Trehalase Deficiency

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Inheritance

2

Reported autosomal dominant inheritance HP:0000006

The current Orphanet-derived NCBI GTR record assigns autosomal dominant inheritance. Historical father-to-son biochemical deficiency is compatible with vertical transmission, but the family was not molecularly resolved; a dominant TREH variant mechanism is therefore not established.

Autosomal dominant inheritance

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/ SUPPORT Other

"alpha, alpha-Trehalase deficiency ... Modes of inheritance ... Autosomal dominant inheritance ... Source: Orphanet"

The current GTR condition record reports autosomal dominant inheritance from Orphanet; this is a structured-source assertion rather than a molecularly solved pedigree.

Reported autosomal recessive inheritance HP:0000007

Later literature describes trehalase deficiency as recessive and identified six adults homozygous for a predicted TREH splice-loss allele. Those participants were not tested for intestinal enzyme activity or challenged with trehalose, so the observation does not by itself establish clinical recessive penetrance.

Autosomal recessive inheritance

Show evidence (1 reference)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"Trehalase deficiency, an autosomal recessive trait, leads to abdominal pain, distention, and flatulence after trehalose ingestion. We identified six participants homozygous for a deletion of a splice acceptor site"

The paper explicitly labels the trait recessive and reports homozygous predicted loss of TREH, but it did not establish the trehalase-deficiency phenotype in the six carriers.

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Discussions and Knowledge Gaps

3

Is primary TREH-associated trehalase deficiency dominantly or recessively inherited, and which variants have sufficient clinical evidence to establish either model?

CONTROVERSY OPEN trehalase_inheritance_and_variant_validity_conflict

Attached to

genetic#TREH-associated primary trehalase deficiency

Current Orphanet-derived structured data report dominant inheritance, whereas a later human-knockout paper labels the trait recessive. The one recurrent splice deletion has conflicting ClinVar classifications and lacks enzyme- or challenge-confirmed phenotyping in its six homozygotes. Recurrence-risk counseling and molecular diagnosis should therefore not assume a settled model.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/ SUPPORT Other

"alpha, alpha-Trehalase deficiency ... Modes of inheritance ... Autosomal dominant inheritance ... Source: Orphanet"

Documents the current dominant structured-source assertion.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"Trehalase deficiency, an autosomal recessive trait"

Documents the conflicting recessive literature assertion.

url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/ SUPPORT Other

"Pathogenic (1); Uncertain significance (1)"

Documents the unresolved variant-classification split.

How often do common activity-lowering TREH genotypes cause enzyme-confirmed, trehalose-provoked clinical disease rather than only a lower biochemical activity?

KNOWLEDGE GAP OPEN treh_genotype_activity_clinical_expression_gap

Attached to

genetic#TREH activity-modifying common variation biochemical#Reduced small-intestinal trehalase activity

Recent population studies genotype rs2276064 and infer enzymopathy without directly measuring intestinal activity or symptoms. Their high genotype frequencies cannot be used as prevalence of MONDO:0012803, and the genotype-to-clinical penetrance bridge remains unquantified.

Show evidence (2 references)

PMID:36880131 SUPPORT Human Clinical

"The question on to what degree the genotype-determined trehalase deficiency comes out clinically needs further elaboration."

The authors explicitly identify the missing genotype-to-clinical bridge.

PMID:39283558 SUPPORT Human Clinical

"genotyping of 1068 DNA samples was carried out"

The current study is a genotype-frequency analysis rather than a clinical penetrance study.

Does a Treh-deficient mouse reproduce the human osmotic and microbiota-dependent gastrointestinal phenotype after a controlled trehalose load?

HUMAN MODEL MISMATCH OPEN trehalase_mouse_human_gastrointestinal_fidelity

Attached to

animal_models#Trehalase-deficient mouse pathophysiology#Microbial fermentation of maldigested trehalose phenotypes#Diarrhea after trehalose ingestion

Mouse knockout studies reproduce an absent glycemic response or examine metabolic endpoints, but do not establish diarrhea, distention, flatulence, transit, or fermentation. Because the human gaseous phenotype is microbiota-dependent, proximal biochemical fidelity cannot be generalized to clinical fidelity.

Show evidence (2 references)

PMID:32206077 SUPPORT Model Organism

"An oral trehalose tolerance test revealed that these trehalase-deficient mice exhibited no changes in blood glucose levels."

Documents the proximal readout that is established in the model.

PMID:40529415 SUPPORT Model Organism

"Systemic trehalase-deficient mice showed no metabolic changes at baseline."

A current independent knockout study again focuses on metabolic rather than human gastrointestinal outcomes.

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Pathophysiology

4

Reduced intestinal brush-border trehalase activity

The defining biochemical lesion is low alpha,alpha-trehalase activity on the apical brush border of small-intestinal enterocytes. Primary isolated deficiency must be distinguished from the broad reduction of disaccharidases caused by villous injury.

enterocyte CL:0000584

TREH hgnc:12266

disaccharide catabolic process GO:0046352 ↓ DECREASED

alpha,alpha-trehalase activity GO:0004555 ↓ DECREASED

brush border membrane GO:0031526

epithelium of small intestine UBERON:0001902

Animal models

Trehalase-deficient mouse Mus musculus partially recapitulates Genetic trehalase deficiency produces the expected absent glycemic response after an oral trehalose challenge.

Downstream

Unhydrolyzed trehalose reaches the colon Low small-bowel trehalase leaves more ingested trehalose undigested and permits it to pass into the colon.

Show evidence (2 references)

PMID:3227291 SUPPORT Human Clinical

"Small-intestinal surgical biopsy specimens from 97 adult Greenlanders showed an incidence of trehalase deficiency in at least 8%."

Directly documents low trehalase activity in human small-intestinal biopsy tissue.

PMID:10884712 SUPPORT Human Clinical

"The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein."

Defines assay-specific duodenal activity in a normal-histology referral cohort.

Unhydrolyzed trehalose reaches the colon

Trehalose that is not hydrolyzed into absorbable glucose remains luminal and reaches the colon. This node is exposure-gated: low activity alone does not produce the downstream gastrointestinal mechanisms without dietary trehalose.

Downstream

Osmotic water flow into the colon Maldigested luminal trehalose creates an osmotic water load.

Microbial fermentation of maldigested trehalose Gas-producing colonic organisms conditionally ferment the delivered trehalose.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"trehalose is maldigested and more trehalose is passed into the colon"

Supports delivery of maldigested trehalose to the colon.

