🔗

Mappings

MONDO

MONDO:0011610 dimethylglycine dehydrogenase deficiency

MONDO exact match for Orphanet ORPHA:243343 and OMIM:605850.

👪

Inheritance

1

Autosomal recessive HP:0000007

The disorder is represented by a homozygous disease-associated DMGDH variant in the reported patient, consistent with recessive inheritance.

Autosomal recessive inheritance

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"A homozygous missense mutation was found in the DMGDH gene of the patient."

The original patient carried a homozygous DMGDH missense variant, supporting recessive inheritance for this single-family disorder.

⚙

Pathophysiology

6

DMGDH molecular function deficiency

DMGDH encodes a mitochondrial matrix enzyme that uses flavin adenine dinucleotide and tetrahydrofolate to catalyse oxidative demethylation of N,N-dimethylglycine to sarcosine. Deficient DMGDH activity blocks this choline and one-carbon metabolic step and causes dimethylglycine accumulation.

DMGDH link

choline metabolic process link ↓ DECREASED one-carbon metabolic process link ↓ DECREASED oxidative demethylation link ↓ DECREASED

dimethylglycine dehydrogenase activity link ↓ DECREASED

mitochondrial matrix link

mitochondrion link

Downstream

Sarcosine-forming oxidative demethylation block Loss of DMGDH activity blocks FAD- and tetrahydrofolate-dependent oxidative demethylation of dimethylglycine to sarcosine.

DMGDH-linked mitochondrial electron-transfer impairment DMGDH normally transfers reducing equivalents from dimethylglycine oxidation through electron-transfer flavoprotein toward the respiratory chain; deficient enzyme activity is expected to reduce that input.

Dimethylglycine accumulation Reduced DMGDH activity blocks oxidative demethylation of dimethylglycine, allowing N,N-dimethylglycine to accumulate in serum and urine.

Show evidence (3 references)

DOI:10.1111/febs.13828 SUPPORT In Vitro

"The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)‐ and tetrahydrofolate (THF)‐dependent, mitochondrial matrix enzyme taking part in choline degradation, one‐carbon metabolism and electron transfer to the respiratory chain."

Recombinant structural and biochemical work places DMGDH in mitochondrial choline and one-carbon metabolism and identifies tetrahydrofolate as a cofactor.

DOI:10.1007/s10545-008-0999-2 SUPPORT In Vitro

"Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine to form sarcosine"

Recombinant enzyme work establishes the DMGDH-catalyzed metabolic reaction and mitochondrial context.

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"The high concentration of DMG was caused by a deficiency of the enzyme dimethylglycine dehydrogenase (DMGDH)."

The discovery study directly links high DMG in the patient to DMGDH deficiency.

H109R DMGDH variant functional impairment

The disease-associated H109R DMGDH variant has reduced bound flavin and markedly impaired catalytic performance in recombinant biochemical assays, providing a mechanistic basis for its pathogenicity.

DMGDH link

dimethylglycine dehydrogenase activity link ↓ DECREASED FAD binding link ↓ DECREASED

Downstream

DMGDH molecular function deficiency H109R-related cofactor and substrate-affinity defects reduce DMGDH molecular function.

DMGDH-linked mitochondrial electron-transfer impairment H109R lowers flavin binding and catalytic activity, reducing the DMGDH reaction that supplies electrons to electron-transfer flavoprotein.

Show evidence (3 references)

DOI:10.1007/s10545-008-0999-2 SUPPORT In Vitro

"The H109R variant, however, had only 47% of the wild‐type level of bound flavin as expressed in E. coli, indicating its reduced affinity for FAD"

The H109R recombinant protein had reduced flavin binding, supporting a cofactor-affinity defect.

DOI:10.1007/s10545-008-0999-2 SUPPORT In Vitro

"The flavinated H109R variant protein exhibited a 27‐fold decrease in specific activity and a 65‐fold increase in Km, explaining its pathogenicity."

Functional enzyme kinetics directly support reduced activity and pathogenicity of H109R.

DOI:10.1111/febs.13828 SUPPORT In Vitro

"A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity."

Later recombinant structural/biochemical work independently supports H109R functional impairment.

Sarcosine-forming oxidative demethylation block

DMGDH normally oxidatively demethylates N,N-dimethylglycine to sarcosine in the mitochondrial matrix using FAD and tetrahydrofolate. In DMGDH deficiency, this enzymatic step is blocked, explaining the upstream dimethylglycine storage product while predicting reduced sarcosine generation at the reaction level.

oxidative demethylation link ↓ DECREASED choline metabolic process link ↓ DECREASED one-carbon metabolic process link ↓ DECREASED

mitochondrial matrix link

Downstream

Dimethylglycine accumulation Blocking sarcosine-forming dimethylglycine demethylation leaves N,N-dimethylglycine as the accumulating upstream substrate.

Show evidence (2 references)

DOI:10.1007/s10545-008-0999-2 SUPPORT In Vitro

"Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine to form sarcosine"

Recombinant enzyme biochemistry defines the sarcosine-forming reaction blocked by DMGDH deficiency.

DOI:10.1111/febs.13828 PARTIAL In Vitro

"The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)‐ and tetrahydrofolate (THF)‐dependent, mitochondrial matrix enzyme taking part in choline degradation, one‐carbon metabolism and electron transfer to the respiratory chain."

Independent recombinant work places hDMGDH in the same FAD/THF-dependent mitochondrial choline and one-carbon metabolic step; the disease block itself is supported by the patient and H109R functional evidence.

