Trimethylaminuria

Mendelian MONDO:0018767 Pathograph 11 Show in embeddings browser disorder of methylamine metabolism Inborn error of metabolism

Trimethylaminuria (TMAU, "fish-odour syndrome") is an autosomal recessive inborn error of methylamine metabolism caused by biallelic loss-of-function variants in FMO3, which encodes hepatic flavin-containing monooxygenase 3. FMO3 normally N-oxidises the volatile, fishy-smelling amine trimethylamine (TMA) — produced by gut bacteria from dietary precursors such as choline and trimethylamine-N-oxide (TMAO) — to the odourless, water-soluble TMAO, which is excreted in urine. When FMO3 activity is deficient, unoxidised TMA accumulates and is excreted in the urine, sweat, saliva, and breath, producing a characteristic body odour reminiscent of rotting fish. The condition is biochemically benign but frequently causes serious psychosocial harm (social isolation, depression). Disease severity spans a spectrum from mild/transient forms (often associated with common hypomorphic FMO3 haplotypes, hormonal state, or high substrate load) to severe primary TMAU caused by two inactivating FMO3 alleles; secondary/acquired forms (e.g., hepatic disease, substrate overload) also occur and are not caused by FMO3 variants. This entry models the primary, FMO3-related disorder (OMIM:602079, Orphanet:468726).

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2
Mappings
1
Inheritance
3
Pathophys.
3
Phenotypes
11
Pathograph
1
Genes
3
Medical Actions
🔗

Mappings

MONDO
MONDO:0018767 severe primary trimethylaminuria
skos:exactMatch MONDO
MONDO gene-specific (FMO3) trimethylaminuria term; exact match for OMIM:602079 and Orphanet:468726. Despite the "severe" in its label, its definition is "any trimethylaminuria in which the cause is a mutation in the FMO3 gene", i.e., the primary/genetic form curated here.
MONDO:0011182 trimethylaminuria Not Yet Curated
skos:broadMatch MONDO
Broader clinical trimethylaminuria grouping (includes secondary/acquired forms) of which the FMO3-related disorder is the primary genetic member.
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:9398858 SUPPORT Human Clinical
"colloquially known as fish-odour syndrome, is inherited recessively as"
Establishes recessive inheritance of the primary disorder.
⚙

Pathophysiology

3
Impaired hepatic trimethylamine N-oxidation (FMO3 deficiency)
Biallelic loss-of-function FMO3 variants reduce or abolish hepatic flavin-containing monooxygenase 3 activity, the enzyme that catalyses the NADPH- and FAD-dependent N-oxidation of trimethylamine to trimethylamine N-oxide. This is the rate-limiting detoxication step for gut-derived TMA in the liver.
FMO3 hgnc:3771
amine (trimethylamine) metabolic process GO:0009308 ↓ DECREASED
flavin-containing monooxygenase (N-oxidation) activity GO:0004499 ↓ DECREASED
Downstream
Trimethylamine accumulation and excretion Loss of hepatic N-oxidation leaves gut-derived TMA unoxidised, so it accumulates systemically and is excreted.
Show evidence (2 references)
PMID:9398858 SUPPORT Human Clinical
"tissue localization and functional studies have established FMO3 as the form"
Establishes FMO3 as the flavin-containing monooxygenase responsible for TMA oxidation and defective in the syndrome.
PMID:31240165 SUPPORT Human Clinical
"hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of"
Identifies the defect as one of hepatic TMA metabolism causing TMA accumulation.
Trimethylamine accumulation and excretion
Trimethylamine is generated by the gut microbiota from reduction of dietary precursors including trimethylamine-N-oxide (abundant in marine fish), choline, and carnitine. With hepatic N-oxidation impaired, the free amine accumulates and is excreted unchanged in urine, sweat, saliva, and expired air.
Downstream
Fishy body odour and psychosocial impact Volatile TMA excreted in body fluids and breath produces the fishy malodour.
Show evidence (2 references)
PMID:21451776 SUPPORT Human Clinical
"trimethylamine (TMA) accumulates and is excreted in the urine, but is also found"
Describes TMA accumulation and excretion in urine, sweat, and breath.
PMID:21451776 SUPPORT Human Clinical
"TMA is formed by bacteria in the mammalian gut from reduction of"
Establishes the gut-microbial origin of TMA from dietary precursors.
Fishy body odour and psychosocial impact
The excreted volatile trimethylamine gives affected individuals a body odour reminiscent of rotting fish. Although the disorder is otherwise benign, the stigmatising odour commonly causes profound psychosocial harm, including social isolation, clinical depression, and, rarely, suicidality.
Show evidence (1 reference)
PMID:9398858 SUPPORT Human Clinical
"sufferers may display a variety of psychosocial reactions, ranging"
Documents the psychosocial reactions associated with the malodour.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Trimethylaminuria 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