Osmotic water flow into the colon

Osmotically active maldigested trehalose draws water into the colonic lumen, increasing stool water and producing loose stools or diarrhea.

Downstream

Diarrhea after trehalose ingestion Increased colonic water produces loose stools or diarrhea.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"osmotic water flow into the colon, resulting in loose stools and diarrhea"

Directly links the osmotic step to diarrhea.

Microbial fermentation of maldigested trehalose

Colonic gas production from trehalose is conditional on the resident microbiota. Without gas-producing organisms, the literature predicts that distention and gas expulsion will not occur even when trehalose is maldigested.

Downstream

Abdominal distention after trehalose ingestion Fermentation-derived gas distends the abdomen.

Flatulence after trehalose ingestion Fermentation-derived gas is expelled as flatus.

Abdominal pain after trehalose ingestion Distention and altered luminal water plausibly contribute to abdominal pain, but the evidence does not resolve a single direct pain mechanism.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"If colonic bacteria cannot produce gases, then distention of the abdomen and intestinal gas expulsion as eructations and flatus will not occur."

Establishes the microbiota-dependent conditionality of gaseous symptoms.

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Pathograph

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

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Phenotypes

5

Digestive 4

Diarrhea after trehalose ingestion HP:0002014

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"osmotic water flow into the colon, resulting in loose stools and diarrhea"

Directly supports diarrhea as an osmotic consequence.

Abdominal distention after trehalose ingestion HP:0003270

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"distention of the abdomen and intestinal gas expulsion as eructations and flatus"

Directly documents distention as a conditional gaseous manifestation.

Flatulence after trehalose ingestion HP:0033589

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"intestinal gas expulsion as eructations and flatus"

Directly documents gas expulsion after trehalose maldigestion.

Vomiting after trehalose ingestion HP:0002013

Show evidence (1 reference)

url:https://www.ebi.ac.uk/ols4/api/ontologies/mondo/terms?obo_id=MONDO:0012803 SUPPORT Other

"This syndrome is characterized by diarrhea and vomiting after ingestion of trehalose, a disaccharide found mainly in mushrooms."

The exact ontology definition includes vomiting after trehalose ingestion, but does not establish its frequency or mechanism.

Constitutional 1

Abdominal pain after trehalose ingestion HP:0002027

Show evidence (1 reference)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"leads to abdominal pain, distention, and flatulence after trehalose ingestion"

Directly associates abdominal pain with trehalose ingestion.

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Genetic Associations

2

TREH-associated primary trehalase deficiency (Biologically implicated; clinical gene-disease validity remains limited)

Gene: TREH hgnc:12266 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/ SUPPORT Other

"Isolated trehalose intolerance due to deficiency of trehalase (TREH; 275360)"

The structured condition record links the deficient enzyme and TREH, but does not provide primary variant-level validity evidence.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"We identified six participants homozygous for a deletion of a splice acceptor site"

Establishes homozygous predicted TREH loss in humans, but not enzyme-confirmed or symptom-confirmed trehalase deficiency.

Variants (1)

NM_007180.3:c.90-9_106del

splice acceptor deletion

Predicted loss-of-function deletion observed homozygously in six PROMIS adults. ClinVar currently reports conflicting classifications (one pathogenic and one uncertain-significance submission), notes a South Asian gnomAD allele frequency of 0.011, and states that no phenotype specific to the homozygotes was provided.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/ SUPPORT Other

"Conflicting classifications of pathogenicity ... Pathogenic (1); Uncertain significance (1)"

ClinVar's current aggregate classification prevents treating this allele as an established pathogenic variant.

url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/ SUPPORT Other

"No phenotypic information specific to the homozygous individuals was provided."

The ClinVar submission summary records the decisive clinical-evidence limitation.

TREH activity-modifying common variation (Modifier of measured trehalase activity; clinical penetrance unestablished)

Gene: TREH hgnc:12266 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (2 references)

PMID:23468175 SUPPORT Human Clinical

"Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907"

Demonstrates association with measured activity without demonstrating clinical trehalose intolerance.

PMID:36880131 SUPPORT Human Clinical

"The G→A substitution in the rs2276064 locus was shown to affect trehalase activity, which is the highest (29.3 IU/g protein) in the carriers of the GG*TREH genotype, the lowest (10.2 IU/g) in the AA homozygotes, and moderate in the AG heterozygotes (20.5 IU/g)."

Reports the graded genotype-activity relationship while leaving clinical expression unresolved.

Variants (1)

rs2276064

single nucleotide variant

Common activity-associated allele used as a proxy for low trehalase activity in population-genetic studies; it is not an established Mendelian pathogenic allele.

Show evidence (1 reference)

PMID:23468175 SUPPORT Human Clinical

"plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907"

Directly supports rs2276064 as an activity-associated variant.

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Medical Actions

1

Reduction or avoidance of symptom-triggering trehalose

Action: Dietary Intervention NCIT:C15447

A pragmatic dietary strategy is to reduce or avoid the amount and sources of trehalose that reproducibly trigger symptoms. The mechanistic rationale is strong, but no controlled treatment study, response rate, or disease-specific guideline was found; this should not be represented as trial-proven efficacy.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"It is obvious that trehalose maldigestion can cause symptoms similar to those of lactose maldigestion and intolerance."

Supports removal of the triggering substrate mechanistically, but does not test a trehalose-restriction intervention.

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Environmental Factors

1

Dietary trehalose ingestion

Dietary trehalose is an obligate exposure for clinical expression. Natural sources include edible mushrooms and yeast; processed foods may also contain added trehalose. The same exposure can be tolerated when residual activity and microbial context are sufficient.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"whether maldigestion of trehalose causes abdominal symptoms"

Supports the exposure-dependent clinical framing.

Mechanism Target:

TRIGGERS Unhydrolyzed trehalose reaches the colon — Ingestion supplies the substrate that remains unhydrolyzed when small-bowel trehalase activity is low.

Show evidence (1 reference)

PMID:10522609 SUPPORT Human Clinical

"A 25-g oral trehalose load test was performed in 64 subjects."

Directly documents dietary trehalose as the challenge substrate.

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Biochemical Markers

1

Reduced small-intestinal trehalase activity (DECREASED)

Context: Quantitative trehalase activity in a duodenal or jejunal mucosal biopsy is the defining biochemical readout. Interpretation is assay-, site-, and population-dependent and must account for mucosal histology and the other disaccharidases.

