidney, and intestine as the primary lesion in HFI.

Fructose-1-phosphate accumulation and ATP depletion

Accumulated fructose-1-phosphate with phosphate and ATP depletion impairs hepatic glucose release and contributes to liver and kidney injury after fructose exposure.

Hepatocyte link

Gluconeogenesis link Glycogen catabolic process link Glucose homeostasis link

Downstream

Fructose-1-phosphate The Fru1P/ATP-depletion mechanism is measured biochemically as increased fructose-1-phosphate.

ATP The Fru1P/ATP-depletion mechanism is measured biochemically as decreased ATP.

Hypoglycemia Impaired hepatic glucose production after fructose exposure produces symptomatic hypoglycemia.

Vomiting Acute gastrointestinal intolerance, including vomiting, is triggered by the toxic metabolic response to fructose ingestion.

Hepatomegaly Recurrent hepatocellular metabolic stress leads to liver enlargement and steatotic liver disease.

Renal Tubular Dysfunction Renal aldolase B deficiency and fructose toxicity can produce proximal tubular dysfunction and chronic kidney injury.

Transaminases Hepatic metabolic injury from the core fructose toxicity mechanism can present as elevated transaminases.

Blood Glucose Impaired hepatic glucose production after fructose exposure is reflected biochemically as low blood glucose.

Nausea Acute fructose toxicity commonly produces nausea along with vomiting and hypoglycemia.

Feeding Difficulty and Sweet Aversion Children often develop feeding difficulty and aversion to sweet foods after fructose-triggered symptoms.

Hepatic Failure Severe hepatic involvement can rarely progress to liver failure.

Renal Tubular Acidosis Renal aldolase B deficiency and fructose toxicity can present specifically as proximal renal tubular acidosis.

Chronic hepatic lipid storage and inflammatory dysregulation Chronic Fru1P-driven hepatic stress is associated with persistent lipid storage and inflammatory abnormalities even in diet-treated patients.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"ingestion of fructose results in accumulation of Fru 1P and"

This review summarizes the central toxic metabolic mechanism linking fructose exposure to acute organ dysfunction.

Chronic hepatic lipid storage and inflammatory dysregulation

Long-term diet-treated HFI patients can show persistent hepatic lipid storage, altered serum lipidomic profiles, and low-grade systemic inflammation, extending the pathograph beyond acute fructose intolerance.

Hepatocyte link

Lipid storage link ↑ INCREASED Lipid metabolic process link ↕ DYSREGULATED Inflammatory response link ↑ INCREASED

Downstream

Hepatic Steatosis Increased hepatic lipid storage presents clinically and radiographically as liver steatosis.

Elevated Transaminases Hepatic lipid and inflammatory stress can accompany elevated transaminases and steatohepatitis.

Show evidence (2 references)

PMID:41806524 SUPPORT Human Clinical

"Top-interacting network analysis revealed abnormalities in lipid metabolism and inflammation as hallmarks of HFI."

This patient lipidomics study supports lipid metabolism and inflammatory dysregulation as recurring HFI mechanisms.

PMID:41806524 SUPPORT Human Clinical

"low-grade systemic inflammation was highly prevalent in HFI patients"

This supports increased inflammatory signaling as part of the chronic metabolic phenotype in treated HFI patients.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Digestive 6

Nausea Nausea (HP:0002018)

Show evidence (1 reference)

PMID:34524712 SUPPORT Human Clinical

"Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea,"

This directly supports nausea as a characteristic clinical symptom of HFI.

Vomiting Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:34524712 SUPPORT Human Clinical

"Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea, in"

This supports vomiting as a characteristic symptomatic response to fructose exposure in HFI.

Feeding Difficulty and Sweet Aversion Feeding difficulties (HP:0011968)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycemia."

This supports feeding issues and sweet aversion as common manifestations in children with HFI.

Hepatomegaly Hepatomegaly (HP:0002240)

Show evidence (1 reference)

PMID:34524712 SUPPORT Human Clinical

"addition to hepatomegaly and other liver and kidney dysfunctions."

This supports hepatomegaly as part of the core hepatic phenotype in HFI.

Hepatic Steatosis Hepatic steatosis (HP:0001397)

Show evidence (1 reference)

PMID:41806524 SUPPORT Human Clinical

"significant liver steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present in 75 % of HFI patients compared to 7 % in the control group."

This cohort directly supports hepatic steatosis as a frequent finding in diet-treated HFI patients.

Hepatic Failure Hepatic failure (HP:0001399)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"transaminases, steatohepatitis and rarely liver failure."

This supports hepatic failure as a rare but clinically important manifestation of HFI.

Genitourinary 1

Renal Tubular Dysfunction Renal tubular dysfunction (HP:0000124)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"usually occurs in the form of proximal renal tubular acidosis and may lead to"

Proximal renal tubular acidosis is a specific form of renal tubular dysfunction in HFI.

Metabolism 2

Hypoglycemia Hypoglycemia (HP:0001943)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"and hypoglycemia. Liver manifestations include an asymptomatic increase of"

This review identifies hypoglycemia as a common clinical manifestation in children with HFI.

Elevated Transaminases Elevated circulating hepatic transaminase concentration (HP:0002910)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"Liver manifestations include an asymptomatic increase of transaminases"

This directly supports elevated transaminases as a liver manifestation of HFI.

Other 1

Renal Tubular Acidosis Renal tubular acidosis (HP:0001947)

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency."

This directly supports renal tubular acidosis as a renal manifestation of HFI.

🧬

Genetic Associations

1

ALDOB (Causative)

Show evidence (2 references)

PMID:34524712 SUPPORT Human Clinical

"of autosomal recessive inheritance caused by pathogenic variants in the ALDOB"

This directly supports ALDOB as the causative gene in HFI.

CGGV:assertion_9997dba9-812f-4480-98d8-d0b3a050dbc7-2025-09-04T170000.000Z SUPPORT Other

ClinGen classifies the ALDOB-hereditary fructose intolerance gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

2

Fructose-, sucrose-, and sorbitol-restricted diet

Action: dietary intervention MAXO:0000088

Absolute avoidance of fructose, sucrose, and sorbitol is the standard lifelong treatment and usually prevents acute metabolic toxicity when started and maintained consistently.

Mechanism Target:

INHIBITS Fructose-1-phosphate accumulation and ATP depletion — Avoiding fructose, sucrose, and sorbitol prevents the fructose-triggered Fru1P accumulation and ATP depletion mechanism.

Show evidence (2 references)

PMID:31713637 SUPPORT Human Clinical

"prevented by a fructose-restricted diet."

The review states that sequelae of Fru1P accumulation and ATP depletion can be prevented by fructose restriction.

PMID:36052111 SUPPORT Human Clinical

"absolute avoidance of foods containing fructose,"

Independent review evidence supports strict dietary avoidance as the management mechanism.

Target Phenotypes: Hypoglycemia ↗ Vomiting ↗ Hepatomegaly ↗

Show evidence (2 references)

PMID:41829941 SUPPORT Human Clinical

"Treatment consists of a lifelong diet"

This cohort study directly states the standard lifelong dietary treatment for HFI.

PMID:36052111 SUPPORT Human Clinical

"absolute avoidance of foods containing fructose,"

This independent review confirms strict FSS avoidance as the central management strategy.

Ketohexokinase inhibition (investigational)

Action: Pharmacotherapy NCIT:C15986

Ketohexokinase-directed therapy is a preclinical, mechanism-based strategy intended to reduce fructose-1-phosphate generation upstream of the blocked aldolase B step. No approved KHK-targeted therapy for HFI currently exists.

Mechanism Target:

INHIBITS Fructose-1-phosphate accumulation and ATP depletion — Reducing ketohexokinase activity can lower hepatic fructose-1-phosphate accumulation and prevent the liver phenotype in aldolase B-deficient mice.

Show evidence (1 reference)

PMID:31713637 SUPPORT Model Organism

"intrahepatic Fru 1P concentrations by crossing these mice with mice deficient"

This provides model-organism proof of concept that blocking upstream Fru1P synthesis can rescue HFI liver pathology.

Show evidence (1 reference)

PMID:31713637 SUPPORT Model Organism

"findings not only provide a potential novel treatment for HFI"

This review explicitly identifies ketohexokinase-directed Fru1P reduction as a potential novel treatment strategy for HFI.

🔬

Biochemical Markers

4

Fructose-1-phosphate (INCREASED)

Context: Fructose ingestion in HFI causes intracellular fructose-1-phosphate accumulation because aldolase B cannot cleave the metabolite efficiently.

Pathograph Readouts

Readout Of Fructose-1-phosphate accumulation and ATP depletion Positive Diagnostic

Increased fructose-1-phosphate reports the substrate accumulation caused by aldolase B deficiency after fructose exposure.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP"

The review states the patient-level biochemical pattern of Fru1P accumulation and ATP depletion.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"ingestion of fructose results in accumulation of Fru 1P and"

This directly supports fructose-1-phosphate accumulation as the core biochemical abnormality in HFI.

ATP (DECREASED)

Context: ATP depletion follows fructose-1-phosphate accumulation and contributes to impaired glucose handling and organ injury.

Pathograph Readouts

Readout Of Fructose-1-phosphate accumulation and ATP depletion Negative Diagnostic

Decreased ATP reports the energy-depletion arm of the toxic Fru1P accumulation mechanism.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP"

The review states the patient-level biochemical pattern of Fru1P accumulation and ATP depletion.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"depletion of ATP, which are believed to cause symptoms, such as nausea,"

This directly supports ATP depletion as a key biochemical consequence of fructose exposure in HFI.

Transaminases (INCREASED)

Context: Liver injury in HFI may present with asymptomatic transaminase elevation, especially around diagnosis or when dietary control is imperfect.

Pathograph Readouts

Readout Of Chronic hepatic lipid storage and inflammatory dysregulation Positive Monitoring

Elevated transaminases report hepatic injury associated with chronic liver involvement in HFI.

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure."

The review supports transaminase elevation as a liver manifestation that can monitor hepatic involvement in HFI.

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"transaminases, steatohepatitis and rarely liver failure."

