Glucose-Galactose Malabsorption

Mendelian MONDO:0011731 Pathograph 7 Show in embeddings browser Gastrointestinal Disease Inborn error of carbohydrate metabolism

Glucose-galactose malabsorption (GGM) is a rare, potentially lethal, autosomal recessive disorder of intestinal monosaccharide transport caused by biallelic loss-of-function variants in SLC5A1, which encodes the brush-border sodium/glucose cotransporter SGLT1. Loss of SGLT1-mediated active transport abolishes intestinal absorption of glucose and galactose (fructose absorption via the facilitated transporter GLUT5/SLC2A5 is spared), so any glucose-, galactose-, or lactose/sucrose-containing feed produces severe osmotic watery diarrhea from the first days of life, leading to life-threatening dehydration unless the infant is switched to a fructose-based, glucose/galactose-free formula.

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1
Inheritance
5
Pathophys.
7
Phenotypes
7
Pathograph
1
Genes
1
Medical Actions
👪

Inheritance

1
Autosomal Recessive HP:0000007
GGM is an autosomal recessive disease caused by biallelic loss-of-function variants in SLC5A1; the founding family study identified a missense mutation cosegregating with the GGM phenotype.
autosomal recessive inheritance
Show evidence (1 reference)
PMID:2008213 SUPPORT Human Clinical
"Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine."
The original SGLT1-mutation discovery paper establishes GGM as an autosomal recessive disorder.
⚙