Pathograph Readouts

Readout Of Reduced intestinal brush-border trehalase activity Negative Diagnostic

Low biopsy trehalase activity reports the proximal biochemical lesion, but is not specific for a primary genetic defect when villous injury is present.

Show evidence (1 reference)

PMID:10884712 SUPPORT Human Clinical

"The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein."

Establishes quantitative biopsy activity as a biochemical readout.

Reference Ranges

4.79–37.12 U/g{protein} (UK gastroenterology referral patients with normal distal-duodenal histology (n=369); Dahlqvist disaccharidase assay)

This is a study-specific mean plus or minus two standard deviations, not a universal clinical decision limit.

Show evidence (1 reference)

PMID:10884712 SUPPORT Human Clinical

"The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein."

Source of the assay-specific reference interval.

Show evidence (1 reference)

PMID:10884712 SUPPORT Human Clinical

"The thirty-one patients with villous atrophy had significantly reduced disaccharidase activities."

Shows why low trehalase activity is not specific for primary deficiency without histologic and multi-enzyme context.

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Diagnosis

2

Small-intestinal biopsy trehalase assay with histologic context

Direct activity measurement in a duodenal or jejunal mucosal biopsy can establish the biochemical deficiency. Simultaneous histology and a disaccharidase panel are needed to separate isolated primary deficiency from global secondary loss due to villous injury.

Biopsy Procedure NCIT:C15189

Show evidence (2 references)

PMID:10884712 SUPPORT Human Clinical

"Endoscopic distal duodenal biopsies were taken for histological assessment and maltase, sucrase, lactase and trehalase estimation."

Documents coupled biopsy histology and enzyme measurement.

PMID:10884712 SUPPORT Human Clinical

"Activity is significantly reduced in untreated coeliac disease and recovers with treatment with a gluten-free diet."

Establishes the central secondary-deficiency confounder.

Oral trehalose challenge with breath hydrogen and methane

A 25-g oral trehalose challenge with symptom recording and breath hydrogen/methane measurement has discriminated symptom-defined intolerance in a small study. It is not a standardized routine diagnostic test: validated doses, concentrations, and comparison with a gold standard are unavailable, and small-intestinal bacterial overgrowth can produce a misleading hydrogen rise.

Breath Test NCIT:C116515

Show evidence (2 references)

PMID:10522609 SUPPORT Human Clinical

"A 25-g oral trehalose load test was performed in 64 subjects. The 19 experiencing clear symptoms constituted the trehalose-intolerant subjects."

Documents the challenge protocol and symptom-defined study group.

PMID:24443064 SUPPORT Other

"neither studies comparing this test with a gold standard, nor validated doses and concentrations to be used, are available."

Review evidence for the lack of validated breath-test standards.

📊

Prevalence

3

Adult Greenlanders undergoing small-intestinal surgical biopsy

Point Prevalence 8000.0 per 100,000 >1 in 1,000

At least 8% of this 97-person surgical biopsy series had biochemical low trehalase activity. This is not symptomatic-disease prevalence, a representative population estimate, or evidence that the same percentage has Mendelian TREH disease.

Show evidence (1 reference)

PMID:3227291 SUPPORT Human Clinical

"Small-intestinal surgical biopsy specimens from 97 adult Greenlanders showed an incidence of trehalase deficiency in at least 8%."

Source of the biochemical biopsy-cohort percentage.

Worldwide (gnomAD variant-frequency model)

Birth Prevalence 0.92 per 100,000 1–9 per 1,000,000

Computational estimate of 9.2 per million births from reported and predicted loss-of-function variants, not observed clinical cases. The published abstract reports a 95% confidence interval of 2.5-3.7 per million, which cannot contain the 9.2 point estimate; the interval is retained only as an identified source error and is not encoded as rate bounds.

Show evidence (1 reference)

PMID:36167617 SUPPORT Computational

"9.2 per 106 births (95% CI: 2.5-3.7) for CTD."

Source of the computational point estimate and its internally inconsistent published confidence interval.

UK gastroenterology referral population (duodenal biopsy cohort)

Point Prevalence Rare

Only one of 369 patients with normal duodenal histology had an isolated borderline trehalase deficiency, indicating isolated trehalase deficiency is rare outside of populations such as Greenlandic Inuit.

Show evidence (1 reference)

PMID:10884712 SUPPORT Human Clinical

"Isolated intestinal trehalase deficiency is found in 8% of Greenlanders, but is rare elsewhere."

States that isolated trehalase deficiency, while present in 8% of Greenlanders, is rare in other populations such as the UK.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Trehalase Deficiency:

Celiac disease with secondary disaccharidase deficiency MONDO:0005130

Overlapping Features Villous injury in untreated celiac disease can reduce trehalase together with the other brush-border disaccharidases and therefore mimic primary deficiency biochemically and symptomatically.

Distinguishing Features

Villous atrophy rather than normal mucosal architecture
Broad reduction of disaccharidases rather than isolated low trehalase
Recovery of trehalase activity with a gluten-free diet

Show evidence (1 reference)

PMID:10884712 SUPPORT Human Clinical

"The thirty-one patients with villous atrophy had significantly reduced disaccharidase activities. With ingestion of a gluten-free diet, maltase, sucrase and trehalase activities recovered to normal in most patients"

Directly documents secondary and reversible reduction with villous injury.

Small-intestinal bacterial overgrowth

Overlapping Features Excess small-intestinal bacteria can ferment multiple test sugars and cause an abnormal breath-hydrogen rise, mimicking trehalose malabsorption even when primary trehalase deficiency has not been established.

Distinguishing Features

Nonspecific fermentation of multiple sugar substrates
Breath-hydrogen positivity does not establish isolated low biopsy trehalase

Show evidence (1 reference)

PMID:24443064 SUPPORT Other

"the large amount of intestinal bacteria may unspecifically ferment sugars, causing an abnormal H2 production and consequently a misleading diagnosis of sugar malabsorption."

Directly supports the breath-test differential.

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Related Datasets

1

Pakistan Risk of Myocardial Infarction Study (PROMIS) human knockout cohort dbgap:phs000917

Whole-exome sequencing of 10,503 adult PROMIS participants identified six adults homozygous for a predicted TREH splice-acceptor deletion. The cohort was assembled for cardiometabolic research rather than trehalase deficiency, and no trehalose challenge or intestinal-enzyme phenotype was reported for the TREH homozygotes.

human WES n=10503

Conditions: Broad adult cardiometabolic cohort

PMID:28406212

Direct variant-cohort relevance, not a disease-specific natural-history dataset. Sequence data are controlled-access through dbGaP.