This review directly supports elevated transaminases as a liver biochemical feature of HFI.

Blood Glucose (DECREASED)

Context: Hypoglycemia during fructose exposure reflects decreased circulating glucose downstream of impaired hepatic glucose output.

Pathograph Readouts

Readout Of Fructose-1-phosphate accumulation and ATP depletion Negative Diagnostic

Low blood glucose is the clinical biochemical readout of impaired hepatic glucose release after fructose-triggered Fru1P accumulation.

Show evidence (1 reference)

PMID:31713637 SUPPORT Human Clinical

"vomiting, hypoglycemia, and liver and kidney failure."

This supports hypoglycemia as part of the acute Fru1P/ATP-depletion syndrome in HFI.

Readout Of Hypoglycemia Negative Diagnostic

Decreased blood glucose is the measured biochemical basis of the hypoglycemia phenotype.

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"feeding issues, aversion to sweets and hypoglycemia."

This supports hypoglycemia as a characteristic clinical biochemical manifestation of HFI.

Show evidence (1 reference)

PMID:36052111 SUPPORT Human Clinical

"feeding issues, aversion to sweets and hypoglycemia."

Hypoglycemia directly supports decreased blood glucose as a diagnostic biochemical readout.

{ }

Source YAML

click to show

name: Hereditary Fructose Intolerance
creation_date: '2026-04-21T04:43:27Z'
updated_date: '2026-05-21T07:09:24Z'
category: Genetic
synonyms:
- HFI
- Aldolase B deficiency
description: >
  Hereditary fructose intolerance (HFI) is an autosomal recessive inborn error
  of fructose metabolism caused by biallelic pathogenic variants in ALDOB,
  leading to aldolase B deficiency in the liver, kidneys, and intestine.
  Fructose exposure causes fructose-1-phosphate accumulation with ATP
  depletion, producing vomiting, hypoglycemia, hepatomegaly, and renal
  tubular dysfunction. Lifelong avoidance of fructose, sucrose, and sorbitol
  is the cornerstone of care and is associated with good long-term prognosis,
  although diet-treated patients can still show hepatic steatosis and other
  metabolic complications.
disease_term:
  preferred_term: hereditary fructose intolerance
  term:
    id: MONDO:0009249
    label: hereditary fructose intolerance
parents:
- Metabolic Disease
- Inborn Error of Carbohydrate Metabolism
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    HFI is inherited in an autosomal recessive pattern due to biallelic ALDOB
    pathogenic variants.
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of autosomal recessive inheritance caused by pathogenic variants in the ALDOB"
    explanation: This directly supports autosomal recessive inheritance and identifies ALDOB as the causal gene.
prevalence:
- population: Carrier-frequency based estimate across gnomAD populations
  percentage: approximately 1 in 10,000
  notes: >-
    This estimate comes from database-based carrier-frequency modeling and may
    be higher than clinically recognized prevalence in many settings.
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HFI has a wide distribution and an estimated prevalence of ~1:10,000."
    explanation: This database study provides a concise prevalence estimate for HFI.
progression:
- phase: Symptom onset after fructose introduction
  notes: >
    Symptoms usually emerge once fructose-containing foods are introduced,
    with gastrointestinal complaints, feeding difficulty, aversion to sweets,
    and acute metabolic symptoms becoming apparent in childhood.
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "are affected with gastrointestinal symptoms, feeding issues, aversion to sweets"
    explanation: This review summarizes the typical early symptomatic phase after dietary fructose exposure begins.
- phase: Persistent hepatic steatosis despite dietary treatment
  notes: >
    Even patients maintained on long-term fructose-, sucrose-, and
    sorbitol-restricted diets may develop steatosis and broader metabolic
    abnormalities, supporting continued surveillance beyond symptom control.
  evidence:
  - reference: PMID:41806524
    reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in 75 % of HFI patients compared to 7 % in the control group."
    explanation: This cohort study shows that clinically important liver disease can persist despite dietary treatment.
pathophysiology:
- name: Aldolase B deficiency
  description: >
    Biallelic ALDOB pathogenic variants reduce aldolase B activity in the liver,
    kidneys, and intestine, blocking normal fructose metabolism after exposure
    to fructose-containing sugars.
  gene:
    preferred_term: ALDOB
    description: >
      ALDOB encodes aldolase B, the fructose-metabolizing aldolase isoenzyme
      expressed in liver, kidney, and intestine.
    modifier: DECREASED
    term:
      id: hgnc:417
      label: ALDOB
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: fructose catabolic process
    term:
      id: GO:0006001
      label: fructose catabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: fructose-bisphosphate aldolase activity
    term:
      id: GO:0004332
      label: fructose-bisphosphate aldolase activity
    modifier: DECREASED
  downstream:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    description: Loss of aldolase B causes fructose-1-phosphate accumulation with downstream ATP depletion after fructose ingestion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ingestion of fructose results in accumulation of Fru 1P and"
      explanation: This directly links aldolase B deficiency to Fru1P accumulation and ATP depletion after fructose exposure.
  evidence:
  - reference: PMID:31713637
    reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules."
    explanation: This supports decreased aldolase B catalytic activity as the proximal fructose-catabolic lesion in HFI.
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gene that lead to aldolase B deficiency in the liver, kidneys, and intestine."
    explanation: This supports ALDOB deficiency in liver, kidney, and intestine as the primary lesion in HFI.
- name: Fructose-1-phosphate accumulation and ATP depletion
  description: >
    Accumulated fructose-1-phosphate with phosphate and ATP depletion impairs
    hepatic glucose release and contributes to liver and kidney injury after
    fructose exposure.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
  - preferred_term: Glycogen catabolic process
    term:
      id: GO:0005980
      label: glycogen catabolic process
  - preferred_term: Glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
  chemical_entities:
  - preferred_term: fructose-1-phosphate
    term:
      id: CHEBI:78737
      label: fructose 1-phosphate
    modifier: INCREASED
  - preferred_term: ATP
    term:
      id: CHEBI:15422
      label: ATP
    modifier: DECREASED
  downstream:
  - target: Fructose-1-phosphate
    description: The Fru1P/ATP-depletion mechanism is measured biochemically as increased fructose-1-phosphate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ingestion of fructose results in accumulation of Fru 1P and"
      explanation: This directly supports fructose-1-phosphate accumulation after fructose exposure in HFI.
  - target: ATP
    description: The Fru1P/ATP-depletion mechanism is measured biochemically as decreased ATP.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "depletion of ATP, which are believed to cause symptoms, such as nausea,"
      explanation: This directly supports ATP depletion as part of the core fructose-exposure mechanism.
  - target: Hypoglycemia
    description: Impaired hepatic glucose production after fructose exposure produces symptomatic hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "vomiting, hypoglycemia, and liver and kidney failure."
      explanation: This supports hypoglycemia as a direct metabolic consequence of Fru1P accumulation and ATP depletion.
  - target: Vomiting
    description: Acute gastrointestinal intolerance, including vomiting, is triggered by the toxic metabolic response to fructose ingestion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "vomiting, hypoglycemia, and liver and kidney failure."
      explanation: This directly ties vomiting to the toxic metabolic consequences of fructose exposure in HFI.
  - target: Hepatomegaly
    description: Recurrent hepatocellular metabolic stress leads to liver enlargement and steatotic liver disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34524712
      reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "addition to hepatomegaly and other liver and kidney dysfunctions."
      explanation: This supports hepatomegaly as part of the downstream hepatic injury phenotype in HFI.
    - reference: PMID:41806524
      reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present"
      explanation: Persistent steatosis in diet-treated patients supports chronic hepatic consequences downstream of the core metabolic defect.
  - target: Renal Tubular Dysfunction
    description: Renal aldolase B deficiency and fructose toxicity can produce proximal tubular dysfunction and chronic kidney injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "usually occurs in the form of proximal renal tubular acidosis and may lead to"
      explanation: This review supports renal tubular dysfunction as a clinically relevant downstream renal consequence in HFI.
  - target: Transaminases
    description: Hepatic metabolic injury from the core fructose toxicity mechanism can present as elevated transaminases.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "transaminases, steatohepatitis and rarely liver failure."
      explanation: The review directly lists transaminase elevation among liver manifestations of HFI.
  - target: Blood Glucose
    description: Impaired hepatic glucose production after fructose exposure is reflected biochemically as low blood glucose.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "feeding issues, aversion to sweets and hypoglycemia."
      explanation: This supports hypoglycemia as a downstream clinical readout of the fructose-triggered metabolic block.
  - target: Nausea
    description: Acute fructose toxicity commonly produces nausea along with vomiting and hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "depletion of ATP, which are believed to cause symptoms, such as nausea,"
      explanation: The review links Fru1P accumulation and ATP depletion to nausea among the acute symptoms of HFI.
  - target: Feeding Difficulty and Sweet Aversion
    description: Children often develop feeding difficulty and aversion to sweet foods after fructose-triggered symptoms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycemia."
      explanation: This supports feeding issues and sweet aversion as downstream clinical manifestations of HFI.
  - target: Hepatic Failure
    description: Severe hepatic involvement can rarely progress to liver failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "transaminases, steatohepatitis and rarely liver failure."
      explanation: The review identifies liver failure as a rare hepatic manifestation downstream of the metabolic disorder.
  - target: Renal Tubular Acidosis
    description: Renal aldolase B deficiency and fructose toxicity can present specifically as proximal renal tubular acidosis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Renal involvement usually occurs in the form of proximal renal tubular acidosis"
      explanation: This directly supports renal tubular acidosis as a downstream renal manifestation of HFI.
  - target: Chronic hepatic lipid storage and inflammatory dysregulation
    description: Chronic Fru1P-driven hepatic stress is associated with persistent lipid storage and inflammatory abnormalities even in diet-treated patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls."
      explanation: This links the HFI metabolic state to persistent hepatic fat accumulation in treated patients.
  evidence:
  - reference: PMID:31713637
    reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ingestion of fructose results in accumulation of Fru 1P and"
    explanation: This review summarizes the central toxic metabolic mechanism linking fructose exposure to acute organ dysfunction.
- name: Chronic hepatic lipid storage and inflammatory dysregulation
  description: >
    Long-term diet-treated HFI patients can show persistent hepatic lipid
    storage, altered serum lipidomic profiles, and low-grade systemic
    inflammation, extending the pathograph beyond acute fructose intolerance.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Lipid storage
    term:
      id: GO:0019915
      label: lipid storage
    modifier: INCREASED
  - preferred_term: Lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DYSREGULATED
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  chemical_entities:
  - preferred_term: lipid
    term:
      id: CHEBI:18059
      label: lipid
    modifier: INCREASED
  downstream:
  - target: Hepatic Steatosis
    description: Increased hepatic lipid storage presents clinically and radiographically as liver steatosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41806524
      reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "significant liver steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present in 75 % of HFI patients compared to 7 % in the control group."
      explanation: This cohort directly supports hepatic steatosis as a prevalent downstream manifestation in diet-treated HFI.
  - target: Elevated Transaminases
    description: Hepatic lipid and inflammatory stress can accompany elevated transaminases and steatohepatitis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure."
      explanation: This supports elevated transaminases and steatohepatitis as liver manifestations connected to chronic hepatic injury.
  evidence:
  - reference: PMID:41806524
    reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Top-interacting network analysis revealed abnormalities in lipid metabolism and inflammation as hallmarks of HFI."
    explanation: This patient lipidomics study supports lipid metabolism and inflammatory dysregulation as recurring HFI mechanisms.
  - reference: PMID:41806524
    reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-grade systemic inflammation was highly prevalent in HFI patients"
    explanation: This supports increased inflammatory signaling as part of the chronic metabolic phenotype in treated HFI patients.
phenotypes:
- name: Hypoglycemia
  category: Metabolic
  diagnostic: true
  description: >
    Hypoglycemia is a hallmark acute manifestation after fructose exposure and
    reflects impaired hepatic glucose output.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and hypoglycemia. Liver manifestations include an asymptomatic increase of"
    explanation: This review identifies hypoglycemia as a common clinical manifestation in children with HFI.
- name: Nausea
  category: Gastrointestinal
  diagnostic: true
  description: >
    Nausea occurs during acute fructose intolerance episodes and clusters with
    vomiting and hypoglycemia after fructose exposure.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea,"
    explanation: This directly supports nausea as a characteristic clinical symptom of HFI.
- name: Vomiting
  category: Gastrointestinal
  diagnostic: true
  description: >
    Vomiting commonly accompanies acute intolerance episodes after fructose
    ingestion.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea, in"