Pathophysiology

5
SLC5A1/SGLT1 Loss of Function
Biallelic pathogenic SLC5A1 variants abolish or severely reduce the Na+/glucose(galactose) cotransport activity of SGLT1 in the intestinal brush-border membrane, either through loss of sugar-binding affinity or through defective apical membrane trafficking of the mutant transporter.
enterocyte of epithelium of small intestine CL:1000334 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enterocyte of epithelium of small intestine (CL:1000334). CL:1000334 is a cell type from the Cell Ontology.
SLC5A1 hgnc:11036 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC5A1 (hgnc:11036). hgnc:11036 is a gene from the HUGO Gene Nomenclature Committee.
D-glucose:sodium symporter activity GO:0005412 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased D-glucose:sodium symporter activity (GO:0005412). GO:0005412 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Active Intestinal Glucose/Galactose Absorption Loss of apical SGLT1 activity directly abolishes active transcellular absorption of glucose and galactose by small-intestinal enterocytes.
Show evidence (1 reference)
PMID:2008213 SUPPORT Human Clinical
"Normal glucose absorption is mediated by the Na+/glucose cotransporter in the brush border membrane of the intestinal epithelium. Cellular influx is driven by the transmembrane Na+ electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the..."
Establishes the normal SGLT1-mediated apical Na+/glucose cotransport mechanism that is disrupted in GGM.
Failure of Active Intestinal Glucose/Galactose Absorption
Active transcellular absorption of dietary glucose and galactose (and, following brush-border disaccharidase hydrolysis, the glucose/galactose moieties of lactose, sucrose, and maltose) fails in enterocytes of the small intestine, while facilitated absorption of fructose via GLUT5 (SLC2A5), which is independent of SGLT1, is unaffected.
enterocyte of epithelium of small intestine CL:1000334 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enterocyte of epithelium of small intestine (CL:1000334). CL:1000334 is a cell type from the Cell Ontology.
Downstream
Fructose Absorption Spared (GLUT5) Because GLUT5-mediated fructose transport is independent of SGLT1, fructose absorption remains intact even as glucose/galactose absorption fails, forming the basis for fructose-based dietary substitution.
Osmotic Diarrhea and Dehydration Unabsorbed luminal glucose and galactose, with accompanying sodium and water that are not reabsorbed because cotransport fails, create an osmotic gradient that drives fluid into the intestinal lumen.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"resulting in bloating, cramping, flatulence, and a dose-dependent osmotic diarrhea"
Documents the direct clinical consequences of failed apical glucose/galactose absorption.
Fructose Absorption Spared (GLUT5)
Unlike glucose and galactose, fructose is absorbed across the apical enterocyte membrane by the facilitated transporter GLUT5 (SLC2A5), which is independent of SGLT1 and functions normally in GGM. This selective sparing is the basis for fructose-based dietary management and explains why fructose becomes the primary dietary carbohydrate source for affected patients.
SLC2A5 hgnc:11010 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC2A5 (hgnc:11010). hgnc:11010 is a gene from the HUGO Gene Nomenclature Committee.
fructose transmembrane transporter activity GO:0005353 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves fructose transmembrane transporter activity (GO:0005353). GO:0005353 is a molecular function from the Gene Ontology.
Show evidence (1 reference)
PMID:36673104 SUPPORT Other
"Often, glucose-galactose malabsorption patients are highly dependent on fructose, their primary source of carbohydrates."
Supports that fructose becomes the primary dietary carbohydrate source in GGM because of intact GLUT5-mediated absorption.
Osmotic Diarrhea and Dehydration
Unabsorbed luminal glucose and galactose create an osmotic gradient that draws water into the intestinal lumen, producing severe watery diarrhea (HP:0033310 Osmotic diarrhea) beginning in the neonatal period; continued fluid and electrolyte losses lead to dehydration (HP:0001944), often hypernatremic, and metabolic acidosis if untreated. Diarrhea resolves rapidly on dietary elimination of glucose/galactose and recurs promptly on rechallenge, a pattern used diagnostically to confirm GGM.
Downstream
Dietary Rechallenge Recurrence Symptoms resolve when glucose/galactose is removed from the diet and recur on rechallenge, confirming the diet-dependence of the osmotic mechanism.
Show evidence (1 reference)
PMID:31142420 SUPPORT Human Clinical
"Persistent diarrhea lead to prolonged hospitalisation and recurrent hypernatremic dehydration."
Clinical case demonstrating recurrent hypernatremic dehydration as a consequence of the persistent osmotic diarrhea of GGM.
Dietary Rechallenge Recurrence
Diarrhea resolves rapidly when glucose, galactose, and their disaccharides (lactose, sucrose) are removed from the diet, and recurs promptly on rechallenge with these sugars, a pattern used diagnostically to confirm GGM and distinguish it from other congenital diarrheal disorders.
Show evidence (1 reference)
PMID:31142420 SUPPORT Human Clinical
"Relevant investigations clinched the diagnosis of ''congenital glucose galactose malabsorption (CGGM)''."
Clinical case in which targeted investigation (including dietary response) established the CGGM diagnosis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Glucose-Galactose Malabsorption Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Digestive 1
Abdominal Distension and Bloating FREQUENT Abdominal distention HP:0003270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal distention (HP:0003270). HP:0003270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"resulting in bloating, cramping, flatulence, and a dose-dependent osmotic diarrhea"
Documents bloating/cramping/flatulence as accompanying symptoms of GGM.
Genitourinary 1
Nephrolithiasis OCCASIONAL HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"Although the kidneys are usually unaffected in GGM, impaired renal function associated with nephrolithiasis as a result of chronic dehydration has been documented"
Directly documents nephrolithiasis as a reported renal complication of GGM linked to chronic dehydration.
Growth 1
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31142420 SUPPORT Human Clinical
"He was failing to thrive and wasted."
Clinical case documenting failure to thrive in an affected infant.
Other 4
Neonatal-Onset Watery Diarrhea VERY_FREQUENT Osmotic diarrhea HP:0033310 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osmotic diarrhea (HP:0033310), qualified as neonatal onset. HP:0033310 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:2008213 SUPPORT Human Clinical
"Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine."
Establishes neonatal onset of diarrhea as the cardinal presenting feature.
Dehydration FREQUENT Hypernatremic dehydration HP:0004906 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypernatremic dehydration (HP:0004906). HP:0004906 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31142420 SUPPORT Human Clinical
"Persistent diarrhea lead to prolonged hospitalisation and recurrent hypernatremic dehydration."
Clinical case documenting hypernatremic dehydration as a recurrent complication.
Elevated Stool Reducing Substances HP:6001295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated stool reducing substances (HP:6001295). HP:6001295 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42160565 SUPPORT Human Clinical
"reducing substances 2+"
Directly documents positive stool reducing substances in a genetically confirmed GGM case.
Positive Hydrogen Breath Test HP:6000259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Positive hydrogen breath test (HP:6000259). HP:6000259 is a phenotype from the Human Phenotype Ontology.
Diagnostic breath testing with a glucose or galactose challenge is a standard ancillary tool alongside stool reducing substances and molecular SLC5A1 testing; a normal disaccharidase panel on small-bowel biopsy helps exclude primary disaccharidase deficiencies as an alternative cause of carbohydrate malabsorption.
🧬