Show evidence (2 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"Here, we sequenced the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS)"

Supports study design and sample count.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML SUPPORT Human Clinical

"DNA sequences have been deposited with the NIH dbGAP repository under accession numbers phs000917."

Supports the public controlled-access dataset identifier.

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Animal Models

1

Trehalase-deficient mouse

RBRC00857 gene-targeted trehalase-deficient mice show no blood-glucose rise on an oral trehalose tolerance test, recapitulating a proximal digestive readout. Published studies use the model mainly to study trehalose and lipid metabolism; diarrhea, distention, flatulence, transit, and microbiome-dependent fermentation have not been established as model phenotypes.

Species

Mus musculus

Genotype

Gene-targeted Treh deficiency

Background

C57BL/6J

Genes

TREH hgnc:12266

Publication

PMID:32206077

Pathograph links

Reduced intestinal brush-border trehalase activity partially recapitulates fidelity: moderate Genetic trehalase deficiency produces the expected absent glycemic response after an oral trehalose challenge.

Limitations: The cited work does not establish intestinal enzyme activity or the human microbiota-dependent gastrointestinal phenotype as readouts.

Show evidence (1 reference)

PMID:32206077 SUPPORT Model Organism

"An oral trehalose tolerance test revealed that these trehalase-deficient mice exhibited no changes in blood glucose levels."

Directly supports the proximal challenge-test phenotype.

Show evidence (1 reference)

PMID:32206077 SUPPORT Model Organism

"and deposited these mice with RIKEN. An oral trehalose tolerance test revealed that these trehalase-deficient mice exhibited no changes in blood glucose levels."

Documents model generation and repository deposition.