DMGDH-linked mitochondrial electron-transfer impairment

DMGDH is an FAD-dependent mitochondrial matrix enzyme whose reduced flavin is normally reoxidized by electron-transfer flavoprotein, which transfers reducing equivalents to the main respiratory chain through ETF-ubiquinone oxidoreductase. The H109R variant reduces flavin binding and catalytic activity, so reduced DMGDH-linked electron transfer is a plausible biochemical branch, but direct patient-level respiratory-chain dysfunction has not been demonstrated.

electron transfer activity link ↓ DECREASED

mitochondrial matrix link

Downstream

Muscle involvement with creatine kinase release The index patient had muscle fatigue and CK elevation; mitochondrial electron-transfer perturbation is a plausible but unproven contributor.

Show evidence (2 references)

DOI:10.1007/s10545-008-0999-2 SUPPORT In Vitro

"Electron‐transfer flavoprotein reoxidizes the reduced flavin and transfers reducing equivalents to the main mitochondrial respiratory chain through the enzyme ETF‐ubiquinone oxidoreductase."

Recombinant biochemical work establishes the normal DMGDH-to-ETF respiratory-chain electron-transfer route.

DOI:10.1111/febs.13828 PARTIAL In Vitro

"A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity."

The disease-related variant affects properties needed for this FAD-dependent mitochondrial enzyme function, but direct electron-transfer flux was not measured in the patient.

Muscle involvement with creatine kinase release

Muscle involvement in DMGDH deficiency is represented by unusual muscle fatigue with increased serum creatine kinase in the single reported patient. The molecular link from dimethylglycine storage or DMGDH-linked electron-transfer impairment to muscle symptoms remains unresolved.

skeletal muscle cell link

skeletal muscle tissue link

Downstream

Muscle fatigue Muscle involvement manifested clinically as unusual fatigue.

Elevated serum creatine kinase Muscle involvement was accompanied by increased serum creatine kinase.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."

The index patient had the paired muscle-fatigue and serum-CK findings represented by this limited-evidence branch.

Dimethylglycine accumulation

Impaired DMGDH activity produces a biochemical phenotype dominated by accumulation of N,N-dimethylglycine in body fluids.

Downstream

Fish-like body odor The relationship between dimethylglycine accumulation and fish-like odor is clinically associated in the index patient, but the odor-generating intermediate is not established.

Muscle involvement with creatine kinase release The defining DMG biochemical abnormality co-occurred with the muscle fatigue and CK-elevation branch, but the intervening mechanism is unknown.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."

NMR-based patient biochemistry identifies serum and urinary DMG accumulation as the defining biomarker.

⬡

Pathograph

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

●

Phenotypes

3

Metabolism 1

Elevated serum creatine kinase Elevated circulating creatine kinase concentration (HP:0003236)

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"unusual muscle fatigue with increased serum creatine kinase."

The original patient had increased serum creatine kinase as part of the presentation.

Constitutional 1

Fish-like body odor Body odor (HP:0500001)

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"A38-year-old man presented with a history of fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."

The original case report states the fish-odor phenotype and age of onset.

Other 1

Muscle fatigue Increased muscle fatiguability (HP:0003750)

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."

The discovery case directly reports unusual muscle fatigue.

🧬

Genetic Associations

1

DMGDH pathogenic variants

Autosomal recessive

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"A homozygous missense mutation was found in the DMGDH gene of the patient."

The discovery report identifies the gene and zygosity in the reported patient.

💊

Treatments

2

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is appropriate for families once biallelic DMGDH pathogenic variation is identified, with discussion of recessive recurrence risk and the very limited human natural-history evidence.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"A homozygous missense mutation was found in the DMGDH gene of the patient."

Identification of a homozygous disease-associated gene finding supports genetic counseling for affected families.

Supportive clinical monitoring

Action: supportive care MAXO:0000950

Supportive care should focus on monitoring the reported manifestations, including fish-like body odor, muscle fatigue, and serum creatine kinase elevation, while confirming the biochemical and genetic diagnosis. No disease-modifying therapy has been established for this ultra-rare disorder.

Target Phenotypes: fish-like body odor ↗ increased muscle fatiguability ↗ elevated serum creatine kinase ↗

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 PARTIAL Human Clinical

"A38-year-old man presented with a history of fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."

The case report supports the manifestations that would be followed clinically; it does not establish a disease-modifying treatment.

🔬

Biochemical Markers

2

N,N-dimethylglycine (INCREASED)

Context: Marked elevation of N,N-dimethylglycine in serum and urine is the defining diagnostic biochemical abnormality.

Pathograph Readouts

Readout Of Dimethylglycine accumulation Positive Diagnostic

Increased serum or urinary N,N-dimethylglycine reports the primary metabolic block in DMGDH deficiency.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."

The biomarker quantitatively reports the dimethylglycine-accumulation node.

Readout Of Sarcosine-forming oxidative demethylation block Positive Diagnostic

Increased N,N-dimethylglycine reports failure of the sarcosine-forming oxidative demethylation step catalyzed by DMGDH.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."

Patient serum and urine DMG elevation is the diagnostic readout of the blocked DMGDH reaction.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."

The discovery study defines the diagnostic serum and urinary DMG elevation.

Creatine kinase (INCREASED)

Context: Serum creatine kinase was increased in the reported patient together with unusual muscle fatigue, making CK a monitoring readout of the limited muscle-involvement branch rather than a primary diagnostic marker of the methylamine metabolic block.

Pathograph Readouts

Readout Of Muscle involvement with creatine kinase release Positive Monitoring

Increased serum creatine kinase reports the observed muscle-involvement branch in the index patient.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"unusual muscle fatigue with increased serum creatine kinase."