Genetic Associations

1
SLC5A1 loss-of-function variants (Causative)
Gene: SLC5A1 hgnc:11036 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC5A1 (hgnc:11036). hgnc:11036 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:2008213 SUPPORT Human Clinical
"Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na(+)-dependent glucose transport in Xenopus oocytes injected with this complementary RNA."
Founding paper identifying SLC5A1/SGLT1 as the causative gene for GGM and demonstrating loss of transport function for the disease-associated missense variant.
PMID:34485913 SUPPORT In Vitro
"Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter."
Demonstrates reduced sugar-binding affinity as one molecular mechanism of SLC5A1 loss of function in GGM, distinct from apical trafficking defects seen in other GGM variants.
💊

Medical Actions

1
Fructose-Based Glucose/Galactose-Free Formula
Category: Therapeutic Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Definitive first-line management is lifelong dietary elimination of glucose, galactose, and their disaccharides (lactose, sucrose, maltose), with fructose substituted as the primary dietary carbohydrate source because fructose absorption via GLUT5 is unaffected. In infancy this is delivered as a fructose-based, carbohydrate-free formula; the diet is progressively liberalized with age as clinical tolerance to small amounts of glucose/galactose develops.
Mechanism Target:
MODULATES Failure of Active Intestinal Glucose/Galactose Absorption — Eliminating dietary glucose/galactose removes the unabsorbed osmotic substrate that drives diarrhea, while fructose substitution exploits the spared GLUT5 pathway to provide dietary carbohydrate.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"The standard of care for patients with GGM is lifelong restriction of dietary glucose and galactose. During infancy, the primary nutrition is a fructose-based formula, either as a Ross Carbohydrate-Free formula (Abbott Nutrition) with fructose supplementation, or a ready-made formula"
Documents the fructose-based, glucose/galactose-free formula as the standard-of-care first-line treatment for GGM.
Show evidence (1 reference)
PMID:31142420 SUPPORT Human Clinical
"an appropriate rational diagnosis can lead to life-saving treatment as depicted in this case report."
Supports that timely diagnosis and initiation of the appropriate carbohydrate-restricted diet is life-saving in GGM.
🔬

Diagnosis

1
Molecular SLC5A1 Genetic Testing
Confirmatory molecular testing for biallelic SLC5A1 variants establishes the diagnosis and distinguishes GGM from other congenital diarrheal disorders and disaccharidase deficiencies.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic SLC5A1 variants.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"All six patients presented with profound diarrhea at birth with a significant improvement after glucose and galactose elimination and were eventually diagnosed with GGM by molecular analysis of the SLC5A1 gene."
Documents molecular SLC5A1 analysis as the diagnostic confirmation method.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
No formal population prevalence estimate is documented; the disorder is described as extremely rare, with approximately several hundred cases diagnosed worldwide in the literature.
Show evidence (1 reference)
PMID:33433815 SUPPORT Human Clinical
"GGM is extremely rare, with approximately several hundred people diagnosed worldwide"
Direct statement of the extreme rarity and approximate worldwide case count of GGM.
Västerbotten County, Northern Sweden
Cases In Literature Not yet documented
A founder Q457R SLC5A1 variant is markedly enriched in this Swedish region relative to general Swedish and European populations, explaining a local cluster of GGM cases traced through a pedigree back to the late 17th century.
Show evidence (1 reference)
PMID:34485913 SUPPORT Human Clinical
"The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden."
Quantifies the founder-variant allele frequency enrichment underlying a regional cluster of GGM cases in Sweden.
{ }

