Hereditary fructose intolerance

Summary

Hereditary fructose intolerance (MONDO:0009249) is a disease caused by ALDOB (GenCC Definitive), with 2 cohort genes and 10 clinical trials. Top therapeutic interventions include alanine.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: ALDOB (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 524
• Phenotypes (HPO): 24
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5	Europe	Validated
Point prevalence	1-9 / 100 000		Switzerland	Validated
Point prevalence	1-9 / 100 000		Germany	Validated
Point prevalence	1-9 / 100 000	3.2	Poland	Validated
Point prevalence	1-9 / 1 000 000	0.753	United States	Validated
Point prevalence	1-9 / 1 000 000	0.38	Specific population	Validated
Point prevalence	1-9 / 1 000 000	0.1981	China	Validated
Prevalence at birth	1-9 / 100 000	5	Switzerland	Validated
Prevalence at birth	1-9 / 100 000	3.8	Germany	Validated
Point prevalence	1-9 / 100 000		United Kingdom	Not yet validated
Point prevalence	1-9 / 100 000	7.5	Finland	Not yet validated
Prevalence at birth	1-9 / 100 000	5	United Kingdom	Not yet validated
Prevalence at birth	1-9 / 100 000		Poland	Not yet validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0012545	Reduced aldolase level	Very frequent (80-99%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001069	Episodic hyperhidrosis	Occasional (5-29%)
HP:0001942	Metabolic acidosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002148	Hypophosphatemia	Occasional (5-29%)
HP:0002149	Hyperuricemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002918	Hypermagnesemia	Occasional (5-29%)
HP:0003256	Abnormality of the coagulation cascade	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0012051	Reactive hypoglycemia	Occasional (5-29%)
HP:0012622	Chronic kidney disease	Occasional (5-29%)
HP:0100626	Chronic hepatic failure	Occasional (5-29%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001254	Lethargy	Very rare (<1-4%)
HP:0001259	Coma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary fructose intolerance
Mondo ID	MONDO:0009249
OMIM	229600
Orphanet	469
DOID	DOID:9869
ICD-10-CM	E74.12
ICD-11	1925240365
NCIT	C84720
SNOMED CT	20052008
UMLS	C0016751
MedGen	42105
GARD	0006622
MedDRA	10019878
NORD	1166
Is cancer (heuristic)	no

Also known as: Fructosaemia · fructose intolerance · Fructose Intolerance, Hereditary · fructose intolerance, hereditary · fructose-1,6-bisphosphate aldolase B deficiency · fructosemia · hereditary fructose intolerance · hereditary fructose intolerance syndrome · hereditary fructose-1-phosphate aldolase deficiency · hereditary fructosemia

Data availability: 524 ClinVar variants · 7 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of fructose metabolism › hereditary fructose intolerance

Related subtypes (2): essential fructosuria, acquired fructose intolerance

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

524 retrieved; paginated sample, class counts are floors:

233 likely benign, 92 uncertain significance, 72 likely pathogenic, 51 pathogenic, 28 pathogenic/likely pathogenic, 28 conflicting classifications of pathogenicity, 16 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065849	NM_000035.4(ALDOB):c.331C>T (p.Gln111Ter)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1065850	NM_000035.4(ALDOB):c.403T>C (p.Cys135Arg)	ALDOB	Pathogenic	no assertion criteria provided
1065851	NM_000035.4(ALDOB):c.469C>T (p.Gln157Ter)	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065855	NM_000035.4(ALDOB):c.770T>C (p.Leu257Pro)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1065867	NM_000035.4(ALDOB):c.841_842del (p.Thr281fs)	ALDOB	Pathogenic	criteria provided, single submitter
1065871	NM_000035.4(ALDOB):c.761dup (p.Thr255fs)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1065872	NM_000035.4(ALDOB):c.1000-1_1006delinsTG	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065878	NM_000035.4(ALDOB):c.799+2T>A	ALDOB	Pathogenic	criteria provided, single submitter
1066407	NM_000035.4(ALDOB):c.949_950insCAGGGCCCGTGCACTGGCTGCCTGGGGTGGCA (p.Lys317fs)	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066749	NM_000035.4(ALDOB):c.379+1G>T	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069392	NM_000035.4(ALDOB):c.607C>T (p.Gln203Ter)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1071688	NM_000035.4(ALDOB):c.325-1G>T	ALDOB	Pathogenic	criteria provided, single submitter
1073061	NC_000009.11:g.(?104188817)(104193189_?)del	ALDOB	Pathogenic	criteria provided, single submitter
1073062	NC_000009.11:g.(?104188827)(104193169_?)del	ALDOB	Pathogenic	criteria provided, single submitter
1379379	NM_000035.4(ALDOB):c.227dup (p.Val77fs)	ALDOB	Pathogenic	criteria provided, single submitter
1410748	NM_000035.4(ALDOB):c.61C>T (p.Gln21Ter)	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1438416	NM_000035.4(ALDOB):c.149_155dup (p.Glu53fs)	ALDOB	Pathogenic	criteria provided, single submitter
1451325	NM_000035.4(ALDOB):c.255C>G (p.Tyr85Ter)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1454003	NM_000035.4(ALDOB):c.34C>T (p.Gln12Ter)	ALDOB	Pathogenic	criteria provided, single submitter
1454872	NM_000035.4(ALDOB):c.360del (p.Asn120fs)	ALDOB	Pathogenic	criteria provided, single submitter
1456001	NM_000035.4(ALDOB):c.427del (p.Val143fs)	ALDOB	Pathogenic	criteria provided, single submitter
1513041	NM_000035.4(ALDOB):c.113-1G>C	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675307	NM_000035.4(ALDOB):c.812T>C (p.Leu271Ser)	ALDOB	Pathogenic	criteria provided, single submitter
188739	NM_000035.4(ALDOB):c.1013C>T (p.Ala338Val)	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188779	NM_000035.4(ALDOB):c.324G>A (p.Lys108=)	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188782	NM_000035.4(ALDOB):c.612T>A (p.Tyr204Ter)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
188837	NM_000035.4(ALDOB):c.625-2A>G	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188861	NM_000035.4(ALDOB):c.360_363del (p.Asn120fs)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
188974	NM_000035.4(ALDOB):c.113-1_115del	ALDOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1954703	NM_000035.4(ALDOB):c.539del (p.Gln180fs)	ALDOB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALDOB	Definitive	Autosomal recessive	hereditary fructose intolerance	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDOB	Orphanet:469	Hereditary fructose intolerance
ANO5	Orphanet:206549	Anoctamin-5-related limb-girdle muscular dystrophy R12
ANO5	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
ANO5	Orphanet:399096	Distal anoctaminopathy
ANO5	Orphanet:53697	Gnathodiaphyseal dysplasia
ANO5	Orphanet:689021	Asymptomatic hyperCKemia-myalgia-rhabdomyolysis syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDOB	HGNC:417	ENSG00000136872	P05062	Fructose-bisphosphate aldolase B	gencc,clinvar
ANO5	HGNC:27337	ENSG00000171714	Q75V66	Anoctamin-5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDOB	Fructose-bisphosphate aldolase B	Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesi…
ANO5	Anoctamin-5	Plays a role in plasma membrane repair in a process involving annexins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDOB	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
ANO5	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
nephron tubule	1
right lobe of liver	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDOB	191	tissue_specific	marker	jejunal mucosa, nephron tubule, right lobe of liver
ANO5	220	broad	marker	cardiac muscle of right atrium, left ventricle myocardium, vastus lateralis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDOB	2,036
ANO5	790