Serum CK elevation is the biochemical readout paired with muscle fatigue in the discovery report.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"unusual muscle fatigue with increased serum creatine kinase."

The discovery report directly supports increased serum CK in the index patient.

🔀

Differential Diagnoses

1

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

Fish-odor syndromes including trimethylaminuria

Overlapping Features Fish-like odor is an overlapping presentation, so DMGDH deficiency should be considered when fish odor is accompanied by marked DMG elevation rather than a primary trimethylamine-oxidation defect.

Distinguishing Features

Increased serum and urinary N,N-dimethylglycine.
Homozygous disease-associated DMGDH variant.

Show evidence (1 reference)

DOI:10.1093/clinchem/45.4.459 SUPPORT Human Clinical

"DMGDH deficiency must be added to the differential diagnosis of patients complaining of a fish odor."

The original authors explicitly frame DMGDH deficiency as a differential diagnosis for fish-odor complaints.

{ }

Source YAML

click to show

name: Dimethylglycine Dehydrogenase Deficiency
creation_date: "2026-05-11T17:50:11Z"
updated_date: "2026-05-19T03:31:01Z"
category: Mendelian
synonyms:
- DMG dehydrogenase deficiency
- DMGDH deficiency
- DMGDHD
- hyperdimethylglycinemia
- defect in dimethylglycine dehydrogenase
description: >-
  Dimethylglycine dehydrogenase deficiency is an extremely rare autosomal
  recessive inborn error of choline, methylamine, and one-carbon metabolism
  caused by deficient mitochondrial DMGDH activity. The original patient
  presented with childhood-onset fish odor, unusual muscle fatigue, increased
  serum creatine kinase, and marked accumulation of N,N-dimethylglycine in
  serum and urine. Functional studies of the disease-associated H109R DMGDH
  variant show impaired flavin binding and reduced catalytic activity,
  supporting a hypomorphic loss-of-function mechanism. Because DMGDH normally
  couples dimethylglycine oxidative demethylation to FAD, tetrahydrofolate, and
  electron transfer toward the respiratory chain, the muscle-fatigue and
  creatine-kinase branch is represented as a limited-evidence downstream
  clinical association rather than an established mechanism.
disease_term:
  preferred_term: dimethylglycine dehydrogenase deficiency
  term:
    id: MONDO:0011610
    label: dimethylglycine dehydrogenase deficiency
parents:
- disorder of methylamine metabolism
- Inborn error of metabolism
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011610
      label: dimethylglycine dehydrogenase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO exact match for Orphanet ORPHA:243343 and OMIM:605850.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The disorder is represented by a homozygous disease-associated DMGDH
    variant in the reported patient, consistent with recessive inheritance.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation was found in the DMGDH gene of the patient."
    explanation: The original patient carried a homozygous DMGDH missense variant, supporting recessive inheritance for this single-family disorder.
progression:
- phase: Childhood-onset odor with adult biochemical diagnosis
  age_range: Childhood to adulthood
  notes: >-
    The reported individual had fish odor from about age 5 and was evaluated
    as an adult with unusual muscle fatigue and increased serum creatine kinase.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
    explanation: The discovery report gives the childhood onset of odor and adult clinical findings.
pathophysiology:
- name: DMGDH molecular function deficiency
  description: >-
    DMGDH encodes a mitochondrial matrix enzyme that uses flavin adenine
    dinucleotide and tetrahydrofolate to catalyse oxidative demethylation of
    N,N-dimethylglycine to sarcosine. Deficient DMGDH activity blocks this
    choline and one-carbon metabolic step and causes dimethylglycine accumulation.
  genes:
  - preferred_term: DMGDH
    term:
      id: hgnc:24475
      label: DMGDH
  molecular_functions:
  - preferred_term: dimethylglycine dehydrogenase activity
    term:
      id: GO:0047865
      label: dimethylglycine dehydrogenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: choline metabolic process
    term:
      id: GO:0019695
      label: choline metabolic process
    modifier: DECREASED
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  - preferred_term: oxidative demethylation
    term:
      id: GO:0070989
      label: oxidative demethylation
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  chemical_entities:
  - preferred_term: N,N-dimethylglycine
    term:
      id: CHEBI:58251
      label: N,N-dimethylglycine zwitterion
    modifier: INCREASED
  - preferred_term: sarcosine
    term:
      id: CHEBI:57433
      label: sarcosine zwitterion
    modifier: DECREASED
  - preferred_term: tetrahydrofolate
    term:
      id: CHEBI:67016
      label: tetrahydrofolate
  evidence:
  - reference: DOI:10.1111/febs.13828
    reference_title: "Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)‐ and tetrahydrofolate (THF)‐dependent, mitochondrial matrix enzyme taking part in choline degradation, one‐carbon metabolism and electron transfer to the respiratory chain."
    explanation: Recombinant structural and biochemical work places DMGDH in mitochondrial choline and one-carbon metabolism and identifies tetrahydrofolate as a cofactor.
  - reference: DOI:10.1007/s10545-008-0999-2
    reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine to form sarcosine"
    explanation: Recombinant enzyme work establishes the DMGDH-catalyzed metabolic reaction and mitochondrial context.
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The high concentration of DMG was caused by a deficiency of the enzyme dimethylglycine dehydrogenase (DMGDH)."
    explanation: The discovery study directly links high DMG in the patient to DMGDH deficiency.
  downstream:
  - target: Sarcosine-forming oxidative demethylation block
    causal_link_type: DIRECT
    description: >-
      Loss of DMGDH activity blocks FAD- and tetrahydrofolate-dependent
      oxidative demethylation of dimethylglycine to sarcosine.
    evidence:
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine to form sarcosine"
      explanation: Recombinant human DMGDH biochemistry defines the blocked oxidative demethylation reaction.
  - target: DMGDH-linked mitochondrial electron-transfer impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced FAD-dependent DMGDH turnover limits electron transfer from dimethylglycine oxidation to electron-transfer flavoprotein.
    description: >-
      DMGDH normally transfers reducing equivalents from dimethylglycine
      oxidation through electron-transfer flavoprotein toward the respiratory