    explanation: This supports vomiting as a characteristic symptomatic response to fructose exposure in HFI.
- name: Feeding Difficulty and Sweet Aversion
  category: Gastrointestinal
  diagnostic: true
  description: >
    Children with HFI commonly have feeding issues and aversion to sweets,
    reflecting learned avoidance of fructose-containing foods that trigger
    symptoms.
  phenotype_term:
    preferred_term: Feeding difficulty and sweet aversion
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycemia."
    explanation: This supports feeding issues and sweet aversion as common manifestations in children with HFI.
- name: Hepatomegaly
  category: Gastrointestinal
  diagnostic: true
  description: >
    Hepatomegaly reflects hepatic metabolic injury and is often accompanied by
    steatosis or transaminase elevation.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "addition to hepatomegaly and other liver and kidney dysfunctions."
    explanation: This supports hepatomegaly as part of the core hepatic phenotype in HFI.
- name: Hepatic Steatosis
  category: Hepatic
  description: >
    Hepatic steatosis can persist despite dietary treatment and is a common
    chronic liver manifestation in contemporary HFI cohorts.
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:41806524
    reference_title: "Lipidomics uncovers metabolic manifestations related to liver steatosis and low-grade systemic inflammation in diet-treated hereditary fructose intolerance patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significant liver steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present in 75 % of HFI patients compared to 7 % in the control group."
    explanation: This cohort directly supports hepatic steatosis as a frequent finding in diet-treated HFI patients.
- name: Elevated Transaminases
  category: Laboratory
  description: >
    HFI liver involvement may include asymptomatic elevation of circulating
    hepatic transaminases.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver manifestations include an asymptomatic increase of transaminases"
    explanation: This directly supports elevated transaminases as a liver manifestation of HFI.
- name: Hepatic Failure
  category: Hepatic
  description: >
    Liver failure is a rare severe hepatic manifestation of HFI, particularly
    when the disorder is unrecognized or fructose exposure continues.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transaminases, steatohepatitis and rarely liver failure."
    explanation: This supports hepatic failure as a rare but clinically important manifestation of HFI.
- name: Renal Tubular Dysfunction
  category: Renal
  description: >
    Renal involvement usually affects the proximal tubule and can progress to
    chronic renal insufficiency if the disorder is not recognized and managed.
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "usually occurs in the form of proximal renal tubular acidosis and may lead to"
    explanation: Proximal renal tubular acidosis is a specific form of renal tubular dysfunction in HFI.
- name: Renal Tubular Acidosis
  category: Renal
  description: >
    Proximal renal tubular acidosis is the characteristic acid-base expression
    of renal tubular involvement in HFI and can contribute to chronic renal
    insufficiency.
  phenotype_term:
    preferred_term: Proximal renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency."
    explanation: This directly supports renal tubular acidosis as a renal manifestation of HFI.
biochemical:
- name: Fructose-1-phosphate
  presence: INCREASED
  context: >
    Fructose ingestion in HFI causes intracellular fructose-1-phosphate
    accumulation because aldolase B cannot cleave the metabolite efficiently.
  biomarker_term:
    preferred_term: fructose-1-phosphate
    term:
      id: CHEBI:78737
      label: fructose 1-phosphate
  readouts:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased fructose-1-phosphate reports the substrate accumulation caused
      by aldolase B deficiency after fructose exposure.
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP"
      explanation: The review states the patient-level biochemical pattern of Fru1P accumulation and ATP depletion.
  evidence:
  - reference: PMID:31713637
    reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ingestion of fructose results in accumulation of Fru 1P and"
    explanation: This directly supports fructose-1-phosphate accumulation as the core biochemical abnormality in HFI.
- name: ATP
  presence: DECREASED
  context: >
    ATP depletion follows fructose-1-phosphate accumulation and contributes to
    impaired glucose handling and organ injury.
  biomarker_term:
    preferred_term: ATP
    term:
      id: CHEBI:15422
      label: ATP
  readouts:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Decreased ATP reports the energy-depletion arm of the toxic Fru1P
      accumulation mechanism.
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP"
      explanation: The review states the patient-level biochemical pattern of Fru1P accumulation and ATP depletion.
  evidence:
  - reference: PMID:31713637
    reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "depletion of ATP, which are believed to cause symptoms, such as nausea,"
    explanation: This directly supports ATP depletion as a key biochemical consequence of fructose exposure in HFI.
- name: Transaminases
  presence: INCREASED
  context: >
    Liver injury in HFI may present with asymptomatic transaminase elevation,
    especially around diagnosis or when dietary control is imperfect.
  readouts:
  - target: Chronic hepatic lipid storage and inflammatory dysregulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Elevated transaminases report hepatic injury associated with chronic liver involvement in HFI.
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure."
      explanation: The review supports transaminase elevation as a liver manifestation that can monitor hepatic involvement in HFI.
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transaminases, steatohepatitis and rarely liver failure."
    explanation: This review directly supports elevated transaminases as a liver biochemical feature of HFI.
- name: Blood Glucose
  presence: DECREASED
  context: >
    Hypoglycemia during fructose exposure reflects decreased circulating glucose
    downstream of impaired hepatic glucose output.
  biomarker_term:
    preferred_term: blood glucose
    term:
      id: CHEBI:17234
      label: glucose
  readouts:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Low blood glucose is the clinical biochemical readout of impaired hepatic
      glucose release after fructose-triggered Fru1P accumulation.
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "vomiting, hypoglycemia, and liver and kidney failure."
      explanation: This supports hypoglycemia as part of the acute Fru1P/ATP-depletion syndrome in HFI.
  - target: Hypoglycemia
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Decreased blood glucose is the measured biochemical basis of the hypoglycemia phenotype.
    evidence:
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "feeding issues, aversion to sweets and hypoglycemia."
      explanation: This supports hypoglycemia as a characteristic clinical biochemical manifestation of HFI.
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "feeding issues, aversion to sweets and hypoglycemia."
    explanation: Hypoglycemia directly supports decreased blood glucose as a diagnostic biochemical readout.
genetic:
- name: ALDOB
  gene_term:
    preferred_term: ALDOB
    term:
      id: hgnc:417
      label: ALDOB
  association: Causative
  notes: >
    Biallelic pathogenic ALDOB variants cause aldolase B deficiency, with the
    highest clinical burden in liver and kidney after fructose exposure.
  evidence:
  - reference: PMID:34524712
    reference_title: "Epidemiological aspects of hereditary fructose intolerance: A database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of autosomal recessive inheritance caused by pathogenic variants in the ALDOB"
    explanation: This directly supports ALDOB as the causative gene in HFI.
  - reference: CGGV:assertion_9997dba9-812f-4480-98d8-d0b3a050dbc7-2025-09-04T170000.000Z
    reference_title: "ALDOB / hereditary fructose intolerance (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALDOB | HGNC:417 | hereditary fructose intolerance | MONDO:0009249 | AR | Definitive"
    explanation: ClinGen classifies the ALDOB-hereditary fructose intolerance gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Molecular genetic testing
  description: >-
    ALDOB sequencing is the preferred confirmatory diagnostic approach and is
    favored over measurement of aldolase B activity in liver biopsy tissue.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: ALDOB
        term:
          id: hgnc:417
          label: ALDOB
  results: Biallelic pathogenic ALDOB variants support the diagnosis of HFI.
  evidence:
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genetic test is favored over"
    explanation: >-
      Review-level evidence directly supports molecular genetic testing as the
      preferred confirmatory diagnostic approach in HFI.
treatments:
- name: Fructose-, sucrose-, and sorbitol-restricted diet
  description: >
    Absolute avoidance of fructose, sucrose, and sorbitol is the standard
    lifelong treatment and usually prevents acute metabolic toxicity when
    started and maintained consistently.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:41829941
    reference_title: "Dietary Patterns in a Nationwide Cohort of Patients with Hereditary Fructose Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment consists of a lifelong diet"
    explanation: This cohort study directly states the standard lifelong dietary treatment for HFI.
  - reference: PMID:36052111
    reference_title: "Hereditary fructose intolerance: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "absolute avoidance of foods containing fructose,"
    explanation: This independent review confirms strict FSS avoidance as the central management strategy.
  target_mechanisms:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    treatment_effect: INHIBITS
    description: Avoiding fructose, sucrose, and sorbitol prevents the fructose-triggered Fru1P accumulation and ATP depletion mechanism.
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "prevented by a fructose-restricted diet."
      explanation: The review states that sequelae of Fru1P accumulation and ATP depletion can be prevented by fructose restriction.
    - reference: PMID:36052111
      reference_title: "Hereditary fructose intolerance: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "absolute avoidance of foods containing fructose,"
      explanation: Independent review evidence supports strict dietary avoidance as the management mechanism.
  target_phenotypes:
  - preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  - preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  - preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- name: Ketohexokinase inhibition (investigational)
  description: >
    Ketohexokinase-directed therapy is a preclinical, mechanism-based strategy
    intended to reduce fructose-1-phosphate generation upstream of the blocked
    aldolase B step. No approved KHK-targeted therapy for HFI currently exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Fructose-1-phosphate accumulation and ATP depletion
    treatment_effect: INHIBITS
    description: >
      Reducing ketohexokinase activity can lower hepatic fructose-1-phosphate
      accumulation and prevent the liver phenotype in aldolase B-deficient mice.
    evidence:
    - reference: PMID:31713637
      reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "intrahepatic Fru 1P concentrations by crossing these mice with mice deficient"
      explanation: This provides model-organism proof of concept that blocking upstream Fru1P synthesis can rescue HFI liver pathology.
  evidence:
  - reference: PMID:31713637
    reference_title: "Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "findings not only provide a potential novel treatment for HFI"
    explanation: This review explicitly identifies ketohexokinase-directed Fru1P reduction as a potential novel treatment strategy for HFI.
notes: >-
  HFI remains primarily a dietary management disorder. The strongest current
  targeted-therapy signal is upstream reduction of fructose-1-phosphate
  formation through ketohexokinase inhibition, but the evidence is still
  preclinical. Diet-treated patients may still develop hepatic steatosis and
  metabolic complications, so long-term follow-up should not stop once acute
  fructose intolerance is controlled.
references:
- reference: DOI:10.1007/s40200-024-01527-y
  title: 'The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review'
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: 'The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review'
    supporting_text: 'The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review'
- reference: DOI:10.1038/s42003-024-06539-1
  title: Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P).
    supporting_text: Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P).
    evidence:
    - reference: DOI:10.1038/s42003-024-06539-1
      reference_title: Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P).
      explanation: Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.
- reference: DOI:10.1172/jci187376
  title: Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance
    supporting_text: Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance
- reference: DOI:10.3390/diseases12030044
  title: Clinical Practice Guidelines for the Diagnosis and Management of Hereditary Fructose Intolerance
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene.
    supporting_text: Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene.
    evidence:
    - reference: DOI:10.3390/diseases12030044
      reference_title: Clinical Practice Guidelines for the Diagnosis and Management of Hereditary Fructose Intolerance
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene.
      explanation: Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.
- reference: DOI:10.3390/healthcare12050573
  title: Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: "(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet."
    supporting_text: "(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet."
    evidence:
    - reference: DOI:10.3390/healthcare12050573
      reference_title: Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet."
      explanation: Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.
- reference: DOI:10.3390/jcm13123394
  title: A Case Study of a Rare Disease (Fructosemia) Diagnosed in a Patient with Abdominal Pain
  found_in:
  - Hereditary_Fructose_Intolerance-deep-research-falcon.md
  findings:
  - statement: Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously.
    supporting_text: Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously.
    evidence:
    - reference: DOI:10.3390/jcm13123394
      reference_title: A Case Study of a Rare Disease (Fructosemia) Diagnosed in a Patient with Abdominal Pain
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously.
      explanation: Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.