{ }

Source YAML

click to show

name: Trehalase Deficiency
creation_date: "2026-07-06T00:00:00Z"
category: Mendelian
synonyms:
- Congenital trehalase deficiency
- Isolated trehalose intolerance
- Trehalose intolerance
- Diarrhea-vomiting due to trehalase deficiency
description: >-
  Primary intestinal trehalase deficiency is an exposure-dependent disorder of
  trehalose digestion. Reduced alpha,alpha-trehalase activity at the small-intestinal
  brush border allows ingested trehalose to reach the colon, where osmotic water
  movement can cause diarrhea and microbial fermentation can cause abdominal pain,
  distention, and flatulence. Symptoms are episodic and require dietary trehalose;
  reduced enzyme activity can therefore be clinically silent. The molecular and
  inheritance evidence is unusually limited and internally conflicting: dominant and
  recessive transmission are both reported, and no TREH variant has an expert-reviewed
  pathogenic classification. This entry is restricted to primary isolated deficiency
  and does not merge common activity-modifying TREH genotypes or secondary reduction of
  trehalase from celiac villous injury into the Mendelian disease entity.
disease_term:
  preferred_term: diarrhea-vomiting due to trehalase deficiency
  term:
    id: MONDO:0012803
    label: diarrhea-vomiting due to trehalase deficiency
parents:
- Gastrointestinal Disease
inheritance:
- name: Reported autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The current Orphanet-derived NCBI GTR record assigns autosomal dominant
    inheritance. Historical father-to-son biochemical deficiency is compatible with
    vertical transmission, but the family was not molecularly resolved; a dominant
    TREH variant mechanism is therefore not established.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/
    reference_title: "alpha, alpha-Trehalase deficiency - NIH Genetic Testing Registry (GTR) - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      alpha, alpha-Trehalase deficiency ... Modes of inheritance ... Autosomal
      dominant inheritance ... Source: Orphanet
    explanation: >-
      The current GTR condition record reports autosomal dominant inheritance from
      Orphanet; this is a structured-source assertion rather than a molecularly solved
      pedigree.
- name: Reported autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Later literature describes trehalase deficiency as recessive and identified six
    adults homozygous for a predicted TREH splice-loss allele. Those participants were
    not tested for intestinal enzyme activity or challenged with trehalose, so the
    observation does not by itself establish clinical recessive penetrance.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trehalase deficiency, an autosomal recessive trait, leads to abdominal pain,
      distention, and flatulence after trehalose ingestion. We identified six
      participants homozygous for a deletion of a splice acceptor site
    explanation: >-
      The paper explicitly labels the trait recessive and reports homozygous predicted
      loss of TREH, but it did not establish the trehalase-deficiency phenotype in the
      six carriers.
genetic:
- name: TREH-associated primary trehalase deficiency
  gene_term:
    preferred_term: TREH
    term:
      id: hgnc:12266
      label: TREH
  association: Biologically implicated; clinical gene-disease validity remains limited
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  features: >-
    TREH encodes the brush-border enzyme that hydrolyzes trehalose. Human knockout and
    structured disease resources implicate the gene, but direct cosegregation of a
    classified pathogenic variant with enzyme-confirmed symptomatic disease has not
    been demonstrated.
  variants:
  - name: NM_007180.3:c.90-9_106del
    type: splice acceptor deletion
    description: >-
      Predicted loss-of-function deletion observed homozygously in six PROMIS adults.
      ClinVar currently reports conflicting classifications (one pathogenic and one
      uncertain-significance submission), notes a South Asian gnomAD allele frequency
      of 0.011, and states that no phenotype specific to the homozygotes was provided.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/
      reference_title: "VCV000488190.3 - ClinVar - NCBI"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Conflicting classifications of pathogenicity ... Pathogenic (1); Uncertain
        significance (1)
      explanation: >-
        ClinVar's current aggregate classification prevents treating this allele as an
        established pathogenic variant.
    - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/
      reference_title: "VCV000488190.3 - ClinVar - NCBI"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        No phenotypic information specific to the homozygous individuals was provided.
      explanation: >-
        The ClinVar submission summary records the decisive clinical-evidence limitation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/
    reference_title: "alpha, alpha-Trehalase deficiency - NIH Genetic Testing Registry (GTR) - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Isolated trehalose intolerance due to deficiency of trehalase (TREH; 275360)
    explanation: >-
      The structured condition record links the deficient enzyme and TREH, but does not
      provide primary variant-level validity evidence.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified six participants homozygous for a deletion of a splice acceptor site
    explanation: >-
      Establishes homozygous predicted TREH loss in humans, but not enzyme-confirmed or
      symptom-confirmed trehalase deficiency.
- name: TREH activity-modifying common variation
  gene_term:
    preferred_term: TREH
    term:
      id: hgnc:12266
      label: TREH
  association: Modifier of measured trehalase activity; clinical penetrance unestablished
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  features: >-
    Common TREH variation, especially rs2276064, is associated with graded trehalase
    activity. Genotype-frequency studies do not demonstrate symptomatic primary
    trehalase deficiency and must not be interpreted as disease prevalence.
  variants:
  - name: rs2276064
    type: single nucleotide variant
    description: >-
      Common activity-associated allele used as a proxy for low trehalase activity in
      population-genetic studies; it is not an established Mendelian pathogenic allele.
    evidence:
    - reference: PMID:23468175
      reference_title: "Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        plasma trehalase activity was highly associated with three SNPs: rs2276064,
        rs117619140 and rs558907
      explanation: Directly supports rs2276064 as an activity-associated variant.
  evidence:
  - reference: PMID:23468175
    reference_title: "Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase
      activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907
    explanation: >-
      Demonstrates association with measured activity without demonstrating clinical
      trehalose intolerance.
  - reference: PMID:36880131
    reference_title: "Prevalence of genetically determined trehalase deficiency in populations of Siberia and Russian Far East."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The G→A substitution in the rs2276064 locus was shown to affect trehalase activity,
      which is the highest (29.3 IU/g protein) in the carriers of the GG*TREH genotype,
      the lowest (10.2 IU/g) in the AA homozygotes, and moderate in the AG heterozygotes
      (20.5 IU/g).
    explanation: >-
      Reports the graded genotype-activity relationship while leaving clinical
      expression unresolved.
pathophysiology:
- name: Reduced intestinal brush-border trehalase activity
  conforms_to: "diet_induced_osmotic_diarrhea#Loss of a Substrate-Specific Brush-Border Digestive or Absorptive Step"
  description: >-
    The defining biochemical lesion is low alpha,alpha-trehalase activity on the apical
    brush border of small-intestinal enterocytes. Primary isolated deficiency must be
    distinguished from the broad reduction of disaccharidases caused by villous injury.
  genes:
  - preferred_term: TREH
    term:
      id: hgnc:12266
      label: TREH
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: epithelium of small intestine
    term:
      id: UBERON:0001902
      label: epithelium of small intestine
  cellular_components:
  - preferred_term: brush border membrane
    term:
      id: GO:0031526
      label: brush border membrane
  molecular_functions:
  - preferred_term: alpha,alpha-trehalase activity
    term:
      id: GO:0004555
      label: alpha,alpha-trehalase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: disaccharide catabolic process
    term:
      id: GO:0046352
      label: disaccharide catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:3227291
    reference_title: "Trehalase deficiency in Greenland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Small-intestinal surgical biopsy specimens from 97 adult Greenlanders showed an
      incidence of trehalase deficiency in at least 8%.