      chain; deficient enzyme activity is expected to reduce that input.
    evidence:
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "Electron‐transfer flavoprotein reoxidizes the reduced flavin and transfers reducing equivalents to the main mitochondrial respiratory chain through the enzyme ETF‐ubiquinone oxidoreductase."
      explanation: The biochemical study places normal DMGDH-derived reducing equivalents upstream of ETF-mediated respiratory-chain electron transfer; reduced flux in patients is inferred from deficient enzyme activity.
  - target: Dimethylglycine accumulation
    causal_link_type: DIRECT
    description: >-
      Reduced DMGDH activity blocks oxidative demethylation of dimethylglycine,
      allowing N,N-dimethylglycine to accumulate in serum and urine.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
      explanation: Patient metabolite measurements show the downstream accumulation expected from DMGDH deficiency.
- name: H109R DMGDH variant functional impairment
  description: >-
    The disease-associated H109R DMGDH variant has reduced bound flavin and
    markedly impaired catalytic performance in recombinant biochemical assays,
    providing a mechanistic basis for its pathogenicity.
  genes:
  - preferred_term: DMGDH
    term:
      id: hgnc:24475
      label: DMGDH
  molecular_functions:
  - preferred_term: dimethylglycine dehydrogenase activity
    term:
      id: GO:0047865
      label: dimethylglycine dehydrogenase activity
    modifier: DECREASED
  - preferred_term: FAD binding
    term:
      id: GO:0071949
      label: FAD binding
    modifier: DECREASED
  chemical_entities:
  - preferred_term: FAD
    term:
      id: CHEBI:57692
      label: FAD(3-)
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1007/s10545-008-0999-2
    reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The H109R variant, however, had only 47% of the wild‐type level of bound flavin as expressed in E. coli, indicating its reduced affinity for FAD"
    explanation: The H109R recombinant protein had reduced flavin binding, supporting a cofactor-affinity defect.
  - reference: DOI:10.1007/s10545-008-0999-2
    reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The flavinated H109R variant protein exhibited a 27‐fold decrease in specific activity and a 65‐fold increase in Km, explaining its pathogenicity."
    explanation: Functional enzyme kinetics directly support reduced activity and pathogenicity of H109R.
  - reference: DOI:10.1111/febs.13828
    reference_title: "Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity."
    explanation: Later recombinant structural/biochemical work independently supports H109R functional impairment.
  downstream:
  - target: DMGDH molecular function deficiency
    causal_link_type: DIRECT
    description: >-
      H109R-related cofactor and substrate-affinity defects reduce DMGDH
      molecular function.
    evidence:
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The flavinated H109R variant protein exhibited a 27‐fold decrease in specific activity and a 65‐fold increase in Km, explaining its pathogenicity."
      explanation: The variant-level biochemical impairment explains the upstream molecular deficiency.
  - target: DMGDH-linked mitochondrial electron-transfer impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - H109R reduces FAD binding and catalytic turnover in the FAD-dependent DMGDH electron-transfer enzyme.
    description: >-
      H109R lowers flavin binding and catalytic activity, reducing the DMGDH
      reaction that supplies electrons to electron-transfer flavoprotein.
    evidence:
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "The H109R variant, however, had only 47% of the wild‐type level of bound flavin as expressed in E. coli, indicating its reduced affinity for FAD"
      explanation: Reduced FAD binding in the disease-associated variant supports reduced FAD-dependent enzyme function; impaired electron-transfer flux is inferred.
- name: Sarcosine-forming oxidative demethylation block
  description: >-
    DMGDH normally oxidatively demethylates N,N-dimethylglycine to sarcosine in
    the mitochondrial matrix using FAD and tetrahydrofolate. In DMGDH
    deficiency, this enzymatic step is blocked, explaining the upstream
    dimethylglycine storage product while predicting reduced sarcosine
    generation at the reaction level.
  biological_processes:
  - preferred_term: oxidative demethylation
    term:
      id: GO:0070989
      label: oxidative demethylation
    modifier: DECREASED
  - preferred_term: choline metabolic process
    term:
      id: GO:0019695
      label: choline metabolic process
    modifier: DECREASED
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  chemical_entities:
  - preferred_term: N,N-dimethylglycine
    term:
      id: CHEBI:58251
      label: N,N-dimethylglycine zwitterion
    modifier: INCREASED
  - preferred_term: sarcosine
    term:
      id: CHEBI:57433
      label: sarcosine zwitterion
    modifier: DECREASED
  - preferred_term: tetrahydrofolate
    term:
      id: CHEBI:67016
      label: tetrahydrofolate
  evidence:
  - reference: DOI:10.1007/s10545-008-0999-2
    reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine to form sarcosine"
    explanation: Recombinant enzyme biochemistry defines the sarcosine-forming reaction blocked by DMGDH deficiency.
  - reference: DOI:10.1111/febs.13828
    reference_title: "Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant"
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)‐ and tetrahydrofolate (THF)‐dependent, mitochondrial matrix enzyme taking part in choline degradation, one‐carbon metabolism and electron transfer to the respiratory chain."
    explanation: Independent recombinant work places hDMGDH in the same FAD/THF-dependent mitochondrial choline and one-carbon metabolic step; the disease block itself is supported by the patient and H109R functional evidence.
  downstream:
  - target: Dimethylglycine accumulation
    causal_link_type: DIRECT
    description: >-
      Blocking sarcosine-forming dimethylglycine demethylation leaves
      N,N-dimethylglycine as the accumulating upstream substrate.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
      explanation: Patient serum and urine measurements show the upstream substrate accumulation expected from the blocked reaction.
- name: DMGDH-linked mitochondrial electron-transfer impairment
  mechanism_confidence: HYPOTHETICAL
  description: >-
    DMGDH is an FAD-dependent mitochondrial matrix enzyme whose reduced flavin
    is normally reoxidized by electron-transfer flavoprotein, which transfers
    reducing equivalents to the main respiratory chain through
    ETF-ubiquinone oxidoreductase. The H109R variant reduces flavin binding and