Source YAML

click to show 
name: Glucose-Galactose Malabsorption
creation_date: "2026-07-06T00:00:00Z"
category: Mendelian
synonyms:
- GGM
- CGGM
- Congenital glucose-galactose malabsorption
- SGLT1 deficiency
- Intestinal sodium-glucose cotransporter 1 deficiency
description: >-
  Glucose-galactose malabsorption (GGM) is a rare, potentially lethal,
  autosomal recessive disorder of intestinal monosaccharide transport caused
  by biallelic loss-of-function variants in SLC5A1, which encodes the
  brush-border sodium/glucose cotransporter SGLT1. Loss of SGLT1-mediated
  active transport abolishes intestinal absorption of glucose and galactose
  (fructose absorption via the facilitated transporter GLUT5/SLC2A5 is
  spared), so any glucose-, galactose-, or lactose/sucrose-containing feed
  produces severe osmotic watery diarrhea from the first days of life,
  leading to life-threatening dehydration unless the infant is switched to a
  fructose-based, glucose/galactose-free formula.
disease_term:
  preferred_term: glucose-galactose malabsorption
  term:
    id: MONDO:0011731
    label: glucose-galactose malabsorption
parents:
- Gastrointestinal 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: >-
    GGM is an autosomal recessive disease caused by biallelic loss-of-function
    variants in SLC5A1; the founding family study identified a missense
    mutation cosegregating with the GGM phenotype.
  evidence:
  - reference: PMID:2008213
    reference_title: "Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glucose/galactose malabsorption (GGM) is an autosomal recessive disease
      manifesting within the first weeks of life and characterized by a
      selective failure to absorb dietary glucose and galactose from the
      intestine.
    explanation: >-
      The original SGLT1-mutation discovery paper establishes GGM as an
      autosomal recessive disorder.
genetic:
- name: SLC5A1 loss-of-function variants
  gene_term:
    preferred_term: SLC5A1
    term:
      id: hgnc:11036
      label: SLC5A1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Biallelic SLC5A1 variants (missense, nonsense, frameshift) abolish or
    severely impair SGLT1 Na+/glucose cotransport activity. Some missense
    variants cause loss of sugar-binding affinity while the protein still
    reaches the plasma membrane; most others cause defective trafficking of
    SGLT1 to the brush-border apical membrane.
  evidence:
  - reference: PMID:2008213
    reference_title: "Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the amplified products has revealed a single
      missense mutation in SGLT1 which cosegregates with the GGM phenotype
      and results in a complete loss of Na(+)-dependent glucose transport in
      Xenopus oocytes injected with this complementary RNA.
    explanation: >-
      Founding paper identifying SLC5A1/SGLT1 as the causative gene for GGM
      and demonstrating loss of transport function for the disease-associated
      missense variant.
  - reference: PMID:34485913
    reference_title: "The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Electrophysiological experiments, both steady-state and presteady-state,
      demonstrated that the mutant bound sugar with an affinity lower than the
      WT transporter.
    explanation: >-
      Demonstrates reduced sugar-binding affinity as one molecular mechanism
      of SLC5A1 loss of function in GGM, distinct from apical trafficking
      defects seen in other GGM variants.
pathophysiology:
- name: SLC5A1/SGLT1 Loss of Function
  conforms_to: "diet_induced_osmotic_diarrhea#Loss of a Substrate-Specific Brush-Border Digestive or Absorptive Step"
  description: >-
    Biallelic pathogenic SLC5A1 variants abolish or severely reduce the
    Na+/glucose(galactose) cotransport activity of SGLT1 in the intestinal
    brush-border membrane, either through loss of sugar-binding affinity or
    through defective apical membrane trafficking of the mutant transporter.
  genes:
  - preferred_term: SLC5A1
    term:
      id: hgnc:11036
      label: SLC5A1
  cell_types:
  - preferred_term: enterocyte of epithelium of small intestine
    term:
      id: CL:1000334
      label: enterocyte of epithelium of small intestine
  molecular_functions:
  - preferred_term: D-glucose:sodium symporter activity
    term:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:2008213