    explanation: >-
      Directly documents low trehalase activity in human small-intestinal biopsy tissue.
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein.
    explanation: >-
      Defines assay-specific duodenal activity in a normal-histology referral cohort.
  downstream:
  - target: Unhydrolyzed trehalose reaches the colon
    description: >-
      Low small-bowel trehalase leaves more ingested trehalose undigested and permits it
      to pass into the colon.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        if it is low, trehalose is maldigested and more trehalose is passed into the colon
      explanation: >-
        Directly states the proximal enzyme-to-luminal-substrate step.
- name: Unhydrolyzed trehalose reaches the colon
  conforms_to: "diet_induced_osmotic_diarrhea#Unabsorbed Dietary Solute Retention in the Intestinal Lumen"
  description: >-
    Trehalose that is not hydrolyzed into absorbable glucose remains luminal and reaches
    the colon. This node is exposure-gated: low activity alone does not produce the
    downstream gastrointestinal mechanisms without dietary trehalose.
  chemical_entities:
  - preferred_term: trehalose
    term:
      id: CHEBI:27082
      label: trehalose
    modifier: INCREASED
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      trehalose is maldigested and more trehalose is passed into the colon
    explanation: >-
      Supports delivery of maldigested trehalose to the colon.
  downstream:
  - target: Osmotic water flow into the colon
    description: Maldigested luminal trehalose creates an osmotic water load.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the maldigested trehalose, which causes osmotic water flow into the colon
      explanation: Directly states the osmotic mechanism.
  - target: Microbial fermentation of maldigested trehalose
    description: >-
      Gas-producing colonic organisms conditionally ferment the delivered trehalose.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        symptoms will arise if there are bacteria capable of producing gases from
        maldigested trehalose
      explanation: Directly supports microbiota-dependent gas production.
- name: Osmotic water flow into the colon
  conforms_to: "diet_induced_osmotic_diarrhea#Osmotic Water Influx and Luminal Distension"
  description: >-
    Osmotically active maldigested trehalose draws water into the colonic lumen,
    increasing stool water and producing loose stools or diarrhea.
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      osmotic water flow into the colon, resulting in loose stools and diarrhea
    explanation: Directly links the osmotic step to diarrhea.
  downstream:
  - target: Diarrhea after trehalose ingestion
    description: Increased colonic water produces loose stools or diarrhea.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        osmotic water flow into the colon, resulting in loose stools and diarrhea
      explanation: Directly supports the mechanism-to-phenotype edge.
- name: Microbial fermentation of maldigested trehalose
  conforms_to: "diet_induced_osmotic_diarrhea#Colonic Microbial Fermentation of the Malabsorbed Substrate"
  description: >-
    Colonic gas production from trehalose is conditional on the resident microbiota.
    Without gas-producing organisms, the literature predicts that distention and gas
    expulsion will not occur even when trehalose is maldigested.
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If colonic bacteria cannot produce gases, then distention of the abdomen and
      intestinal gas expulsion as eructations and flatus will not occur.
    explanation: Establishes the microbiota-dependent conditionality of gaseous symptoms.
  downstream:
  - target: Abdominal distention after trehalose ingestion
    description: Fermentation-derived gas distends the abdomen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        distention of the abdomen and intestinal gas expulsion as eructations and flatus
      explanation: Directly supports the gas-to-distention edge.
  - target: Flatulence after trehalose ingestion
    description: Fermentation-derived gas is expelled as flatus.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        distention of the abdomen and intestinal gas expulsion as eructations and flatus
      explanation: Directly supports the gas-to-flatulence phenotype edge.
  - target: Abdominal pain after trehalose ingestion
    description: >-
      Distention and altered luminal water plausibly contribute to abdominal pain, but
      the evidence does not resolve a single direct pain mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
      reference_title: "Methods"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        leads to abdominal pain, distention, and flatulence after trehalose ingestion
      explanation: >-
        Supports the phenotype association but not a uniquely resolved pain pathway.
phenotypes:
- category: Gastrointestinal
  name: Diarrhea after trehalose ingestion
  description: >-
    Episodic loose stools or diarrhea after a sufficient trehalose exposure, produced by
    the osmotic load of maldigested trehalose.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      osmotic water flow into the colon, resulting in loose stools and diarrhea
    explanation: Directly supports diarrhea as an osmotic consequence.
- category: Gastrointestinal
  name: Abdominal pain after trehalose ingestion
  description: >-
    Episodic abdominal pain or cramping associated with ingestion of trehalose-containing
    food; the relative contributions of osmotic distention and fermentation are not
    resolved.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leads to abdominal pain, distention, and flatulence after trehalose ingestion
    explanation: Directly associates abdominal pain with trehalose ingestion.
- category: Gastrointestinal
  name: Abdominal distention after trehalose ingestion
  description: >-
    Episodic abdominal distention caused by gas production when the colonic microbiota
    can ferment maldigested trehalose.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distention of the abdomen and intestinal gas expulsion as eructations and flatus
    explanation: Directly documents distention as a conditional gaseous manifestation.
- category: Gastrointestinal
  name: Flatulence after trehalose ingestion
  description: >-
    Episodic passage of intestinal gas after microbial fermentation of maldigested
    trehalose.
  phenotype_term:
    preferred_term: Flatulence
    term:
      id: HP:0033589
      label: Flatulence
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intestinal gas expulsion as eructations and flatus
    explanation: Directly documents gas expulsion after trehalose maldigestion.
- category: Gastrointestinal
  name: Vomiting after trehalose ingestion
  description: >-
    Vomiting is retained because it is part of the exact MONDO disease concept and the
    historical syndrome label. Modern primary studies located for this review document
    the other gastrointestinal manifestations more directly, so its frequency and
    mechanism remain unresolved.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: url:https://www.ebi.ac.uk/ols4/api/ontologies/mondo/terms?obo_id=MONDO:0012803
    reference_title: "https://www.ebi.ac.uk/ols4/api/ontologies/mondo/terms?obo_id=MONDO:0012803"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This syndrome is characterized by diarrhea and vomiting after ingestion of
      trehalose, a disaccharide found mainly in mushrooms.
    explanation: >-
      The exact ontology definition includes vomiting after trehalose ingestion, but
      does not establish its frequency or mechanism.
biochemical:
- name: Reduced small-intestinal trehalase activity
  presence: DECREASED
  context: >-
    Quantitative trehalase activity in a duodenal or jejunal mucosal biopsy is the
    defining biochemical readout. Interpretation is assay-, site-, and
    population-dependent and must account for mucosal histology and the other
    disaccharidases.
  readouts:
  - target: Reduced intestinal brush-border trehalase activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low biopsy trehalase activity reports the proximal biochemical lesion, but is not
      specific for a primary genetic defect when villous injury is present.
    evidence:
    - reference: PMID:10884712
      reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein.
      explanation: Establishes quantitative biopsy activity as a biochemical readout.
  reference_ranges:
  - lower_bound: 4.79
    upper_bound: 37.12
    unit: "U/g{protein}"
    population: >-
      UK gastroenterology referral patients with normal distal-duodenal histology
      (n=369); Dahlqvist disaccharidase assay
    evidence:
    - reference: PMID:10884712
      reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The normal range (mean +/- 2 SD) was 4.79-37.12 U/g protein.
      explanation: Source of the assay-specific reference interval.
    notes: >-
      This is a study-specific mean plus or minus two standard deviations, not a