    catalytic activity, so reduced DMGDH-linked electron transfer is a plausible
    biochemical branch, but direct patient-level respiratory-chain dysfunction
    has not been demonstrated.
  molecular_functions:
  - preferred_term: electron transfer activity
    term:
      id: GO:0009055
      label: electron transfer activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  chemical_entities:
  - preferred_term: FAD
    term:
      id: CHEBI:57692
      label: FAD(3-)
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1007/s10545-008-0999-2
    reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electron‐transfer flavoprotein reoxidizes the reduced flavin and transfers reducing equivalents to the main mitochondrial respiratory chain through the enzyme ETF‐ubiquinone oxidoreductase."
    explanation: Recombinant biochemical work establishes the normal DMGDH-to-ETF respiratory-chain electron-transfer route.
  - reference: DOI:10.1111/febs.13828
    reference_title: "Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant"
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity."
    explanation: The disease-related variant affects properties needed for this FAD-dependent mitochondrial enzyme function, but direct electron-transfer flux was not measured in the patient.
  downstream:
  - target: Muscle involvement with creatine kinase release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The index patient had muscle fatigue and CK elevation; mitochondrial
      electron-transfer perturbation is a plausible but unproven contributor.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
      explanation: The clinical report supports muscle involvement in the index patient, but does not prove the electron-transfer intermediate.
- name: Muscle involvement with creatine kinase release
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Muscle involvement in DMGDH deficiency is represented by unusual muscle
    fatigue with increased serum creatine kinase in the single reported
    patient. The molecular link from dimethylglycine storage or DMGDH-linked
    electron-transfer impairment to muscle symptoms remains unresolved.
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
    explanation: The index patient had the paired muscle-fatigue and serum-CK findings represented by this limited-evidence branch.
  downstream:
  - target: Muscle fatigue
    causal_link_type: DIRECT
    description: Muscle involvement manifested clinically as unusual fatigue.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
      explanation: The discovery report directly states unusual muscle fatigue.
  - target: Elevated serum creatine kinase
    causal_link_type: DIRECT
    description: Muscle involvement was accompanied by increased serum creatine kinase.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "unusual muscle fatigue with increased serum creatine kinase."
      explanation: The discovery report directly states increased serum creatine kinase together with muscle fatigue.
- name: Dimethylglycine accumulation
  description: >-
    Impaired DMGDH activity produces a biochemical phenotype dominated by
    accumulation of N,N-dimethylglycine in body fluids.
  chemical_entities:
  - preferred_term: N,N-dimethylglycine
    term:
      id: CHEBI:58251
      label: N,N-dimethylglycine zwitterion
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
    explanation: NMR-based patient biochemistry identifies serum and urinary DMG accumulation as the defining biomarker.
  downstream:
  - target: Fish-like body odor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The relationship between dimethylglycine accumulation and fish-like odor
      is clinically associated in the index patient, but the odor-generating
      intermediate is not established.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
      explanation: The discovery case links the biochemical disorder to a fish-odor presentation.
  - target: Muscle involvement with creatine kinase release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The defining DMG biochemical abnormality co-occurred with the muscle
      fatigue and CK-elevation branch, but the intervening mechanism is unknown.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
      explanation: The index case supports co-occurrence of DMG accumulation with the muscle branch, but not a defined causal intermediate.
phenotypes:
- category: Clinical
  name: Fish-like body odor
  description: >-
    The reported patient had fish odor beginning in childhood; this presentation
    overlaps clinically with trimethylaminuria and related fish-odor syndromes.
  phenotype_term:
    preferred_term: fish-like body odor
    term:
      id: HP:0500001
      label: Body odor
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A38-year-old man presented with a history of fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
    explanation: The original case report states the fish-odor phenotype and age of onset.
- category: Clinical
  name: Muscle fatigue
  description: >-
    Unusual muscle fatigue was part of the reported presentation.
  phenotype_term:
    preferred_term: increased muscle fatiguability
    term:
      id: HP:0003750
      label: Increased muscle fatiguability
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
    explanation: The discovery case directly reports unusual muscle fatigue.
- category: Biochemical
  name: Elevated serum creatine kinase
  description: >-
    Increased serum creatine kinase was reported alongside muscle fatigue in
    the index patient, suggesting biochemical evidence of muscle involvement.
  phenotype_term:
    preferred_term: elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unusual muscle fatigue with increased serum creatine kinase."
    explanation: The original patient had increased serum creatine kinase as part of the presentation.
biochemical:
- name: N,N-dimethylglycine
  biomarker_term:
    preferred_term: N,N-dimethylglycine
    term:
      id: CHEBI:58251
      label: N,N-dimethylglycine zwitterion
  presence: INCREASED
  context: >-
    Marked elevation of N,N-dimethylglycine in serum and urine is the defining
    diagnostic biochemical abnormality.
  readouts:
  - target: Dimethylglycine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased serum or urinary N,N-dimethylglycine reports the primary
      metabolic block in DMGDH deficiency.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
      explanation: The biomarker quantitatively reports the dimethylglycine-accumulation node.
  - target: Sarcosine-forming oxidative demethylation block
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased N,N-dimethylglycine reports failure of the sarcosine-forming
      oxidative demethylation step catalyzed by DMGDH.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