    reference_title: "Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Normal glucose absorption is mediated by the Na+/glucose cotransporter
      in the brush border membrane of the intestinal epithelium. Cellular
      influx is driven by the transmembrane Na+ electrochemical potential
      gradient; thereafter the sugar moves to the blood across the basolateral
      membrane via the facilitated glucose carrier.
    explanation: >-
      Establishes the normal SGLT1-mediated apical Na+/glucose cotransport
      mechanism that is disrupted in GGM.
  downstream:
  - target: Failure of Active Intestinal Glucose/Galactose Absorption
    causal_link_type: DIRECT
    description: >-
      Loss of apical SGLT1 activity directly abolishes active transcellular
      absorption of glucose and galactose by small-intestinal enterocytes.
    evidence:
    - reference: PMID:33433815
      reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Glucose galactose malabsorption (GGM) is a congenital diarrheal
        disorder of intestinal Na+/glucose cotransport (SGLT1/SLC5A1).
      explanation: >-
        Supports that GGM is a congenital intestinal SGLT1/SLC5A1 glucose
        cotransport disorder; the upstream evidence item establishes the
        SLC5A1 loss-of-function lesion.
- name: Failure of Active Intestinal Glucose/Galactose Absorption
  conforms_to: "diet_induced_osmotic_diarrhea#Unabsorbed Dietary Solute Retention in the Intestinal Lumen"
  description: >-
    Active transcellular absorption of dietary glucose and galactose (and,
    following brush-border disaccharidase hydrolysis, the glucose/galactose
    moieties of lactose, sucrose, and maltose) fails in enterocytes of the
    small intestine, while facilitated absorption of fructose via GLUT5
    (SLC2A5), which is independent of SGLT1, is unaffected.
  cell_types:
  - preferred_term: enterocyte of epithelium of small intestine
    term:
      id: CL:1000334
      label: enterocyte of epithelium of small intestine
  evidence:
  - reference: PMID:33433815
    reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in bloating, cramping, flatulence, and a
      dose-dependent osmotic diarrhea
    explanation: >-
      Documents the direct clinical consequences of failed apical
      glucose/galactose absorption.
  downstream:
  - target: Fructose Absorption Spared (GLUT5)
    causal_link_type: DIRECT
    description: >-
      Because GLUT5-mediated fructose transport is independent of SGLT1,
      fructose absorption remains intact even as glucose/galactose absorption
      fails, forming the basis for fructose-based dietary substitution.
    evidence:
    - reference: PMID:33433815
      reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        membrane-facilitated transporter (GLUT5/SLC2A5), and its function is
        retained in GGM.
      explanation: >-
        States explicitly that fructose absorption via GLUT5 is retained in
        GGM, distinguishing it mechanistically from glucose/galactose
        transport.
  - target: Osmotic Diarrhea and Dehydration
    causal_link_type: DIRECT
    description: >-
      Unabsorbed luminal glucose and galactose, with accompanying sodium and
      water that are not reabsorbed because cotransport fails, create an
      osmotic gradient that drives fluid into the intestinal lumen.
    evidence:
    - reference: PMID:2008213
      reference_title: "Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The consequent severe diarrhoea and dehydration are usually fatal
        unless these sugars are eliminated from the diet.
      explanation: >-
        Establishes that unabsorbed glucose/galactose causes severe,
        potentially fatal diarrhea and dehydration in GGM.
- name: Fructose Absorption Spared (GLUT5)
  description: >-
    Unlike glucose and galactose, fructose is absorbed across the apical
    enterocyte membrane by the facilitated transporter GLUT5 (SLC2A5), which
    is independent of SGLT1 and functions normally in GGM. This selective
    sparing is the basis for fructose-based dietary management and explains
    why fructose becomes the primary dietary carbohydrate source for
    affected patients.
  genes:
  - preferred_term: SLC2A5
    term:
      id: hgnc:11010
      label: SLC2A5
  molecular_functions:
  - preferred_term: fructose transmembrane transporter activity
    term:
      id: GO:0005353