3
Nervous System 1
Depression Depression HP:0000716
Show evidence (1 reference)
PMID:9398858 SUPPORT Human Clinical
"from social isolation of clinical depression and attempted suicide"
Reports depression among the psychosocial reactions to the disorder.
Other 2
Fish-like body odour Fish odor HP:0410020
Show evidence (1 reference)
PMID:9398858 SUPPORT Human Clinical
"Individuals with primary trimethylaminuria exhibit a body odour reminiscent of"
Describes the fish-like body odour that defines the syndrome.
Trimethylaminuria (urinary trimethylamine excretion) Trimethylaminuria HP:0003614
Show evidence (1 reference)
PMID:21451776 SUPPORT Human Clinical
"trimethylamine (TMA) accumulates and is excreted in the urine, but is also found"
Documents excretion of TMA in the urine.
🧬

Genetic Associations

1
FMO3 variants
Gene: FMO3 hgnc:3771
Autosomal recessive
Show evidence (1 reference)
PMID:9398858 SUPPORT Human Clinical
"coding exons of FMO3 amplified from a patient with fish-odour syndrome"
Identifies causal FMO3 coding variants in an affected patient.
💊

Medical Actions

3
Dietary precursor restriction
Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447
First-line management is dietary restriction of TMA precursors, especially trimethylamine-N-oxide (concentrated in marine fish) and choline-rich foods, to reduce the gut-derived substrate load presented to the impaired liver.
Target Phenotypes: Fish odor HP:0410020
Show evidence (1 reference)
PMID:21451776 SUPPORT Human Clinical
"trimethylaminuria can be improved by changes in the diet to avoid precursors, in"
Dietary avoidance of precursors improves symptoms.
Gut-flora-suppressing antibiotics
Action: Pharmacotherapy NCIT:C15986
Agent: metronidazole CHEBI:6909 neomycin CHEBI:7507
Short intermittent courses of poorly absorbed or gut-active antibiotics (e.g., metronidazole, neomycin) reduce the TMA-producing intestinal microbiota and lower TMA generation.
Target Phenotypes: Fish odor HP:0410020
Show evidence (1 reference)
PMID:21451776 SUPPORT Human Clinical
"with antibiotics to control bacteria in the gut, or activated charcoal to"
Gut-directed antibiotics reduce bacterial TMA production.
Trimethylamine sequestration (activated charcoal)
Action: supportive care Ontology label: Supportive Care NCIT:C15747
Oral sequestrants such as activated charcoal bind intestinal trimethylamine, reducing its absorption and systemic load as an adjunct to dietary measures.
Target Phenotypes: Fish odor HP:0410020
Show evidence (1 reference)
PMID:21451776 SUPPORT Human Clinical
"with antibiotics to control bacteria in the gut, or activated charcoal to"
Activated charcoal sequesters TMA to lower body burden.
🔬

Biochemical Markers

2
Increased urinary free trimethylamine (INCREASED)
Context: Elevated free (unoxidised) trimethylamine in urine is the hallmark biochemical abnormality, reflecting the failure of hepatic N-oxidation.
Pathograph Readouts
Readout Of Trimethylamine accumulation and excretion Positive Diagnostic
Increased urinary free TMA directly reports systemic TMA accumulation.
Show evidence (1 reference)
PMID:21451776 SUPPORT Human Clinical
"Diagnosis of trimethylaminuria requires the measurement of TMA and"
Urinary TMA measurement is the basis of diagnosis.
Reduced TMA-to-TMAO N-oxidation capacity (DECREASED)
Context: The fraction of a TMA load converted to TMAO (the FMO trimethylamine conversion capacity) is reduced; genetic testing is recommended when conversion falls below ~90% of the total TMA load, and severe primary cases convert far less.
Pathograph Readouts
Readout Of Impaired hepatic trimethylamine N-oxidation (FMO3 deficiency) Negative Diagnostic
Reduced TMA-to-TMAO conversion is the functional readout of hepatic FMO3 deficiency.
Show evidence (2 references)
PMID:31240165 SUPPORT Human Clinical
"individuals who convert less than 90% of the total TMA load to TMAO."
Defines the diagnostic threshold of reduced TMA-to-TMAO conversion capacity.
PMID:31240165 SUPPORT Human Clinical
"is made by biochemical analysis of urine, with the calculation of flavin"
Diagnosis rests on urinary biochemistry and calculated FMO conversion capacity.
{ }