      explanation: Patient serum and urine DMG elevation is the diagnostic readout of the blocked DMGDH reaction.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The concentration of N,N-dimethylglycine (DMG) was increased ∼100-fold in the serum and ∼20-fold in the urine."
    explanation: The discovery study defines the diagnostic serum and urinary DMG elevation.
- name: Creatine kinase
  biomarker_term:
    preferred_term: creatine kinase measurement
    term:
      id: NCIT:C64489
      label: Creatine Kinase Measurement
  presence: INCREASED
  context: >-
    Serum creatine kinase was increased in the reported patient together with
    unusual muscle fatigue, making CK a monitoring readout of the limited
    muscle-involvement branch rather than a primary diagnostic marker of the
    methylamine metabolic block.
  readouts:
  - target: Muscle involvement with creatine kinase release
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased serum creatine kinase reports the observed muscle-involvement
      branch in the index patient.
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "unusual muscle fatigue with increased serum creatine kinase."
      explanation: Serum CK elevation is the biochemical readout paired with muscle fatigue in the discovery report.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unusual muscle fatigue with increased serum creatine kinase."
    explanation: The discovery report directly supports increased serum CK in the index patient.
genetic:
- name: DMGDH pathogenic variants
  gene_term:
    preferred_term: DMGDH
    term:
      id: hgnc:24475
      label: DMGDH
  presence: PRESENT
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: DOI:10.1093/clinchem/45.4.459
      reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A homozygous missense mutation was found in the DMGDH gene of the patient."
      explanation: The homozygous DMGDH missense variant supports recessive inheritance within the genetic section.
  variants:
  - name: H109R
    description: >-
      Homozygous missense variant p.His109Arg (H109R), also described as
      A326G in the Falcon report, identified in the reported patient and shown
      to impair DMGDH flavin binding and catalytic activity in vitro.
    evidence:
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the H109R variant identified in a DMGDH‐deficient patient"
      explanation: The recombinant biochemical study identifies H109R as the patient variant studied.
    - reference: DOI:10.1007/s10545-008-0999-2
      reference_title: "Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The flavinated H109R variant protein exhibited a 27‐fold decrease in specific activity and a 65‐fold increase in Km, explaining its pathogenicity."
      explanation: The same study provides variant-level functional evidence.
  features: >-
    Dimethylglycine dehydrogenase deficiency is associated with homozygous
    pathogenic variation affecting DMGDH.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation was found in the DMGDH gene of the patient."
    explanation: The discovery report identifies the gene and zygosity in the reported patient.
diagnosis:
- name: Serum and urine NMR metabolite analysis
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  description: >-
    Proton NMR spectroscopy of serum and urine can detect the characteristic
    DMG elevation; the original study also used carbon-13 NMR and GC-MS to
    confirm DMG as the storage product.
  markers: N,N-dimethylglycine
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used 1H NMR spectroscopy to study serum and urine from the patient."
    explanation: The original diagnosis used serum and urine proton NMR spectroscopy.
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of DMG as a storage product was confirmed by use of 13C NMR spectroscopy and gas chromatography–mass spectrometry."
    explanation: The same report used orthogonal chemical methods to confirm the DMG biomarker.
- name: Molecular genetic testing of DMGDH
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >-
    DMGDH sequencing confirms the diagnosis by identifying biallelic pathogenic
    variants in a compatible biochemical phenotype.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation was found in the DMGDH gene of the patient."
    explanation: The discovery study used DMGDH molecular findings to establish the genetic cause.
differential_diagnoses:
- name: Fish-odor syndromes including trimethylaminuria
  description: >-
    Fish-like odor is an overlapping presentation, so DMGDH deficiency should
    be considered when fish odor is accompanied by marked DMG elevation rather
    than a primary trimethylamine-oxidation defect.
  distinguishing_features:
  - Increased serum and urinary N,N-dimethylglycine.
  - Homozygous disease-associated DMGDH variant.
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DMGDH deficiency must be added to the differential diagnosis of patients complaining of a fish odor."
    explanation: The original authors explicitly frame DMGDH deficiency as a differential diagnosis for fish-odor complaints.
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling is appropriate for families once biallelic DMGDH
    pathogenic variation is identified, with discussion of recessive recurrence
    risk and the very limited human natural-history evidence.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation was found in the DMGDH gene of the patient."
    explanation: Identification of a homozygous disease-associated gene finding supports genetic counseling for affected families.
- name: Supportive clinical monitoring
  description: >-
    Supportive care should focus on monitoring the reported manifestations,
    including fish-like body odor, muscle fatigue, and serum creatine kinase
    elevation, while confirming the biochemical and genetic diagnosis. No
    disease-modifying therapy has been established for this ultra-rare disorder.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: fish-like body odor
    term:
      id: HP:0500001
      label: Body odor
  - preferred_term: increased muscle fatiguability
    term:
      id: HP:0003750
      label: Increased muscle fatiguability
  - preferred_term: elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: DOI:10.1093/clinchem/45.4.459
    reference_title: "Defect in Dimethylglycine Dehydrogenase, a New Inborn Error of Metabolism: NMR Spectroscopy Study"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "A38-year-old man presented with a history of fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase."
    explanation: The case report supports the manifestations that would be followed clinically; it does not establish a disease-modifying treatment.