📚

References & Deep Research

References

6

DOI:10.1007/s40200-024-01527-y

The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review

1 finding

The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review

"The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review"

DOI:10.1038/s42003-024-06539-1

Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance

1 finding

Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P).

"Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P)."

Show evidence (1 reference)

DOI:10.1038/s42003-024-06539-1 SUPPORT Model Organism

"Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P)."

Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.

DOI:10.1172/jci187376

Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance

1 finding

Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance

"Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance"

DOI:10.3390/diseases12030044

Clinical Practice Guidelines for the Diagnosis and Management of Hereditary Fructose Intolerance

1 finding

Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene.

"Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene."

Show evidence (1 reference)

DOI:10.3390/diseases12030044 SUPPORT Other

"Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene."

Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.

DOI:10.3390/healthcare12050573

Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy

1 finding

(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet.

"(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet."

Show evidence (1 reference)

DOI:10.3390/healthcare12050573 SUPPORT Human Clinical

"(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet."

Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.

DOI:10.3390/jcm13123394

A Case Study of a Rare Disease (Fructosemia) Diagnosed in a Patient with Abdominal Pain

1 finding

Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously.

"Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously."

Show evidence (1 reference)

DOI:10.3390/jcm13123394 SUPPORT Human Clinical

"Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously."

Deep research cited this publication as relevant literature for Hereditary Fructose Intolerance.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 30 citations 2026-05-08T19:53:14.549307

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Hereditary Fructose Intolerance
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Hereditary Fructose Intolerance covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hereditary Fructose Intolerance (HFI): comprehensive disease characteristics report (2023–2024 prioritized)

Executive summary

Hereditary fructose intolerance (HFI) is a rare autosomal recessive inborn error of fructose metabolism caused by biallelic loss-of-function variants in ALDOB (aldolase B), leading to fructose-1-phosphate (F1P) accumulation (“phosphate trap”), ATP depletion, and inhibition of glycogenolysis and gluconeogenesis. Clinically, it presents after introduction of fructose/sucrose/sorbitol with vomiting, abdominal pain/distension, and postprandial hypoglycemia, and can progress to chronic hepatic steatosis and renal proximal tubular dysfunction (Fanconi syndrome) even with treatment. Current standard of care is a lifelong fructose/sucrose/sorbitol (FSS)-free diet and avoidance of offending excipients in medicines. Recent mechanistic work (2023–2024) implicates endogenous fructose generation via the polyol pathway and a newly highlighted AMPD2-driven purine degradation axis as contributors to ongoing liver disease in aldolase B deficiency, while early-phase translational work suggests ketohexokinase (KHK) inhibition (PF‑06835919) may increase fructose tolerance and reduce acute toxicity risk. (andreshernando2024activationofampd2 pages 1-2, ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4, garbowski2024acasestudy pages 9-10, ubeda2024clinicalpracticeguidelines pages 4-5, NCT06089265 chunk 1)

1. Disease information

1.1 Definition and overview

HFI (also called hereditary fructosemia and sometimes “fructosemia”) is an autosomal recessive metabolic disorder due to aldolase B (ALDOB) deficiency, with clinical manifestations triggered by exposure to fructose, sucrose, and sorbitol. (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 5-6)

1.2 Key identifiers (with availability in retrieved sources)

OMIM: 229600 (explicitly stated in multiple 2024 sources). (biancalana2024hereditaryfructoseintolerancea pages 36-38, zuriaga2024descriptiveanalysisof pages 1-2)
MONDO / Orphanet / ICD-10/ICD-11 / MeSH: not explicitly stated in the retrieved full-text snippets; therefore not asserted here.

1.3 Synonyms and alternative names

Hereditary fructose intolerance (HFI)
Hereditary fructosemia
Fructosemia (used in clinical case-report context) (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 5-6)

1.4 Evidence sources and aggregation level

The information summarized below is derived from: (i) disease-level resources (clinical practice guideline and systematic reviews), (ii) aggregated cohort/case series summaries, and (iii) individual case reports and mechanistic mouse-model studies. (ubeda2024clinicalpracticeguidelines pages 1-2, maines2024theroleof pages 1-2, garbowski2024acasestudy pages 5-6, andreshernando2024activationofampd2 pages 1-2)

Structured identifiers & epidemiology summary table: | Item | Summary | Publication year/source | |---|---|---| | Disease name / synonyms | Hereditary fructose intolerance (HFI); also called hereditary fructosemia or fructosemia (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 5-6) | 2024 — Diseases guideline; 2024 adult-management report; 2024 Journal of Clinical Medicine case study | | OMIM | OMIM: 229600 (biancalana2024hereditaryfructoseintolerancea pages 36-38, zuriaga2024descriptiveanalysisof pages 1-2) | 2024 adult-management report; 2024 Healthcare pregnancy study | | Gene | ALDOB (aldolase B; NM_000035.3 reported in adult-management report); located on chromosome 9q22.3/9q22.3 region in reviewed sources (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 5-6) | 2024 — Diseases guideline; 2024 adult-management report; 2024 Journal of Clinical Medicine case study | | Inheritance | Autosomal recessive inborn error of metabolism / metabolic disorder (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, zuriaga2024descriptiveanalysisof pages 1-2) | 2024 — Diseases guideline; 2024 adult-management report; 2024 Healthcare pregnancy study | | Prevalence | Reported estimates vary: ~1 in 10,000 worldwide; ~1 in 20,000 people; around 1 in 26,000 live births in Europe and 1 in 20,000 births in the US (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, maines2024theroleof pages 1-2, zuriaga2024descriptiveanalysisof pages 1-2) | 2024 — Diseases guideline; 2024 adult-management report; 2024 Journal of Diabetes & Metabolic Disorders systematic review; 2024 Healthcare pregnancy study | | Carrier frequency | Predicted heterozygous carrier frequency ranges from 1:55 to 1:122 in the general population (zuriaga2024descriptiveanalysisof pages 1-2) | 2024 — Healthcare pregnancy study | | Common variants | Frequently reported ALDOB variants include p.Ala150Pro / c.448G>C and p.Ala175Asp / c.524C>A; broader review also lists c.178C>T p.Arg60Ter, c.360_363del p.Asn120LysfsTer32, and c.1005C>G p.Asn335Lys. p.Ala150Pro and p.Ala175Asp together account for ~68% of alleles, with p.Ala150Pro alone ~53% worldwide in one summarized review (ubeda2024clinicalpracticeguidelines pages 1-2, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 5-6) | 2024 — Diseases guideline; 2024 adult-management report; 2024 Journal of Clinical Medicine case study | | Key tissues affected | Liver, kidney/renal proximal tubules, and small intestine are key tissues expressing aldolase B and affected in HFI; pregnancy study also notes primary effects in liver and renal tubules (ubeda2024clinicalpracticeguidelines pages 1-2, zuriaga2024descriptiveanalysisof pages 1-2) | 2024 — Diseases guideline; 2024 Healthcare pregnancy study |

Table: This table summarizes standardized nomenclature, core genetic facts, inheritance, prevalence, carrier frequency, common ALDOB variants, and major affected tissues for hereditary fructose intolerance. It is restricted to details explicitly supported by the cited 2024 sources requested by the user.