Source YAML

click to show 
name: Trimethylaminuria
category: Mendelian
creation_date: '2026-07-08T00:00:00Z'
synonyms:
- TMAU
- Primary trimethylaminuria
- Fish odor syndrome
- Fish-odour syndrome
- Fish malodor syndrome
- FMO3 deficiency
- Flavin-containing monooxygenase 3 deficiency
description: >
  Trimethylaminuria (TMAU, "fish-odour syndrome") is an autosomal recessive
  inborn error of methylamine metabolism caused by biallelic loss-of-function
  variants in FMO3, which encodes hepatic flavin-containing monooxygenase 3.
  FMO3 normally N-oxidises the volatile, fishy-smelling amine trimethylamine
  (TMA) — produced by gut bacteria from dietary precursors such as choline and
  trimethylamine-N-oxide (TMAO) — to the odourless, water-soluble TMAO, which is
  excreted in urine. When FMO3 activity is deficient, unoxidised TMA accumulates
  and is excreted in the urine, sweat, saliva, and breath, producing a
  characteristic body odour reminiscent of rotting fish. The condition is
  biochemically benign but frequently causes serious psychosocial harm (social
  isolation, depression). Disease severity spans a spectrum from mild/transient
  forms (often associated with common hypomorphic FMO3 haplotypes, hormonal
  state, or high substrate load) to severe primary TMAU caused by two
  inactivating FMO3 alleles; secondary/acquired forms (e.g., hepatic disease,
  substrate overload) also occur and are not caused by FMO3 variants. This
  entry models the primary, FMO3-related disorder (OMIM:602079,
  Orphanet:468726).
disease_term:
  preferred_term: primary trimethylaminuria (FMO3-related)
  term:
    id: MONDO:0018767
    label: severe primary trimethylaminuria
parents:
- disorder of methylamine metabolism
- Inborn error of metabolism
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018767
      label: severe primary trimethylaminuria
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO gene-specific (FMO3) trimethylaminuria term; exact match for
      OMIM:602079 and Orphanet:468726. Despite the "severe" in its label, its
      definition is "any trimethylaminuria in which the cause is a mutation in
      the FMO3 gene", i.e., the primary/genetic form curated here.
  - term:
      id: MONDO:0011182
      label: trimethylaminuria
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      Broader clinical trimethylaminuria grouping (includes secondary/acquired
      forms) of which the FMO3-related disorder is the primary genetic member.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >
    A rare, almost certainly under-diagnosed disorder known predominantly from
    case reports and small cohorts; population-based rates are not established.
    Mild and transient presentations linked to common hypomorphic FMO3
    haplotypes are more frequent than the severe primary form.
  evidence:
  - reference: PMID:31240165
    reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited trimethylaminuria (TMAU), a rare genetic disorder of"
    explanation: Characterises inherited TMAU as a rare genetic disorder.
progression:
- phase: Severity spectrum (mild/transient to severe primary)
  notes: >
    Clinical severity ranges from mild or intermittent odour (unmasked by
    hormonal changes, menstruation, or a high substrate/precursor load, often on
    a background of common hypomorphic FMO3 haplotypes) to severe, constant
    malodour in individuals homozygous or compound heterozygous for inactivating
    FMO3 variants. In milder or intermittent cases the biochemical abnormality
    may only be demonstrable after a high-substrate (marine-fish) challenge meal.
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "or intermittent cases, most simply, a marine-fish meal. The symptoms of"
    explanation: Notes intermittent/milder cases requiring a high-substrate challenge for detection.
pathophysiology:
- name: Impaired hepatic trimethylamine N-oxidation (FMO3 deficiency)
  description: >
    Biallelic loss-of-function FMO3 variants reduce or abolish hepatic
    flavin-containing monooxygenase 3 activity, the enzyme that catalyses the
    NADPH- and FAD-dependent N-oxidation of trimethylamine to trimethylamine
    N-oxide. This is the rate-limiting detoxication step for gut-derived TMA in
    the liver.
  genes:
  - preferred_term: FMO3
    term:
      id: hgnc:3771
      label: FMO3
  molecular_functions:
  - preferred_term: flavin-containing monooxygenase (N-oxidation) activity
    term:
      id: GO:0004499
      label: N,N-dimethylaniline monooxygenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: amine (trimethylamine) metabolic process
    term:
      id: GO:0009308
      label: amine metabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: trimethylamine
    term:
      id: CHEBI:18139
      label: trimethylamine
  - preferred_term: trimethylamine N-oxide
    term:
      id: CHEBI:15724
      label: trimethylamine N-oxide
    modifier: DECREASED
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tissue localization and functional studies have established FMO3 as the form"
    explanation: Establishes FMO3 as the flavin-containing monooxygenase responsible for TMA oxidation and defective in the syndrome.