      universal clinical decision limit.
  evidence:
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The thirty-one patients with villous atrophy had significantly reduced
      disaccharidase activities.
    explanation: >-
      Shows why low trehalase activity is not specific for primary deficiency without
      histologic and multi-enzyme context.
diagnosis:
- name: Small-intestinal biopsy trehalase assay with histologic context
  description: >-
    Direct activity measurement in a duodenal or jejunal mucosal biopsy can establish
    the biochemical deficiency. Simultaneous histology and a disaccharidase panel are
    needed to separate isolated primary deficiency from global secondary loss due to
    villous injury.
  diagnosis_term:
    preferred_term: Biopsy Procedure
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endoscopic distal duodenal biopsies were taken for histological assessment and
      maltase, sucrase, lactase and trehalase estimation.
    explanation: Documents coupled biopsy histology and enzyme measurement.
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activity is significantly reduced in untreated coeliac disease and recovers with
      treatment with a gluten-free diet.
    explanation: Establishes the central secondary-deficiency confounder.
- name: Oral trehalose challenge with breath hydrogen and methane
  description: >-
    A 25-g oral trehalose challenge with symptom recording and breath hydrogen/methane
    measurement has discriminated symptom-defined intolerance in a small study. It is
    not a standardized routine diagnostic test: validated doses, concentrations, and
    comparison with a gold standard are unavailable, and small-intestinal bacterial
    overgrowth can produce a misleading hydrogen rise.
  diagnosis_term:
    preferred_term: Breath Test
    term:
      id: NCIT:C116515
      label: Breath Test
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 25-g oral trehalose load test was performed in 64 subjects. The 19 experiencing
      clear symptoms constituted the trehalose-intolerant subjects.
    explanation: Documents the challenge protocol and symptom-defined study group.
  - reference: PMID:24443064
    reference_title: "Fructose, trehalose and sorbitol malabsorption."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      neither studies comparing this test with a gold standard, nor validated doses and
      concentrations to be used, are available.
    explanation: Review evidence for the lack of validated breath-test standards.
environmental:
- name: Dietary trehalose ingestion
  exposure_term:
    preferred_term: Dietary trehalose ingestion
    term:
      id: ECTO:9000195
      label: exposure to trehalose
  description: >-
    Dietary trehalose is an obligate exposure for clinical expression. Natural sources
    include edible mushrooms and yeast; processed foods may also contain added
    trehalose. The same exposure can be tolerated when residual activity and microbial
    context are sufficient.
  chemicals:
  - trehalose
  influences_mechanisms:
  - target: Unhydrolyzed trehalose reaches the colon
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Ingestion supplies the substrate that remains unhydrolyzed when small-bowel
      trehalase activity is low.
    evidence:
    - reference: PMID:10522609
      reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A 25-g oral trehalose load test was performed in 64 subjects.
      explanation: Directly documents dietary trehalose as the challenge substrate.
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whether maldigestion of trehalose causes abdominal symptoms
    explanation: Supports the exposure-dependent clinical framing.
treatments:
- name: Reduction or avoidance of symptom-triggering trehalose
  description: >-
    A pragmatic dietary strategy is to reduce or avoid the amount and sources of
    trehalose that reproducibly trigger symptoms. The mechanistic rationale is strong,
    but no controlled treatment study, response rate, or disease-specific guideline was
    found; this should not be represented as trial-proven efficacy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:10522609
    reference_title: "Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is obvious that trehalose maldigestion can cause symptoms similar to those of
      lactose maldigestion and intolerance.
    explanation: >-
      Supports removal of the triggering substrate mechanistically, but does not test a
      trehalose-restriction intervention.
prevalence:
- population: Adult Greenlanders undergoing small-intestinal surgical biopsy
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 8000.0
  notes: >-
    At least 8% of this 97-person surgical biopsy series had biochemical low trehalase
    activity. This is not symptomatic-disease prevalence, a representative population
    estimate, or evidence that the same percentage has Mendelian TREH disease.
  evidence:
  - reference: PMID:3227291
    reference_title: "Trehalase deficiency in Greenland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Small-intestinal surgical biopsy specimens from 97 adult Greenlanders showed an
      incidence of trehalase deficiency in at least 8%.
    explanation: Source of the biochemical biopsy-cohort percentage.
- population: Worldwide (gnomAD variant-frequency model)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.92
  notes: >-
    Computational estimate of 9.2 per million births from reported and predicted
    loss-of-function variants, not observed clinical cases. The published abstract
    reports a 95% confidence interval of 2.5-3.7 per million, which cannot contain the
    9.2 point estimate; the interval is retained only as an identified source error and
    is not encoded as rate bounds.
  evidence:
  - reference: PMID:36167617
    reference_title: "Estimating the prevalence of congenital disaccharidase deficiencies using allele frequencies from gnomAD."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      9.2 per 106 births (95% CI: 2.5-3.7) for CTD.
    explanation: >-
      Source of the computational point estimate and its internally inconsistent
      published confidence interval.
- population: UK gastroenterology referral population (duodenal biopsy cohort)
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  notes: >-
    Only one of 369 patients with normal duodenal histology had an isolated borderline
    trehalase deficiency, indicating isolated trehalase deficiency is rare outside of
    populations such as Greenlandic Inuit.
  evidence:
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated intestinal trehalase deficiency is found in 8% of Greenlanders, but is
      rare elsewhere.
    explanation: >-
      States that isolated trehalase deficiency, while present in 8% of Greenlanders,
      is rare in other populations such as the UK.
differential_diagnoses:
- name: Celiac disease with secondary disaccharidase deficiency
  disease_term:
    preferred_term: celiac disease
    term:
      id: MONDO:0005130
      label: celiac disease
  description: >-
    Villous injury in untreated celiac disease can reduce trehalase together with the
    other brush-border disaccharidases and therefore mimic primary deficiency
    biochemically and symptomatically.
  distinguishing_features:
  - Villous atrophy rather than normal mucosal architecture
  - Broad reduction of disaccharidases rather than isolated low trehalase
  - Recovery of trehalase activity with a gluten-free diet
  evidence:
  - reference: PMID:10884712
    reference_title: "Intestinal trehalase activity in a UK population: establishing a normal range and the effect of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The thirty-one patients with villous atrophy had significantly reduced
      disaccharidase activities. With ingestion of a gluten-free diet, maltase, sucrase
      and trehalase activities recovered to normal in most patients
    explanation: Directly documents secondary and reversible reduction with villous injury.
- name: Small-intestinal bacterial overgrowth
  description: >-
    Excess small-intestinal bacteria can ferment multiple test sugars and cause an
    abnormal breath-hydrogen rise, mimicking trehalose malabsorption even when primary
    trehalase deficiency has not been established.
  distinguishing_features:
  - Nonspecific fermentation of multiple sugar substrates
  - Breath-hydrogen positivity does not establish isolated low biopsy trehalase
  evidence:
  - reference: PMID:24443064
    reference_title: "Fructose, trehalose and sorbitol malabsorption."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the large amount of intestinal bacteria may unspecifically ferment sugars, causing
      an abnormal H2 production and consequently a misleading diagnosis of sugar
      malabsorption.
    explanation: Directly supports the breath-test differential.
animal_models:
- name: Trehalase-deficient mouse
  species: Mus musculus
  genotype: Gene-targeted Treh deficiency
  background: C57BL/6J
  genes:
  - preferred_term: TREH
    term:
      id: hgnc:12266
      label: TREH
  description: >-