      label: fructose transmembrane transporter activity
  evidence:
  - reference: PMID:36673104
    reference_title: "Fructose Metabolism and Its Effect on Glucose-Galactose Malabsorption Patients: A Literature Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Often, glucose-galactose malabsorption patients are highly dependent on
      fructose, their primary source of carbohydrates.
    explanation: >-
      Supports that fructose becomes the primary dietary carbohydrate source
      in GGM because of intact GLUT5-mediated absorption.
- name: Osmotic Diarrhea and Dehydration
  conforms_to: "diet_induced_osmotic_diarrhea#Substrate-Dependent Watery Diarrhea and Nutritional Consequences"
  description: >-
    Unabsorbed luminal glucose and galactose create an osmotic gradient that
    draws water into the intestinal lumen, producing severe watery diarrhea
    (HP:0033310 Osmotic diarrhea) beginning in the neonatal period; continued
    fluid and electrolyte losses lead to dehydration (HP:0001944), often
    hypernatremic, and metabolic acidosis if untreated. Diarrhea resolves
    rapidly on dietary elimination of glucose/galactose and recurs promptly
    on rechallenge, a pattern used diagnostically to confirm GGM.
  evidence:
  - reference: PMID:31142420
    reference_title: "A Rare Cause of Intractable Diarrhea of Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistent diarrhea lead to prolonged hospitalisation and recurrent
      hypernatremic dehydration.
    explanation: >-
      Clinical case demonstrating recurrent hypernatremic dehydration as a
      consequence of the persistent osmotic diarrhea of GGM.
  downstream:
  - target: Dietary Rechallenge Recurrence
    causal_link_type: DIRECT
    description: >-
      Symptoms resolve when glucose/galactose is removed from the diet and
      recur on rechallenge, confirming the diet-dependence of the osmotic
      mechanism.
    evidence:
    - reference: PMID:33433815
      reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All six patients presented with profound diarrhea at birth with a
        significant improvement after glucose and galactose elimination and
        were eventually diagnosed with GGM by molecular analysis of the
        SLC5A1 gene.
      explanation: >-
        Documents the characteristic resolution of diarrhea upon glucose and
        galactose elimination that supports the GGM diagnosis.
- name: Dietary Rechallenge Recurrence
  description: >-
    Diarrhea resolves rapidly when glucose, galactose, and their
    disaccharides (lactose, sucrose) are removed from the diet, and recurs
    promptly on rechallenge with these sugars, a pattern used diagnostically
    to confirm GGM and distinguish it from other congenital diarrheal
    disorders.
  evidence:
  - reference: PMID:31142420
    reference_title: "A Rare Cause of Intractable Diarrhea of Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Relevant investigations clinched the diagnosis of ''congenital glucose
      galactose malabsorption (CGGM)''.
    explanation: >-
      Clinical case in which targeted investigation (including dietary
      response) established the CGGM diagnosis.
phenotypes:
- name: Neonatal-Onset Watery Diarrhea
  category: Gastrointestinal
  description: >-
    Severe, watery, osmotic diarrhea beginning within the first days to weeks
    of life upon any feed containing glucose, galactose, or lactose/sucrose.
  phenotype_term:
    preferred_term: Osmotic diarrhea
    term:
      id: HP:0033310
      label: Osmotic diarrhea
    onset:
      onset_category: NEONATAL
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:2008213
    reference_title: "Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glucose/galactose malabsorption (GGM) is an autosomal recessive disease
      manifesting within the first weeks of life and characterized by a
      selective failure to absorb dietary glucose and galactose from the
      intestine.
    explanation: Establishes neonatal onset of diarrhea as the cardinal presenting feature.
- name: Dehydration
  category: General
  description: >-
    Recurrent dehydration, often hypernatremic, resulting from ongoing
    osmotic fluid losses if glucose/galactose exposure continues.
  phenotype_term:
    preferred_term: Hypernatremic dehydration
    term:
      id: HP:0004906
      label: Hypernatremic dehydration
  frequency: FREQUENT