  - reference: PMID:31240165
    reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of"
    explanation: Identifies the defect as one of hepatic TMA metabolism causing TMA accumulation.
  downstream:
  - target: Trimethylamine accumulation and excretion
    causal_link_type: DIRECT
    description: Loss of hepatic N-oxidation leaves gut-derived TMA unoxidised, so it accumulates systemically and is excreted.
    evidence:
    - reference: PMID:21451776
      reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "trimethylaminuria sufferers have an inherited enzyme deficiency where TMA is not"
      explanation: Links the inherited enzyme deficiency to inefficient conversion of TMA to TMAO.
- name: Trimethylamine accumulation and excretion
  description: >
    Trimethylamine is generated by the gut microbiota from reduction of dietary
    precursors including trimethylamine-N-oxide (abundant in marine fish),
    choline, and carnitine. With hepatic N-oxidation impaired, the free amine
    accumulates and is excreted unchanged in urine, sweat, saliva, and expired
    air.
  chemical_entities:
  - preferred_term: trimethylamine
    term:
      id: CHEBI:18139
      label: trimethylamine
    modifier: INCREASED
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "trimethylamine (TMA) accumulates and is excreted in the urine, but is also found"
    explanation: Describes TMA accumulation and excretion in urine, sweat, and breath.
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TMA is formed by bacteria in the mammalian gut from reduction of"
    explanation: Establishes the gut-microbial origin of TMA from dietary precursors.
  downstream:
  - target: Fishy body odour and psychosocial impact
    causal_link_type: DIRECT
    description: Volatile TMA excreted in body fluids and breath produces the fishy malodour.
    evidence:
    - reference: PMID:9398858
      reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with primary trimethylaminuria exhibit a body odour reminiscent of"
      explanation: Links TMA excretion to the characteristic fishy body odour.
- name: Fishy body odour and psychosocial impact
  description: >
    The excreted volatile trimethylamine gives affected individuals a body odour
    reminiscent of rotting fish. Although the disorder is otherwise benign, the
    stigmatising odour commonly causes profound psychosocial harm, including
    social isolation, clinical depression, and, rarely, suicidality.
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sufferers may display a variety of psychosocial reactions, ranging"
    explanation: Documents the psychosocial reactions associated with the malodour.
phenotypes:
- name: Fish-like body odour
  category: Physiological
  phenotype_term:
    preferred_term: Fish odor
    term:
      id: HP:0410020
      label: Fish odor
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with primary trimethylaminuria exhibit a body odour reminiscent of"
    explanation: Describes the fish-like body odour that defines the syndrome.
- name: Trimethylaminuria (urinary trimethylamine excretion)
  category: Biochemical
  phenotype_term:
    preferred_term: Trimethylaminuria
    term:
      id: HP:0003614
      label: Trimethylaminuria
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "trimethylamine (TMA) accumulates and is excreted in the urine, but is also found"
    explanation: Documents excretion of TMA in the urine.
- name: Depression
  category: Neuropsychiatric
  description: >
    Secondary psychosocial consequence of the chronic stigmatising odour rather
    than a primary neurological feature of the metabolic defect.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "from social isolation of clinical depression and attempted suicide"
    explanation: Reports depression among the psychosocial reactions to the disorder.
biochemical:
- name: Increased urinary free trimethylamine
  presence: INCREASED
  context: >
    Elevated free (unoxidised) trimethylamine in urine is the hallmark
    biochemical abnormality, reflecting the failure of hepatic N-oxidation.
  biomarker_term:
    preferred_term: trimethylamine
    term:
      id: CHEBI:18139
      label: trimethylamine
  readouts:
  - target: Trimethylamine accumulation and excretion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary free TMA directly reports systemic TMA accumulation.
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of trimethylaminuria requires the measurement of TMA and"
    explanation: Urinary TMA measurement is the basis of diagnosis.
- name: Reduced TMA-to-TMAO N-oxidation capacity
  presence: DECREASED
  context: >
    The fraction of a TMA load converted to TMAO (the FMO trimethylamine
    conversion capacity) is reduced; genetic testing is recommended when
    conversion falls below ~90% of the total TMA load, and severe primary cases
    convert far less.
  biomarker_term:
    preferred_term: trimethylamine N-oxide
    term:
      id: CHEBI:15724
      label: trimethylamine N-oxide
  readouts:
  - target: Impaired hepatic trimethylamine N-oxidation (FMO3 deficiency)