    RBRC00857 gene-targeted trehalase-deficient mice show no blood-glucose rise on an
    oral trehalose tolerance test, recapitulating a proximal digestive readout. Published
    studies use the model mainly to study trehalose and lipid metabolism; diarrhea,
    distention, flatulence, transit, and microbiome-dependent fermentation have not been
    established as model phenotypes.
  publication: PMID:32206077
  associated_phenotypes:
  - Absent blood-glucose rise after oral trehalose
  modeled_mechanisms:
  - target: Reduced intestinal brush-border trehalase activity
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Genetic trehalase deficiency produces the expected absent glycemic response after
      an oral trehalose challenge.
    fidelity: MODERATE
    limitations: >-
      The cited work does not establish intestinal enzyme activity or the human
      microbiota-dependent gastrointestinal phenotype as readouts.
    evidence:
    - reference: PMID:32206077
      reference_title: "Trehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        An oral trehalose tolerance test revealed that these trehalase-deficient mice
        exhibited no changes in blood glucose levels.
      explanation: Directly supports the proximal challenge-test phenotype.
  evidence:
  - reference: PMID:32206077
    reference_title: "Trehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      and deposited these mice with RIKEN. An oral trehalose tolerance test revealed
      that these trehalase-deficient mice exhibited no changes in blood glucose levels.
    explanation: Documents model generation and repository deposition.
datasets:
- accession: dbgap:phs000917
  title: Pakistan Risk of Myocardial Infarction Study (PROMIS) human knockout cohort
  description: >-
    Whole-exome sequencing of 10,503 adult PROMIS participants identified six adults
    homozygous for a predicted TREH splice-acceptor deletion. The cohort was assembled
    for cardiometabolic research rather than trehalase deficiency, and no trehalose
    challenge or intestinal-enzyme phenotype was reported for the TREH homozygotes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WES
  sample_count: 10503
  conditions:
  - Broad adult cardiometabolic cohort
  genes:
  - preferred_term: TREH
    term:
      id: hgnc:12266
      label: TREH
  publication: PMID:28406212
  notes: >-
    Direct variant-cohort relevance, not a disease-specific natural-history dataset.
    Sequence data are controlled-access through dbGaP.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we sequenced the protein-coding regions of 10,503 adult participants in the
      Pakistan Risk of Myocardial Infarction Study (PROMIS)
    explanation: Supports study design and sample count.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA sequences have been deposited with the NIH dbGAP repository under accession
      numbers phs000917.
    explanation: Supports the public controlled-access dataset identifier.
discussions:
- discussion_id: trehalase_inheritance_and_variant_validity_conflict
  prompt: >-
    Is primary TREH-associated trehalase deficiency dominantly or recessively inherited,
    and which variants have sufficient clinical evidence to establish either model?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - genetic#TREH-associated primary trehalase deficiency
  rationale: >-
    Current Orphanet-derived structured data report dominant inheritance, whereas a
    later human-knockout paper labels the trait recessive. The one recurrent splice
    deletion has conflicting ClinVar classifications and lacks enzyme- or
    challenge-confirmed phenotyping in its six homozygotes. Recurrence-risk counseling
    and molecular diagnosis should therefore not assume a settled model.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268187/
    reference_title: "alpha, alpha-Trehalase deficiency - NIH Genetic Testing Registry (GTR) - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      alpha, alpha-Trehalase deficiency ... Modes of inheritance ... Autosomal
      dominant inheritance ... Source: Orphanet
    explanation: Documents the current dominant structured-source assertion.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5600291/fullTextXML
    reference_title: "Methods"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trehalase deficiency, an autosomal recessive trait"
    explanation: Documents the conflicting recessive literature assertion.
  - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/488190/
    reference_title: "VCV000488190.3 - ClinVar - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathogenic (1); Uncertain significance (1)"
    explanation: Documents the unresolved variant-classification split.
- discussion_id: treh_genotype_activity_clinical_expression_gap
  prompt: >-
    How often do common activity-lowering TREH genotypes cause enzyme-confirmed,
    trehalose-provoked clinical disease rather than only a lower biochemical activity?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#TREH activity-modifying common variation
  - biochemical#Reduced small-intestinal trehalase activity
  rationale: >-
    Recent population studies genotype rs2276064 and infer enzymopathy without directly
    measuring intestinal activity or symptoms. Their high genotype frequencies cannot
    be used as prevalence of MONDO:0012803, and the genotype-to-clinical penetrance bridge
    remains unquantified.
  evidence:
  - reference: PMID:36880131
    reference_title: "Prevalence of genetically determined trehalase deficiency in populations of Siberia and Russian Far East."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The question on to what degree the genotype-determined trehalase deficiency comes
      out clinically needs further elaboration.
    explanation: The authors explicitly identify the missing genotype-to-clinical bridge.
  - reference: PMID:39283558
    reference_title: "Prevalence of Trehalase Enzymopathy Genetic Determinants in Siberian and Russian Far East Populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genotyping of 1068 DNA samples was carried out
    explanation: >-
      The current study is a genotype-frequency analysis rather than a clinical
      penetrance study.
- discussion_id: trehalase_mouse_human_gastrointestinal_fidelity
  prompt: >-
    Does a Treh-deficient mouse reproduce the human osmotic and
    microbiota-dependent gastrointestinal phenotype after a controlled trehalose load?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Trehalase-deficient mouse
  - pathophysiology#Microbial fermentation of maldigested trehalose
  - phenotypes#Diarrhea after trehalose ingestion
  rationale: >-
    Mouse knockout studies reproduce an absent glycemic response or examine metabolic
    endpoints, but do not establish diarrhea, distention, flatulence, transit, or
    fermentation. Because the human gaseous phenotype is microbiota-dependent, proximal
    biochemical fidelity cannot be generalized to clinical fidelity.
  evidence:
  - reference: PMID:32206077
    reference_title: "Trehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      An oral trehalose tolerance test revealed that these trehalase-deficient mice
      exhibited no changes in blood glucose levels.
    explanation: Documents the proximal readout that is established in the model.
  - reference: PMID:40529415
    reference_title: "Assessing the efficacy of the natural disaccharide trehalose in ameliorating diet-induced obesity and metabolic dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Systemic trehalase-deficient mice showed no metabolic changes at baseline.
    explanation: >-
      A current independent knockout study again focuses on metabolic rather than human
      gastrointestinal outcomes.
review_notes: >-
  The 2026 review kept the exact MONDO:0012803 disorder but narrowed it to primary
  isolated trehalase deficiency. Common rs2276064-associated low activity is represented
  only as a biochemical modifier, secondary low activity from celiac villous injury is a
  differential diagnosis, and neither is counted as Mendelian-disease prevalence. The
  former recessive loss-of-function claim was replaced by an explicit
  dominant-versus-recessive controversy because current structured resources and the
  later human-knockout literature disagree. The c.90-9_106del allele remains
  classification-conflicted and clinically underphenotyped. The pathograph separates
  the exposure-gated enzyme defect, luminal substrate, osmotic arm, and conditional
  microbial arm.
  Asymptomatic low activity is no longer misrepresented as a diarrhea phenotype.
  Biopsy and breath testing are evidence-calibrated, dietary reduction is mechanistically
  reasonable but not trial-proven, and the gnomAD prevalence confidence interval is
  flagged as internally impossible rather than silently repaired. No GeneReviews chapter,
  disease-specific clinical trial, controlled treatment study, or natural-history cohort
  was identified. PROMIS is retained only as a direct TREH variant cohort with explicit
  non-disease-specific limitations.

Trehalase Deficiency

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