2. Etiology

2.1 Disease causal factors

Primary cause: germline biallelic pathogenic ALDOB variants causing deficiency of aldolase B activity. (ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4)

Immediate biochemical trigger: ingestion of fructose and fructose-generating sugars/sugar alcohols (sucrose, sorbitol) leading to F1P accumulation. (ubeda2024clinicalpracticeguidelines pages 2-4, garbowski2024acasestudy pages 9-10)

2.2 Risk factors

Genetic: autosomal recessive inheritance; risk increases with parental carrier status. (zuriaga2024descriptiveanalysisof pages 1-2)
Environmental/dietary: exposure to fructose/sucrose/sorbitol (including hidden sources in formulas and medications) triggers acute toxicity and chronic injury. (ubeda2024clinicalpracticeguidelines pages 4-5, ubeda2024clinicalpracticeguidelines pages 2-4)

2.3 Protective factors

Dietary avoidance of fructose/sucrose/sorbitol is protective against acute crises and prevents many complications. (ubeda2024clinicalpracticeguidelines pages 4-5, ubeda2024clinicalpracticeguidelines pages 2-4)
Experimental genetic protection in models: aldolase B knockout mice are protected from toxic fructose effects when fructokinase/KHK is absent (mechanistic rationale supporting KHK inhibition strategy). (koene2025safetyandefficacy pages 1-3)

2.4 Gene–environment interactions

HFI is a prototypical gene–diet interaction: ALDOB deficiency is necessary but clinical toxicity depends on dietary exposure to fructose-containing compounds; however, newer evidence suggests endogenous fructose generation can also drive disease. (andreshernando2024activationofampd2 pages 1-2)

3. Phenotypes

3.1 Core phenotype spectrum (acute and chronic)

Acute manifestations typically appear after introduction of fructose-containing foods (often around weaning) and include vomiting, abdominal pain/distension, and postprandial hypoglycemia, with biochemical abnormalities including lactic/metabolic acidosis, hypophosphatemia, and hyperuricemia. (ubeda2024clinicalpracticeguidelines pages 2-4, ubeda2024clinicalpracticeguidelines pages 5-8, garbowski2024acasestudy pages 9-10)

Chronic manifestations can include hepatic steatosis (fatty liver), persistent transaminase elevation, growth deficiency/failure to thrive, and renal proximal tubular dysfunction/Fanconi syndrome with potential progression to chronic kidney disease. (ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 9-10, ubeda2024clinicalpracticeguidelines pages 5-8)

3.2 Age of onset and temporal development

Typical onset is ~6 months with the introduction of fructose-containing foods. (ubeda2024clinicalpracticeguidelines pages 2-4)
Disease course is lifelong; prognosis is generally favorable with dietary treatment, but chronic complications may persist. (ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4)

3.3 Phenotype frequencies / statistics from recent literature

Hepatic steatosis persistence: one long-term cohort summary reported steatosis persisted in 93.8% of patients on a fructose-restricted diet (<1.5 g/day), and 37.5% had elevated transaminases despite adherence—supporting ongoing morbidity risk. (garbowski2024acasestudy pages 9-10)
Adult cohort symptoms: in one adult cohort, gastrointestinal symptoms occurred in 9/14 and symptomatic hypoglycemia in 7/14, with universal lifelong aversion to sweets/fruit. (biancalana2024hereditaryfructoseintolerance pages 38-40, biancalana2024hereditaryfructoseintolerancea pages 38-40)

3.4 Quality of life impact

While validated QoL instruments are not reported in the retrieved snippets, chronic food avoidance burden, persistent liver disease (steatosis), and renal tubular complications imply significant long-term management impact and need for multidisciplinary follow-up. (garbowski2024acasestudy pages 9-10, ubeda2024clinicalpracticeguidelines pages 2-4)

3.5 Suggested HPO terms (selected)

A phenotype-to-HPO mapping table (restricted to explicitly evidenced features) is provided below.

Phenotype category	Clinical feature	Trigger/onset	Frequency/statistic (if stated)	Suggested HPO terms	Key sources
Acute metabolic / gastrointestinal	Postprandial hypoglycemia	Typically after fructose-containing foods are introduced, often around weaning (~6 months); triggered by fructose/sucrose/sorbitol ingestion	Hypoglycemia threshold cited as blood glucose <0.50 g/L (<2.75 mmol/L); neonatal threshold may be ~0.40 g/L	HP:0001943 Hypoglycemia	(ubeda2024clinicalpracticeguidelines pages 2-4, ubeda2024clinicalpracticeguidelines pages 5-8, garbowski2024acasestudy pages 9-10)
Acute gastrointestinal	Vomiting / nausea after fructose exposure	After intake of fructose or related sugars; commonly at weaning/after introduction of complementary foods	Not quantified	HP:0002013 Vomiting; HP:0002018 Nausea	(ubeda2024clinicalpracticeguidelines pages 1-2, maines2024theroleof pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4)
Acute gastrointestinal	Abdominal distension / abdominal pain	Postprandial after fructose ingestion; may present in infancy or later with food-triggered symptoms	Not quantified	HP:0003270 Abdominal distension; HP:0002027 Abdominal pain	(ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4)
Acute metabolic	Lactic/metabolic acidosis	Consequence of fructose-1-phosphate accumulation with impaired gluconeogenesis/glycogenolysis after fructose exposure	Not quantified	HP:0001942 Metabolic acidosis; HP:0002151 Increased lactate level	(ubeda2024clinicalpracticeguidelines pages 2-4, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 9-10)
Acute biochemical	Hypophosphatemia / phosphate depletion	After fructose ingestion due to intracellular phosphate trapping and ongoing phosphorylation of fructose	Not quantified	HP:0002148 Hypophosphatemia	(ubeda2024clinicalpracticeguidelines pages 2-4, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 9-10, koene2025safetyandefficacy pages 1-3)
Acute biochemical	Hyperuricemia	Secondary to ATP depletion and increased AMP degradation after fructose exposure	Not quantified	HP:0003251 Hyperuricemia	(ubeda2024clinicalpracticeguidelines pages 2-4, garbowski2024acasestudy pages 9-10)
Renal acute/chronic	Proximal renal tubular dysfunction / Fanconi-type syndrome / renal tubular acidosis	May accompany ongoing fructose exposure; due to aldolase B deficiency in proximal tubules	Tubular bicarbonate reabsorption reduction 15–30% reported	HP:0000114 Renal tubular dysfunction; HP:0001992 Fanconi syndrome; HP:0001941 Renal tubular acidosis	(ubeda2024clinicalpracticeguidelines pages 2-4, ubeda2024clinicalpracticeguidelines pages 5-8)
Hepatic acute/chronic	Hepatomegaly / liver dysfunction	Often recognized after introduction of fructose-containing foods; may persist chronically	Not quantified	HP:0002240 Hepatomegaly; HP:0002910 Elevated hepatic transaminases	(ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 9-10, garbowski2024acasestudy pages 7-9)
Hepatic chronic	Hepatic steatosis / fatty liver	Chronic complication despite treatment in some patients; can persist on fructose-restricted diets	Hepatic steatosis persisted in 93.8% in one long-term cohort on fructose-restricted diet	HP:0001397 Hepatic steatosis	(ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 9-10, ubeda2024clinicalpracticeguidelines pages 2-4)
Hepatic chronic	Elevated transaminases	Chronic residual liver dysfunction despite diet in some patients	Elevated transaminases in 37.5% in one long-term cohort	HP:0002910 Elevated hepatic transaminases	(garbowski2024acasestudy pages 9-10)
Growth/nutrition	Failure to thrive / growth retardation	Chronic ingestion after weaning in untreated or incompletely controlled disease	Not quantified	HP:0001508 Failure to thrive; HP:0001510 Growth delay	(maines2024theroleof pages 1-2, ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 5-8)
Behavioral/feeding	Aversion to sweets / fructose-containing foods	Often longstanding from infancy/childhood; key historical clue for diagnosis	In adult cohort, all patients had lifelong aversion to sweet foods/fruit	HP:0033813 Food aversion	(biancalana2024hereditaryfructoseintolerance pages 36-38, biancalana2024hereditaryfructoseintolerance pages 38-40, garbowski2024acasestudy pages 9-10)
Chronic multisystem	Kidney damage / chronic kidney disease	Longer-term complication with continued exposure or incomplete control	Not quantified	HP:0000083 Renal insufficiency; HP:0012622 Chronic kidney disease	(andreshernando2024activationofampd2 pages 1-2, maines2024theroleof pages 1-2, garbowski2024acasestudy pages 9-10)
Severe acute / neurologic	Seizures, coma, life-threatening decompensation	Severe untreated exposure with profound hypoglycemia/metabolic derangement	Not quantified	HP:0001250 Seizure; HP:0001259 Coma	(biancalana2024hereditaryfructoseintolerancea pages 36-38, andreshernando2024activationofampd2 pages 1-2)
Chronic gastrointestinal	Irritable bowel syndrome–like symptoms / chronic abdominal complaints	Reported as chronic complication despite treatment in some patients	Not quantified	HP:0002027 Abdominal pain; HP:0002014 Diarrhea; HP:0012531 Chronic gastrointestinal discomfort	(ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 11-12)
Biomarker / glycosylation	Abnormal carbohydrate-deficient transferrin (CDT) / abnormal sialotransferrin isoforms	Untreated patients; proposed for monitoring dietary fructose/sucrose/sorbitol exposure and individual tolerance	Not quantified in excerpt; described as abnormal Tf glycosylation suggestive of N-hypoglycosylation	HP:0012125 Abnormal transferrin glycosylation	(maines2024theroleof pages 1-2, ubeda2024clinicalpracticeguidelines pages 4-5, garbowski2024acasestudy pages 9-10)
Pregnancy-associated observations	Lower infant birth weight in affected mothers; persistent maternal hepatic steatosis/adenomas/hemangiomas after pregnancy	In women with HFI during/after pregnancy	Babies of affected mothers had lower weights than babies of carrier mothers; cohort included 30 women and 45 pregnancies	HP:0001518 Small for gestational age; HP:0001402 Hepatic fibrosis/structural liver abnormality (approximate liver phenotype mapping)	(zuriaga2024descriptiveanalysisof pages 1-2, zuriaga2024descriptiveanalysisof pages 5-7)
Emerging complication spectrum / mechanistic model	NASH, cirrhosis, liver inflammation/fibrosis in model systems and reported chronic human complication spectrum	Chronic disease/continued metabolic stress; mechanistic evidence from aldob-deficient mice	Not quantified in excerpt	HP:0001394 Cirrhosis; HP:0012844 Liver fibrosis; HP:0001399 Hepatic failure	(andreshernando2024activationofampd2 pages 1-2)