📚

References & Deep Research

Deep Research

1

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Dimethylglycine Dehydrogenase Deficiency (DMGDH deficiency; hyperdimethylglycinemia): Comprehensive Disease Characteristics Report

Edison Scientific Literature 25 citations 2026-05-11T14:13:30.425167

Dimethylglycine Dehydrogenase Deficiency (DMGDH deficiency; hyperdimethylglycinemia): Comprehensive Disease Characteristics Report

Target disease

Disease name: Dimethylglycine dehydrogenase deficiency
Category: Mendelian / inborn error of metabolism (one‑carbon/choline degradation pathway)
Key identifier available from retrieved sources: OMIM 605850 (reported in mechanistic/structural papers) (augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3)
MONDO / Orphanet / MeSH / ICD-10/ICD-11: Not identified in the retrieved corpus for this run; these identifiers should be added from external ontology resources during curation (limitation of this tool-run).

Executive summary

Dimethylglycine dehydrogenase deficiency is an ultra‑rare inborn error of choline catabolism/one‑carbon metabolism caused by loss of function in DMGDH, a mitochondrial FAD- and tetrahydrofolate (THF)‑dependent enzyme that oxidatively demethylates N,N‑dimethylglycine (DMG) to sarcosine. The canonical human phenotype is mild and has been described primarily in a single adult patient, featuring a lifelong fish‑like odor, muscle fatigue/weakness, and persistent creatine kinase (CK) elevation, with massively increased DMG in serum and urine. Diagnosis relies on targeted metabolite measurement (historically by ^1H NMR spectroscopy of urine/serum) and confirmatory molecular genetic testing identifying biallelic DMGDH variants (e.g., A326G; p.His109Arg). Evidence for disease mechanism and variant pathogenicity is strengthened by biochemical/structural characterization of the H109R variant showing marked impairment in substrate affinity/cofactor incorporation and catalytic efficiency. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, mcandrew2008molecularbasisof pages 1-3, moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 1-1)

Disease name / synonym used	Causal gene	Key reported patient findings (clinical, biochemical, diagnostics)	Key quantitative lab values	Pathogenic variant / frequency	Evidence type
Dimethylglycine dehydrogenase deficiency; hyperdimethylglycinemia; “defect in dimethylglycine dehydrogenase”; sometimes discussed with fish-odor syndromes because odor was a presenting complaint (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-1, moolenaar2001invivoand pages 89-94)	DMGDH (mitochondrial dimethylglycine dehydrogenase) (mcandrew2008molecularbasisof pages 1-3, augustin2016structureandbiochemical pages 1-3)	Single reported index patient: 38-year-old man of African ancestry; fish-like body odor since age 5, worse with stress/exertion; unusual muscle fatigue/weakness; normal intelligence/overall good health; persistent CK elevation. Biochemical hallmark was marked accumulation of dimethylglycine with absent detectable sarcosine. Diagnosis used 1H NMR of urine/serum, confirmed by 13C NMR, GC-MS, and later molecular testing; trimethylaminuria was excluded by fish challenge and low urinary trimethylamine (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 1-1, moolenaar2001invivoand pages 94-98, moolenaar1999defectindimethylglycine pages 1-2, moolenaar1999defectindimethylglycine pages 3-4, moolenaar1999defectindimethylglycine pages 5-5, moolenaar2001invivoand pages 98-101)	Serum DMG 221 vs ref 1–5; urine DMG 457 and 441 mmol/mol creatinine vs ref 1–26 (age >2 months); CK 1066 U/L vs ref 30–270 U/L (~4× ULN). Urine trimethylamine <2 mmol/mol creatinine; trimethylamine N-oxide 55 mmol/mol creatinine (ref 20–125) (moolenaar1999defectindimethylglycine pages 4-5, moolenaar2001invivoand pages 94-98, moolenaar1999defectindimethylglycine pages 1-2, moolenaar1999defectindimethylglycine pages 3-4, moolenaar2001invivoand pages 98-101, moolenaar1999defectindimethylglycine media 773767bc)	Homozygous A326G causing H109R (His109Arg) near flavin attachment site; reported as disease-causing in the index patient (walker2012trimethylaminuriaanddimethylglycine pages 3-5, mcandrew2008molecularbasisof pages 1-3, moolenaar1999defectindimethylglycine pages 1-1)	Human case report / diagnostic discovery study (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 1-1)
Dimethylglycine dehydrogenase deficiency (OMIM 605850); mild/non-fatal disorder with DMG accumulation and fish-like odor (augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3)	DMGDH (augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3)	Recombinant/structural studies linked H109R to decreased expression, reduced FAD saturation, lower thermal stability, impaired substrate affinity, and lower catalytic efficiency, providing mechanistic support for the patient phenotype of DMG accumulation, muscle fatigue, and odor (mcandrew2008molecularbasisof pages 4-6, mcandrew2008molecularbasisof pages 6-8, augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3)	WT kinetics: Km1 0.039 ± 0.010 mmol/L, Km2 15.4 ± 1.2 mmol/L; with 4 mmol/L THF, Km2 1.10 ± 0.55 mmol/L. H109R: ~47% WT bound flavin in one expression system; 27-fold lower specific activity, 65-fold higher Km, ~1800-fold lower catalytic efficiency in one study; other study reported ~10-fold lower catalytic efficiency and 15–25-fold higher Km (mcandrew2008molecularbasisof pages 4-6, augustin2016structureandbiochemical pages 7-9, mcandrew2008molecularbasisof pages 1-3, augustin2016structureandbiochemical pages 1-3, mcandrew2008molecularbasisof pages 6-8)	H109R present in ExAC 58/118,656 alleles (0.049%), noted as predominantly in individuals of African descent (augustin2016structureandbiochemical pages 1-3)	Biochemical / structural study (mcandrew2008molecularbasisof pages 4-6, augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3)
Dimethylglycine dehydrogenase deficiency in choline-related inherited metabolic disease reviews; very rare / likely autosomal recessive disorder (walker2012trimethylaminuriaanddimethylglycine pages 3-5)	DMGDH (walker2012trimethylaminuriaanddimethylglycine pages 3-5)	Chapter/review sources summarize that only one case had been reported at that time; disease blocks choline catabolism, causing major DMG accumulation in plasma/urine; suggested practical diagnosis is raised plasma/urine DMG, ideally sampled when odor present. Proton NMR is emphasized as useful; routine liver biopsy would be needed for enzyme confirmation because activity is not normally detectable in blood cells/fibroblasts. Management suggestions included counseling, dietary choline restriction, avoiding excessive sweating; antibiotics to alter gut flora not indicated; riboflavin alone did not help, and folate plus riboflavin was suggested as a trial (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 5-5)	Plasma DMG increase described as ~100-fold and urine increase ~20-fold; healthy adult plasma reference 1–5 µmol/L; urine reference <26 mmol/mol creatinine after age 2 months, with higher neonatal values up to ~550 mmol/mol creatinine in first 2 months (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 4-5)	Homozygous A326G / H109R summarized as causative in the known patient (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-1)	Review / book chapter (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