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDOB	P05062	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO5	Q75V66	82.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hereditary fructose intolerance	1	5710.0×	0.004	ALDOB
Fructose metabolism	1	1142.0×	0.006	ALDOB
Fructose catabolism	1	1142.0×	0.006	ALDOB
Glucose metabolism	1	439.2×	0.009	ALDOB
Induction of Cell-Cell Fusion	1	439.2×	0.009	ANO5
Diseases of carbohydrate metabolism	1	407.9×	0.009	ALDOB
Gluconeogenesis	1	219.6×	0.014	ALDOB
Late SARS-CoV-2 Infection Events	1	146.4×	0.015	ANO5
Glycolysis	1	142.8×	0.015	ALDOB
Disease	2	13.1×	0.015	ALDOB, ANO5
Regulation of clotting cascade	1	116.5×	0.016	ANO5
Stimuli-sensing channels	1	68.0×	0.026	ANO5
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.027	ALDOB
Ion channel transport	1	48.0×	0.031	ANO5
Diseases of metabolism	1	40.2×	0.032	ALDOB
SARS-CoV-2 Infection	1	40.2×	0.032	ANO5
SARS-CoV Infections	1	27.7×	0.044	ANO5
Viral Infection Pathways	1	15.4×	0.075	ANO5
Transport of small molecules	1	12.6×	0.083	ANO5
Infectious disease	1	12.4×	0.083	ANO5
Metabolism	1	5.8×	0.165	ALDOB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of pentose-phosphate shunt	1	4213.0×	0.002	ALDOB
obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate	1	2808.7×	0.002	ALDOB
vacuolar proton-transporting V-type ATPase complex assembly	1	1404.3×	0.002	ALDOB
fructose 1,6-bisphosphate metabolic process	1	1053.2×	0.002	ALDOB
fructose metabolic process	1	842.6×	0.002	ALDOB
plasma membrane repair	1	290.6×	0.006	ANO5
glycolytic process	1	191.5×	0.007	ALDOB
gluconeogenesis	1	162.0×	0.008	ALDOB
chloride transmembrane transport	1	118.7×	0.009	ANO5
monoatomic ion transmembrane transport	1	104.0×	0.010	ANO5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDOB	0	0
ANO5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDOB	4.1.2.13	fructose-bisphosphate aldolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDOB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANO5

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDOB	0	—
ANO5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01185210	Not specified	UNKNOWN	Investigation of Alanine in Fructose Intolerance: A Dose Ranging Study
NCT01705171	Not specified	COMPLETED	Is the Expression of the GLUT5 Specific Fructose Transport Protein Abnormal in Patients With Fructose Intolerance?
NCT02085889	Not specified	UNKNOWN	Fructose and Lactose Intolerance and Malabsorption in Functional Gastrointestinal Disorders
NCT02979106	Not specified	COMPLETED	Metabolic Consequences of Heterozygous Hereditary Fructose Intolerance
NCT03261856	Not specified	COMPLETED	Clinical Utility of Breath Tests in GI
NCT03545581	Not specified	COMPLETED	Fructose Supplementation in Carriers for Hereditary Fructose Intolerance
NCT04022434	Not specified	UNKNOWN	Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06044389	Not specified	UNKNOWN	Observational Study on the Safety and Efficacy of the Medical Product Fructosin.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALANINE	3	2