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced TMA-to-TMAO conversion is the functional readout of hepatic FMO3 deficiency.
  evidence:
  - reference: PMID:31240165
    reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals who convert less than 90% of the total TMA load to TMAO."
    explanation: Defines the diagnostic threshold of reduced TMA-to-TMAO conversion capacity.
  - reference: PMID:31240165
    reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is made by biochemical analysis of urine, with the calculation of flavin"
    explanation: Diagnosis rests on urinary biochemistry and calculated FMO conversion capacity.
treatments:
- name: Dietary precursor restriction
  description: >
    First-line management is dietary restriction of TMA precursors, especially
    trimethylamine-N-oxide (concentrated in marine fish) and choline-rich foods,
    to reduce the gut-derived substrate load presented to the impaired liver.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Fish odor
    term:
      id: HP:0410020
      label: Fish odor
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "trimethylaminuria can be improved by changes in the diet to avoid precursors, in"
    explanation: Dietary avoidance of precursors improves symptoms.
- name: Gut-flora-suppressing antibiotics
  description: >
    Short intermittent courses of poorly absorbed or gut-active antibiotics
    (e.g., metronidazole, neomycin) reduce the TMA-producing intestinal
    microbiota and lower TMA generation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
    - preferred_term: neomycin
      term:
        id: CHEBI:7507
        label: neomycin
  target_phenotypes:
  - preferred_term: Fish odor
    term:
      id: HP:0410020
      label: Fish odor
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with antibiotics to control bacteria in the gut, or activated charcoal to"
    explanation: Gut-directed antibiotics reduce bacterial TMA production.
- name: Trimethylamine sequestration (activated charcoal)
  description: >
    Oral sequestrants such as activated charcoal bind intestinal trimethylamine,
    reducing its absorption and systemic load as an adjunct to dietary measures.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Fish odor
    term:
      id: HP:0410020
      label: Fish odor
  evidence:
  - reference: PMID:21451776
    reference_title: "Trimethylaminuria: causes and diagnosis of a socially distressing condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with antibiotics to control bacteria in the gut, or activated charcoal to"
    explanation: Activated charcoal sequesters TMA to lower body burden.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "colloquially known as fish-odour syndrome, is inherited recessively as"
    explanation: Establishes recessive inheritance of the primary disorder.
genetic:
- name: FMO3 variants
  gene_term:
    preferred_term: FMO3
    term:
      id: hgnc:3771
      label: FMO3
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:9398858
      reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "colloquially known as fish-odour syndrome, is inherited recessively as"
      explanation: Establishes autosomal recessive inheritance.
  variants:
  - name: Biallelic inactivating FMO3 variants
    description: >
      Severe primary TMAU results from homozygous or compound-heterozygous
      inactivating FMO3 variants. Recurrent severe alleles include the
      catalytically inactivating p.Pro153Leu missense variant and the
      p.Glu305* nonsense variant; milder/intermittent disease is associated with
      common hypomorphic haplotypes (e.g., p.Glu158Lys;p.Glu308Gly).
    evidence:
    - reference: PMID:31240165
      reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "and c.458C>T;p.(Pro153Leu) mutations in this Irish population with severe TMAU"
      explanation: Reports recurrent severe FMO3 alleles including p.Pro153Leu.
    - reference: PMID:31240165
      reference_title: The genetic and biochemical basis of trimethylaminuria in an Irish cohort.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "homozygous for the common variant haplotype"
      explanation: Documents common hypomorphic FMO3 haplotypes underlying milder presentations.
  evidence:
  - reference: PMID:9398858
    reference_title: "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coding exons of FMO3 amplified from a patient with fish-odour syndrome"
    explanation: Identifies causal FMO3 coding variants in an affected patient.
notes: >-
  This entry models the primary, FMO3-related form of trimethylaminuria
  (MONDO:0018767; OMIM:602079; Orphanet:468726). Secondary/acquired
  trimethylaminuria (from hepatic disease, precursor overload, or transient
  states such as menstruation) shares the biochemical and odour phenotype but is
  not caused by FMO3 variants and is out of scope here. Low-dose riboflavin
  (an FAD precursor) is sometimes used to maximise residual FMO3 activity, and
  acidic soaps/lotions can reduce cutaneous odour, but these adjuncts are not
  captured as evidence-backed treatments in this increment. Curated as the first
  methylamine-metabolism new-entry increment for IEMbase WP-006 (issue #5561).