Table: This table summarizes the major acute and chronic phenotypes of hereditary fructose intolerance, their typical triggers or age of onset, key laboratory/biomarker findings, and suggested HPO mappings. It is restricted to points explicitly supported in the cited 2024-focused evidence base and includes quantitative findings where reported.

4. Genetic / molecular information

4.1 Causal gene

Gene: ALDOB (aldolase B), located on chromosome 9q22.3 in retrieved sources. (ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 5-6)

4.2 Pathogenic variants (examples supported by evidence)

A systematic review summarized in a 2024 case report analyzed 1,426 alleles across 29 countries and identified 68 distinct ALDOB variants in 85 genotypic combinations. Widely distributed pathogenic variants include: - c.178C>T p.(Arg60Ter) - c.360_363del p.(Asn120LysfsTer32) - c.448G>C p.(Ala150Pro) - c.524C>A p.(Ala175Asp) - c.1005C>G p.(Asn335Lys) It further reported that p.(Ala150Pro) and p.(Ala175Asp) together account for ~68% of alleles, with p.(Ala150Pro) alone ~53% worldwide. (garbowski2024acasestudy pages 5-6)

In a 2024 adult cohort, the most frequent variants were again p.Ala150Pro and p.Ala175Asp, with additional variants including splice variants, duplications, and large deletions. (biancalana2024hereditaryfructoseintolerance pages 38-40, biancalana2024hereditaryfructoseintolerancea pages 38-40)

4.3 Functional consequence

ALDOB deficiency results in inability to cleave F1P, driving accumulation of F1P and secondary metabolic toxicity (phosphate/ATP depletion and impaired gluconeogenesis/glycogenolysis). (ubeda2024clinicalpracticeguidelines pages 2-4, biancalana2024hereditaryfructoseintolerancea pages 36-38)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities were explicitly supported in the retrieved evidence snippets; these remain a knowledge gap in the current evidence set.

5. Environmental information

5.1 Environmental/lifestyle contributors

For HFI, the key non-genetic contributor is dietary exposure to fructose-containing ingredients and sugar alcohols. - Hidden fructose/sorbitol sources in infant formulas and OTC medicines are specifically flagged as under-recognized exposure risks in guidelines. (ubeda2024clinicalpracticeguidelines pages 4-5)

5.2 Infectious agents

Not applicable; HFI is not infectious.

6. Mechanism / pathophysiology

6.1 Canonical biochemical mechanism (current consensus)

Dietary fructose is phosphorylated by fructokinase (KHK) to fructose-1-phosphate (F1P). In normal physiology, aldolase B cleaves F1P; in HFI, aldolase B deficiency causes F1P accumulation, which: - traps inorganic phosphate (Pi) and depletes ATP, - inhibits glycogenolysis and gluconeogenesis, - triggers hypoglycemia and metabolic derangements, and - contributes to liver and kidney toxicity, including proximal tubular dysfunction. (ubeda2024clinicalpracticeguidelines pages 2-4, biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 9-10)

6.2 Recent mechanistic developments (2023–2024)

(i) Endogenous fructose hypothesis: A 2024 mechanistic study emphasizes that even with dietary restriction, symptoms may persist because fructose can be produced endogenously from glucose (polyol pathway), which can then feed into the toxic pathway in aldolase B deficiency. (andreshernando2024activationofampd2 pages 1-2)

(ii) AMPD2/purine degradation axis: A 2024 Communications Biology study identified AMPD2 activation and downstream purine degradation as a critical pathway activated by very low fructose exposure “via a phosphate trap,” contributing to metabolic dysregulation and liver disease. Hepatocyte-specific AMPD2 deletion improved hepatic fat/glycogen storage and reduced inflammation/fibrosis in aldob-deficient mice, without preventing F1P accumulation or hypoglycemia risk. (andreshernando2024activationofampd2 pages 1-2)

Key mechanistic figure (AMPD2 pathway): The figure below schematizes the phosphate-trap mechanism and the AMPD2-driven purine degradation pathway in aldolase B deficiency. (andreshernando2024activationofampd2 media 8a89ee1b)

6.3 Pathway and ontology suggestions

GO (biological process) candidate terms (suggested based on mechanism described in sources): fructose metabolic process; gluconeogenesis; glycogen catabolic process; purine nucleotide catabolic process; regulation of cellular phosphate ion homeostasis. (ubeda2024clinicalpracticeguidelines pages 2-4, andreshernando2024activationofampd2 pages 1-2)
Cell types (Cell Ontology, suggested): hepatocyte; enterocyte; renal proximal tubule epithelial cell. (koene2025safetyandefficacy pages 1-3)

7. Anatomical structures affected

7.1 Organ/tissue involvement

Key affected tissues are those expressing mutant aldolase B: - Liver (hepatocyte injury; steatosis; possible progression to NASH/cirrhosis) - Small intestine (enterocytes) - Kidney (proximal tubules; Fanconi-type dysfunction) (koene2025safetyandefficacy pages 1-3, ubeda2024clinicalpracticeguidelines pages 5-8)

Suggested UBERON terms (examples): liver; kidney; renal proximal tubule; small intestine. (koene2025safetyandefficacy pages 1-3)

8. Temporal development

Onset: typically after weaning (~6 months) when fructose-containing foods are introduced; can be missed and diagnosed in adulthood due to dietary self-restriction and nonspecific chronic liver findings. (ubeda2024clinicalpracticeguidelines pages 2-4, biancalana2024hereditaryfructoseintolerance pages 38-40)
Course: can be episodic (triggered by accidental ingestion) and/or chronic (fatty liver, renal tubular dysfunction). Prognosis is generally favorable with strict diet, but chronic pathology can persist. (ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 9-10)

9. Inheritance and population

9.1 Inheritance

Autosomal recessive. (ubeda2024clinicalpracticeguidelines pages 1-2, zuriaga2024descriptiveanalysisof pages 1-2)

9.2 Epidemiology (recent summaries)

Prevalence estimates vary by source: - ~1/10,000 worldwide (adult-management report). (biancalana2024hereditaryfructoseintolerancea pages 36-38) - ~1/20,000 and also ~1/10,000 reported in a 2024 guideline. (ubeda2024clinicalpracticeguidelines pages 1-2) - ~1/26,000 live births in Europe and 1/20,000 births in the US reported in a 2024 systematic review. (maines2024theroleof pages 1-2)

9.3 Carrier frequency

A 2024 pregnancy-focused cohort paper reports predicted heterozygous carrier frequency ranging from 1:55 to 1:122. (zuriaga2024descriptiveanalysisof pages 1-2)

9.4 Population/variant distribution

Common variants p.Ala150Pro and p.Ala175Asp are described as globally distributed with regional patterns in Europe, and a summarized allele study indicates these variants dominate worldwide allele counts. (ubeda2024clinicalpracticeguidelines pages 1-2, garbowski2024acasestudy pages 5-6)

10. Diagnostics

10.1 Clinical suspicion

Key historical clue: lifelong or early childhood aversion to sweets and fruit, with symptom onset after fructose exposure; chronic presentations may be unexplained hepatomegaly, elevated aminotransferases, or fatty liver. (biancalana2024hereditaryfructoseintolerancea pages 36-38, garbowski2024acasestudy pages 7-9)

10.2 Laboratory abnormalities (supportive)

Supportive findings include: - hypoglycemia (threshold <0.50 g/L), - lactic/metabolic acidosis, - hypophosphatemia, - hyperuricemia, - transaminase elevations, - Fanconi-type proximal tubular dysfunction (e.g., phosphaturia, aminoaciduria, bicarbonate wasting). (ubeda2024clinicalpracticeguidelines pages 5-8, garbowski2024acasestudy pages 9-10, biancalana2024hereditaryfructoseintolerancea pages 36-38)

10.3 Genetic testing strategy (recommended)

Clinical guidelines favor molecular diagnosis: ALDOB testing (PCR/sequencing on leukocyte DNA) to detect biallelic pathogenic variants as the preferred confirmatory test. (ubeda2024clinicalpracticeguidelines pages 2-4)

10.4 Historical/confirmatory tests and safety

Liver biopsy with aldolase B activity is historically definitive but invasive; reserved for inconclusive genetic results or uncertain variants. (ubeda2024clinicalpracticeguidelines pages 2-4)
Fructose loading/tolerance testing is now rarely used / discouraged due to risk of severe reactions. (ubeda2024clinicalpracticeguidelines pages 2-4, souza2024intolerânciahereditáriaà pages 4-5)