  evidence:
  - reference: PMID:31142420
    reference_title: "A Rare Cause of Intractable Diarrhea of Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistent diarrhea lead to prolonged hospitalisation and recurrent
      hypernatremic dehydration.
    explanation: Clinical case documenting hypernatremic dehydration as a recurrent complication.
- name: Failure to Thrive
  category: Growth
  description: >-
    Poor weight gain and growth failure secondary to chronic diarrhea and
    malabsorption when the disorder is unrecognized or dietary management is
    inadequate.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:31142420
    reference_title: "A Rare Cause of Intractable Diarrhea of Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was failing to thrive and wasted.
    explanation: Clinical case documenting failure to thrive in an affected infant.
- name: Abdominal Distension and Bloating
  category: Gastrointestinal
  description: >-
    Bloating, cramping, and flatulence accompany the osmotic diarrhea,
    reflecting colonic fermentation of unabsorbed sugars.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  frequency: FREQUENT
  evidence:
  - reference: PMID:33433815
    reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in bloating, cramping, flatulence, and a
      dose-dependent osmotic diarrhea
    explanation: Documents bloating/cramping/flatulence as accompanying symptoms of GGM.
- name: Nephrolithiasis
  category: Renal
  description: >-
    Nephrolithiasis has been reported as a complication in GGM, attributed to
    chronic dehydration rather than a direct effect of the transport defect
    on the kidney.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33433815
    reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the kidneys are usually unaffected in GGM, impaired renal
      function associated with nephrolithiasis as a result of chronic
      dehydration has been documented
    explanation: >-
      Directly documents nephrolithiasis as a reported renal complication of
      GGM linked to chronic dehydration.
- name: Elevated Stool Reducing Substances
  category: Laboratory
  description: >-
    Stool testing shows positive reducing substances because unabsorbed
    glucose and galactose remain in the intestinal lumen. Small-bowel biopsy
    disaccharidase (lactase, sucrase, maltase) activities are normal,
    distinguishing GGM from primary disaccharidase deficiencies such as
    congenital lactase deficiency or sucrase-isomaltase deficiency.
  phenotype_term:
    preferred_term: Elevated stool reducing substances
    term:
      id: HP:6001295
      label: Elevated stool reducing substances
  evidence:
  - reference: PMID:42160565
    reference_title: "Congenital glucose-galactose malabsorption due to SLC5A1 mutation: A case of hypernatraemic dehydration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reducing substances 2+"
    explanation: >-
      Directly documents positive stool reducing substances in a genetically
      confirmed GGM case.
- name: Positive Hydrogen Breath Test
  category: Laboratory
  description: >-
    An oral glucose or galactose challenge followed by a positive hydrogen
    breath test supports malabsorption of the challenged sugar, consistent
    with GGM; the test is negative for a fructose challenge.
  phenotype_term:
    preferred_term: Positive hydrogen breath test
    term:
      id: HP:6000259
      label: Positive hydrogen breath test
  notes: >-
    Diagnostic breath testing with a glucose or galactose challenge is a
    standard ancillary tool alongside stool reducing substances and molecular
    SLC5A1 testing; a normal disaccharidase panel on small-bowel biopsy helps
    exclude primary disaccharidase deficiencies as an alternative cause of
    carbohydrate malabsorption.
diagnosis:
- name: Molecular SLC5A1 Genetic Testing
  description: >-
    Confirmatory molecular testing for biallelic SLC5A1 variants establishes
    the diagnosis and distinguishes GGM from other congenital diarrheal
    disorders and disaccharidase deficiencies.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic SLC5A1 variants.
  evidence:
  - reference: PMID:33433815
    reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All six patients presented with profound diarrhea at birth with a
      significant improvement after glucose and galactose elimination and were