10.5 Adjunct / monitoring biomarkers

Urinary fructose by thin-layer chromatography (TLC) can be used to monitor adherence. (biancalana2024hereditaryfructoseintolerancea pages 36-38)
Carbohydrate-deficient transferrin (CDT) / sialotransferrin isoforms: untreated patients show abnormal transferrin glycosylation (N-hypoglycosylation pattern). Methods include Tf isoelectric focusing and high-resolution MS; CDT metrics may correlate with fructose intake and support monitoring/personalized tolerability targets. (maines2024theroleof pages 1-2, ubeda2024clinicalpracticeguidelines pages 4-5)

10.6 Screening

Newborn screening: generally not performed because there is no reliable biomarker in dried blood spots without fructose exposure; normal newborn screens may occur in affected infants. (ubeda2024clinicalpracticeguidelines pages 2-4, garbowski2024acasestudy pages 9-10)
Cascade screening: recommended after proband identification; prenatal and preimplantation genetic testing are advised as options. (souza2024intolerânciahereditáriaà pages 4-5)

11. Outcome / prognosis

11.1 Prognosis with treatment

Guidelines describe favorable prognosis with strict diet adherence, including normalization of weight and laboratory abnormalities in many patients; however, chronic complications (notably fatty liver) can persist. (ubeda2024clinicalpracticeguidelines pages 1-2, ubeda2024clinicalpracticeguidelines pages 2-4)

11.2 Morbidity (persistent complications)

Long-term cohort summaries indicate persistent hepatic steatosis (93.8%) and continued transaminase elevation (37.5%) despite stringent dietary restriction (<1.5 g/day), suggesting ongoing liver morbidity risk. (garbowski2024acasestudy pages 9-10)

11.3 Pregnancy outcomes

In a 2024 cohort of Spanish women (30 women; 45 pregnancies), affected mothers had lower infant birth weights compared with carrier mothers and persistent hepatic issues (steatosis/adenomas/hemangiomas) were noted after pregnancy, supporting need for monitoring. (zuriaga2024descriptiveanalysisof pages 1-2)

12. Treatment

12.1 Standard of care (real-world implementation)

Dietary treatment is the only established effective therapy in current clinical guidance: - Lifelong FSS-free diet (avoid fructose, sucrose, sorbitol); glucose/maltose/starch are suitable substitutes. (ubeda2024clinicalpracticeguidelines pages 4-5, ubeda2024clinicalpracticeguidelines pages 2-4) - Avoid medications/products containing fructose or sorbitol excipients; hidden sources in infant formulas and OTC baby medicines are specifically highlighted. (ubeda2024clinicalpracticeguidelines pages 4-5)

Quantitative diet thresholds reported: - Restrict total fructose to <40 mg/kg/day (reported in pregnancy cohort context). (zuriaga2024descriptiveanalysisof pages 1-2) - Advice not to exceed 2 g/day fructose (adult cohort recommendation) and some adults may tolerate <6 g/day (guideline). (biancalana2024hereditaryfructoseintolerancea pages 38-40, ubeda2024clinicalpracticeguidelines pages 2-4)

12.2 Acute decompensation management

After accidental ingestion and acute metabolic crisis, recommended management includes hospitalization (ICU if severe) with intravenous glucose (dextrose), treatment of metabolic acidosis if present, and supportive care. (garbowski2024acasestudy pages 6-7)

12.3 Monitoring and supportive care

Periodic follow-up from childhood to adulthood is recommended; chronic liver fat can persist and warrants surveillance. (ubeda2024clinicalpracticeguidelines pages 11-12)
Vitamin deficiency risk (e.g., vitamin C) is noted and supplementation may be needed. (ubeda2024clinicalpracticeguidelines pages 2-4)

12.4 Experimental / advanced therapeutics

KHK inhibition (pharmacologic fructokinase inhibition) aims to block fructose phosphorylation and prevent F1P formation. - A clinical trial record describes an open-label pilot in HFI using PF‑06835919 (300 mg daily × 9 days), with endpoints assessing intestinal symptoms, serum glucose/phosphate, urine markers, liver fat by 1H‑MRS, and glycosylated transferrin (ClinicalTrials.gov NCT06089265, registry year 2023). (NCT06089265 chunk 1) - A clinical study report (JCI, Feb 2025; doi:10.1172/jci187376) describes graded fructose challenges in 3 HFI patients after PF‑06835919, with reported short-term tolerability and absence of proximal tubular dysfunction during challenges. (koene2025safetyandefficacy pages 1-3)

Mechanism-guided targets (preclinical): AMPD2/purine degradation axis and phosphate homeostasis interventions are proposed based on mouse-model work. (andreshernando2024activationofampd2 pages 5-7, andreshernando2024activationofampd2 pages 1-2)

12.5 MAXO term suggestions (examples)

Dietary fructose restriction / dietary sucrose restriction / dietary sorbitol restriction (FSS-free diet)
Intravenous dextrose administration (acute crisis)
Genetic counseling / carrier testing / prenatal genetic testing

(MAXO identifiers are not provided in the retrieved sources; the above are term suggestions for ontology mapping.)

12.6 CHEBI term suggestions (examples)

Fructose; sucrose; sorbitol; glucose; uric acid; fructose-1-phosphate

13. Prevention

Primary prevention is largely genetic/dietary: - Avoidance of fructose/sucrose/sorbitol exposure in diagnosed individuals, including careful checking of drug excipients and infant formula composition. (ubeda2024clinicalpracticeguidelines pages 4-5) - Genetic counseling and cascade carrier testing for families after identification of an affected proband; prenatal and preimplantation genetic testing are suggested options. (souza2024intolerânciahereditáriaà pages 4-5)

Secondary prevention: - Early diagnosis through recognition of weaning-associated symptoms and immediate withdrawal of fructose/sucrose with rapid improvement (2–3 days) supports early case finding. (ubeda2024clinicalpracticeguidelines pages 2-4)

Tertiary prevention: - Long-term monitoring for liver steatosis and renal tubular complications even with dietary adherence. (garbowski2024acasestudy pages 9-10, ubeda2024clinicalpracticeguidelines pages 5-8)

14. Other species / natural disease

No naturally occurring non-human HFI cases were identified in the retrieved evidence set.

15. Model organisms

Mechanistic studies in aldolase B–deficient (aldob−/−) mice recapitulate key features of HFI and are used to investigate drivers of liver disease and metabolic dysregulation. - A 2024 study shows very low fructose activates AMPD2 via phosphate trapping, and hepatocyte-specific AMPD2 deletion reduces liver pathology in aldolase B deficiency. (andreshernando2024activationofampd2 pages 1-2)

Model utility: mechanistic dissection of hepatic fat/glycogen dysregulation and identification of drug targets (AMPD2 axis; phosphate homeostasis; fructose metabolism inhibition). (andreshernando2024activationofampd2 pages 1-2)

Direct abstract quotes supporting key claims (from retrieved abstracts)

AMPD2 mechanism (2024): “Very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap.” (Communications Biology, Jul 2024; doi:10.1038/s42003-024-06539-1) (andreshernando2024activationofampd2 pages 1-2)
Sialotransferrin/CDT review (2024): “Subjects with HFI usually present at the time of weaning with episodes of hypoglycaemia and vomiting after the intake of fructose or related sugars,” and management is “fructose-, sucrose-, and sorbitol (FSS)-restrictive life-long diet.” (J Diabetes Metab Disord, online 2024-12-27; doi:10.1007/s40200-024-01527-y) (maines2024theroleof pages 1-2)
Guideline definition (2024): HFI is “an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene.” (Diseases, published 2024-02-23; doi:10.3390/diseases12030044) (ubeda2024clinicalpracticeguidelines pages 1-2)

Notes on evidence gaps vs. requested template

MONDO, Orphanet, ICD, and MeSH identifiers were not present in the retrieved text chunks; these should be pulled from dedicated ontologies/databases (e.g., MONDO/Orphanet/MeSH/ICD) in a subsequent retrieval pass.
PMIDs: Several 2024 MDPI articles and the adult-management report excerpts did not include PMIDs in the retrieved text snippets; DOIs/URLs and publication dates are provided where available.
Multi-omics (transcriptomics/proteomics/metabolomics) in humans: not covered in the retrieved excerpts.

Key recent sources (URLs and dates)

Úbeda F, et al. Diseases (published 2024-02-23). “Clinical Practice Guidelines for the Diagnosis and Management of Hereditary Fructose Intolerance.” https://doi.org/10.3390/diseases12030044 (ubeda2024clinicalpracticeguidelines pages 1-2)
Andres-Hernando A, et al. Communications Biology (Jul 2024). “Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance.” https://doi.org/10.1038/s42003-024-06539-1 (andreshernando2024activationofampd2 pages 1-2)
Maines E, et al. J Diabetes Metab Disord (online 2024-12-27). “The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review.” https://doi.org/10.1007/s40200-024-01527-y (maines2024theroleof pages 1-2)
Garbowski L, et al. J Clin Med (published 2024-06-10). “A Case Study of a Rare Disease (Fructosemia) Diagnosed in a Patient with Abdominal Pain.” https://doi.org/10.3390/jcm13123394 (garbowski2024acasestudy pages 1-2)
Zuriaga E, et al. Healthcare (Feb 2024). “Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy.” https://doi.org/10.3390/healthcare12050573 (zuriaga2024descriptiveanalysisof pages 1-2)
ClinicalTrials.gov (registry record 2023). “Ketohexokinase Inhibition in Hereditary Fructose Intolerance.” NCT06089265. https://clinicaltrials.gov/study/NCT06089265 (NCT06089265 chunk 1)