      eventually diagnosed with GGM by molecular analysis of the SLC5A1 gene.
    explanation: Documents molecular SLC5A1 analysis as the diagnostic confirmation method.
treatments:
- name: Fructose-Based Glucose/Galactose-Free Formula
  description: >-
    Definitive first-line management is lifelong dietary elimination of
    glucose, galactose, and their disaccharides (lactose, sucrose, maltose),
    with fructose substituted as the primary dietary carbohydrate source
    because fructose absorption via GLUT5 is unaffected. In infancy this is
    delivered as a fructose-based, carbohydrate-free formula; the diet is
    progressively liberalized with age as clinical tolerance to small amounts
    of glucose/galactose develops.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Failure of Active Intestinal Glucose/Galactose Absorption
    treatment_effect: MODULATES
    description: >-
      Eliminating dietary glucose/galactose removes the unabsorbed osmotic
      substrate that drives diarrhea, while fructose substitution exploits
      the spared GLUT5 pathway to provide dietary carbohydrate.
    evidence:
    - reference: PMID:33433815
      reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The standard of care for patients with GGM is lifelong restriction of
        dietary glucose and galactose. During infancy, the primary nutrition
        is a fructose-based formula, either as a Ross Carbohydrate-Free
        formula (Abbott Nutrition) with fructose supplementation, or a
        ready-made formula
      explanation: >-
        Documents the fructose-based, glucose/galactose-free formula as the
        standard-of-care first-line treatment for GGM.
  evidence:
  - reference: PMID:31142420
    reference_title: "A Rare Cause of Intractable Diarrhea of Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an appropriate rational diagnosis can lead to life-saving treatment as
      depicted in this case report.
    explanation: >-
      Supports that timely diagnosis and initiation of the appropriate
      carbohydrate-restricted diet is life-saving in GGM.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No formal population prevalence estimate is documented; the disorder is
    described as extremely rare, with approximately several hundred cases
    diagnosed worldwide in the literature.
  evidence:
  - reference: PMID:33433815
    reference_title: "Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GGM is extremely rare, with approximately several hundred people
      diagnosed worldwide
    explanation: >-
      Direct statement of the extreme rarity and approximate worldwide case
      count of GGM.
- population: Västerbotten County, Northern Sweden
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    A founder Q457R SLC5A1 variant is markedly enriched in this Swedish
    region relative to general Swedish and European populations, explaining a
    local cluster of GGM cases traced through a pedigree back to the late
    17th century.
  evidence:
  - reference: PMID:34485913
    reference_title: "The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of the Q457R variant in Västerbotten County genomes,
      0.0067, is higher than in the general Swedish population, 0.0015, and
      higher than the general European population, 0.000067. This explains
      the high number of GGM cases in this region of Sweden.
    explanation: >-
      Quantifies the founder-variant allele frequency enrichment underlying a
      regional cluster of GGM cases in Sweden.
notes: >-
  SLC5A1 also has an independent, mechanistically distinct role: common
  SLC5A1 variants have been examined in GWAS for association with type 2
  diabetes and glucose-absorption-related metabolic traits in adults. That
  common-variant/complex-trait literature is NOT part of this entry, which is
  scoped strictly to the congenital, biallelic-loss-of-function disorder
  (OMIM:606824 / MONDO:0011731). SGLT2 inhibitors (e.g., gliflozins used in
  type 2 diabetes and heart failure) act on the renal paralog SGLT2/SLC5A2,
  not SGLT1, and are likewise out of scope for this entry (see
  Familial_Renal_Glucosuria for SLC5A2). Severe diarrheal episodes can raise
  acid-base concerns clinically, but no exact quote in the reviewed GGM cache
  directly documented metabolic acidosis; it is therefore not modeled as a
  structured phenotype here.