References

(andreshernando2024activationofampd2 pages 1-2): Ana Andres-Hernando, David J. Orlicky, Masanari Kuwabara, Mehdi A. Fini, Dean R. Tolan, Richard J. Johnson, and Miguel A. Lanaspa. Activation of ampd2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance. Communications Biology, Jul 2024. URL: https://doi.org/10.1038/s42003-024-06539-1, doi:10.1038/s42003-024-06539-1. This article has 2 citations and is from a peer-reviewed journal.
(ubeda2024clinicalpracticeguidelines pages 1-2): Félix Úbeda, Sonia Santander, and María José Luesma. Clinical practice guidelines for the diagnosis and management of hereditary fructose intolerance. Diseases, 12:44, Feb 2024. URL: https://doi.org/10.3390/diseases12030044, doi:10.3390/diseases12030044. This article has 11 citations.
(ubeda2024clinicalpracticeguidelines pages 2-4): Félix Úbeda, Sonia Santander, and María José Luesma. Clinical practice guidelines for the diagnosis and management of hereditary fructose intolerance. Diseases, 12:44, Feb 2024. URL: https://doi.org/10.3390/diseases12030044, doi:10.3390/diseases12030044. This article has 11 citations.
(garbowski2024acasestudy pages 9-10): Leszek Garbowski, Marzena Walasek, Rafał Firszt, Ewelina Chilińska-Kopko, Paulina Błażejewska-Gała, Daniel Popielnicki, and Zofia Dzięcioł-Anikiej. A case study of a rare disease (fructosemia) diagnosed in a patient with abdominal pain. Journal of Clinical Medicine, 13:3394, Jun 2024. URL: https://doi.org/10.3390/jcm13123394, doi:10.3390/jcm13123394. This article has 3 citations.
(ubeda2024clinicalpracticeguidelines pages 4-5): Félix Úbeda, Sonia Santander, and María José Luesma. Clinical practice guidelines for the diagnosis and management of hereditary fructose intolerance. Diseases, 12:44, Feb 2024. URL: https://doi.org/10.3390/diseases12030044, doi:10.3390/diseases12030044. This article has 11 citations.
(NCT06089265 chunk 1): Ketohexokinase Inhibition in Hereditary Fructose Intolerance. Maastricht University Medical Center. 2023. ClinicalTrials.gov Identifier: NCT06089265
(biancalana2024hereditaryfructoseintolerancea pages 36-38): E BIANCALANA and C PISTOLESI. Hereditary fructose intolerance in adults: from differential diagnosis to long-term management. a report from the …. Unknown journal, 2024.
(garbowski2024acasestudy pages 5-6): Leszek Garbowski, Marzena Walasek, Rafał Firszt, Ewelina Chilińska-Kopko, Paulina Błażejewska-Gała, Daniel Popielnicki, and Zofia Dzięcioł-Anikiej. A case study of a rare disease (fructosemia) diagnosed in a patient with abdominal pain. Journal of Clinical Medicine, 13:3394, Jun 2024. URL: https://doi.org/10.3390/jcm13123394, doi:10.3390/jcm13123394. This article has 3 citations.
(zuriaga2024descriptiveanalysisof pages 1-2): Estefanía Zuriaga, Sonia Santander, Laura Lomba, Elsa Izquierdo-García, and María José Luesma. Descriptive analysis of carrier and affected hereditary fructose intolerance in women during pregnancy. Healthcare, 12:573, Feb 2024. URL: https://doi.org/10.3390/healthcare12050573, doi:10.3390/healthcare12050573. This article has 1 citations.
(maines2024theroleof pages 1-2): Evelina Maines, Giorgia Gugelmo, Arianna Maiorana, Diego Martinelli, Nicola Vitturi, Livia Lenzini, Giovanni Piccoli, Massimo Soffiati, and Roberto Franceschi. The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review. Journal of diabetes and metabolic disorders, 24 1:27, Dec 2024. URL: https://doi.org/10.1007/s40200-024-01527-y, doi:10.1007/s40200-024-01527-y. This article has 0 citations and is from a peer-reviewed journal.
(koene2025safetyandefficacy pages 1-3): Evi J.C. Koene, Amée M. Buziau, David Cassiman, Timothy M. Cox, Judith Bons, Jean L. J. M. Scheijen, Casper G. Schalkwijk, Steven J.R. Meex, Aditi R. Saxena, William P. Esler, Vera B. Schrauwen-Hinderling, Patrick Schrauwen, and Martijn C.G.J. Brouwers. Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance. The Journal of Clinical Investigation, Feb 2025. URL: https://doi.org/10.1172/jci187376, doi:10.1172/jci187376. This article has 7 citations.
(ubeda2024clinicalpracticeguidelines pages 5-8): Félix Úbeda, Sonia Santander, and María José Luesma. Clinical practice guidelines for the diagnosis and management of hereditary fructose intolerance. Diseases, 12:44, Feb 2024. URL: https://doi.org/10.3390/diseases12030044, doi:10.3390/diseases12030044. This article has 11 citations.
(biancalana2024hereditaryfructoseintolerance pages 38-40): E BIANCALANA and C PISTOLESI. Hereditary fructose intolerance in adults: from differential diagnosis to long-term management. a report from the …. Unknown journal, 2024.
(biancalana2024hereditaryfructoseintolerancea pages 38-40): E BIANCALANA and C PISTOLESI. Hereditary fructose intolerance in adults: from differential diagnosis to long-term management. a report from the …. Unknown journal, 2024.
(garbowski2024acasestudy pages 7-9): Leszek Garbowski, Marzena Walasek, Rafał Firszt, Ewelina Chilińska-Kopko, Paulina Błażejewska-Gała, Daniel Popielnicki, and Zofia Dzięcioł-Anikiej. A case study of a rare disease (fructosemia) diagnosed in a patient with abdominal pain. Journal of Clinical Medicine, 13:3394, Jun 2024. URL: https://doi.org/10.3390/jcm13123394, doi:10.3390/jcm13123394. This article has 3 citations.
(biancalana2024hereditaryfructoseintolerance pages 36-38): E BIANCALANA and C PISTOLESI. Hereditary fructose intolerance in adults: from differential diagnosis to long-term management. a report from the …. Unknown journal, 2024.
(ubeda2024clinicalpracticeguidelines pages 11-12): Félix Úbeda, Sonia Santander, and María José Luesma. Clinical practice guidelines for the diagnosis and management of hereditary fructose intolerance. Diseases, 12:44, Feb 2024. URL: https://doi.org/10.3390/diseases12030044, doi:10.3390/diseases12030044. This article has 11 citations.
(zuriaga2024descriptiveanalysisof pages 5-7): Estefanía Zuriaga, Sonia Santander, Laura Lomba, Elsa Izquierdo-García, and María José Luesma. Descriptive analysis of carrier and affected hereditary fructose intolerance in women during pregnancy. Healthcare, 12:573, Feb 2024. URL: https://doi.org/10.3390/healthcare12050573, doi:10.3390/healthcare12050573. This article has 1 citations.
(andreshernando2024activationofampd2 media 8a89ee1b): Ana Andres-Hernando, David J. Orlicky, Masanari Kuwabara, Mehdi A. Fini, Dean R. Tolan, Richard J. Johnson, and Miguel A. Lanaspa. Activation of ampd2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance. Communications Biology, Jul 2024. URL: https://doi.org/10.1038/s42003-024-06539-1, doi:10.1038/s42003-024-06539-1. This article has 2 citations and is from a peer-reviewed journal.
(souza2024intolerânciahereditáriaà pages 4-5): RF de Souza, RP Erdmann, and NB Ferreira. Intolerância hereditária à frutose: etiologia e principais características clínicas. Unknown journal, 2024.
(garbowski2024acasestudy pages 6-7): Leszek Garbowski, Marzena Walasek, Rafał Firszt, Ewelina Chilińska-Kopko, Paulina Błażejewska-Gała, Daniel Popielnicki, and Zofia Dzięcioł-Anikiej. A case study of a rare disease (fructosemia) diagnosed in a patient with abdominal pain. Journal of Clinical Medicine, 13:3394, Jun 2024. URL: https://doi.org/10.3390/jcm13123394, doi:10.3390/jcm13123394. This article has 3 citations.
(andreshernando2024activationofampd2 pages 5-7): Ana Andres-Hernando, David J. Orlicky, Masanari Kuwabara, Mehdi A. Fini, Dean R. Tolan, Richard J. Johnson, and Miguel A. Lanaspa. Activation of ampd2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance. Communications Biology, Jul 2024. URL: https://doi.org/10.1038/s42003-024-06539-1, doi:10.1038/s42003-024-06539-1. This article has 2 citations and is from a peer-reviewed journal.
(garbowski2024acasestudy pages 1-2): Leszek Garbowski, Marzena Walasek, Rafał Firszt, Ewelina Chilińska-Kopko, Paulina Błażejewska-Gała, Daniel Popielnicki, and Zofia Dzięcioł-Anikiej. A case study of a rare disease (fructosemia) diagnosed in a patient with abdominal pain. Journal of Clinical Medicine, 13:3394, Jun 2024. URL: https://doi.org/10.3390/jcm13123394, doi:10.3390/jcm13123394. This article has 3 citations.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Hereditary Fructose Intolerance (HFI): comprehensive disease characteristics report (2023–2024 prioritized)

Executive summary

1. Disease information

1.1 Definition and overview

1.2 Key identifiers (with availability in retrieved sources)

1.3 Synonyms and alternative names

1.4 Evidence sources and aggregation level

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype spectrum (acute and chronic)

3.2 Age of onset and temporal development

3.3 Phenotype frequencies / statistics from recent literature

3.4 Quality of life impact

3.5 Suggested HPO terms (selected)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (examples supported by evidence)

4.3 Functional consequence

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

5.1 Environmental/lifestyle contributors

5.2 Infectious agents

6. Mechanism / pathophysiology

6.1 Canonical biochemical mechanism (current consensus)

6.2 Recent mechanistic developments (2023–2024)

6.3 Pathway and ontology suggestions

7. Anatomical structures affected

7.1 Organ/tissue involvement

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology (recent summaries)

9.3 Carrier frequency

9.4 Population/variant distribution

10. Diagnostics

10.1 Clinical suspicion

10.2 Laboratory abnormalities (supportive)

10.3 Genetic testing strategy (recommended)

10.4 Historical/confirmatory tests and safety

10.5 Adjunct / monitoring biomarkers

10.6 Screening

11. Outcome / prognosis

11.1 Prognosis with treatment