Table: This table condenses the core literature on dimethylglycine dehydrogenase deficiency, including the nomenclature used, the causal gene, the single well-described human case, key quantitative laboratory abnormalities, and the main pathogenic variant with biochemical evidence. It is useful as a quick reference for disease curation and knowledge base population.

1. Disease information

1.1 What is the disease?

Dimethylglycine dehydrogenase deficiency (also called hyperdimethylglycinemia) is a genetic metabolic disorder in which impaired DMGDH activity blocks the mitochondrial step converting DMG to sarcosine, leading to marked accumulation of DMG in body fluids and a mild clinical phenotype in the best‑described patient. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-1, moolenaar1999defectindimethylglycine pages 1-2)

1.2 Common synonyms / alternative names (from primary literature)

“Dimethylglycine dehydrogenase deficiency” (walker2012trimethylaminuriaanddimethylglycine pages 3-5, augustin2016structureandbiochemical pages 7-9)
“Hyperdimethylglycinemia” (used as a descriptor for DMG elevation in the discovery paper) (moolenaar1999defectindimethylglycine pages 1-1)
“Defect in dimethylglycine dehydrogenase” (title/terminology of original case report) (moolenaar1999defectindimethylglycine pages 1-1)

1.3 Evidence source type

The disease description is derived primarily from: - Individual human case report/discovery study using metabolomics/NMR and molecular genetics (moolenaar1999defectindimethylglycine pages 1-1, moolenaar1999defectindimethylglycine pages 1-2) - Authoritative chapter-level synthesis describing rarity, diagnostic approach, and management suggestions (walker2012trimethylaminuriaanddimethylglycine pages 3-5) - Biochemical/structural functional studies of the disease-associated variant (mcandrew2008molecularbasisof pages 1-3, augustin2016structureandbiochemical pages 1-3)

2. Etiology

2.1 Disease causal factors

Genetic cause: Biallelic pathogenic variants in DMGDH. The index patient was homozygous for A326G, encoding p.His109Arg (H109R). (walker2012trimethylaminuriaanddimethylglycine pages 3-5, mcandrew2008molecularbasisof pages 1-3)
Mechanistic cause: Loss of DMGDH enzymatic function causing failure of DMG demethylation and consequent accumulation of DMG in blood/urine. (augustin2016structureandbiochemical pages 1-3, moolenaar1999defectindimethylglycine pages 1-1)

2.2 Risk factors

Genetic: Having biallelic loss‑of‑function or severely hypomorphic variants in DMGDH (autosomal recessive inferred). A chapter review states the disorder is “likely autosomal recessive” and notes “only one case” had been reported at that time. (walker2012trimethylaminuriaanddimethylglycine pages 3-5)
Environmental: No validated environmental risk factors were identified; symptoms (odor) were reported to worsen with stress/exertion in the index patient (not a cause, but a trigger/modifier of symptom expression). (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2)

2.3 Protective factors / gene–environment interactions

No protective genetic variants or gene–environment interactions specific to disease penetrance were reported in the retrieved literature. Given the extremely limited case count, these remain unknown.

3. Phenotypes

3.1 Reported human phenotypes (best-described index case)

Clinical signs/symptoms - Fish‑like body odor beginning in childhood (age 5) and persisting into adulthood. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2) - Unusual muscle fatigue and/or mild muscle weakness. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, mcandrew2008molecularbasisof pages 1-3, moolenaar1999defectindimethylglycine pages 1-2) - Normal intelligence and generally good health otherwise reported in the original case. (moolenaar1999defectindimethylglycine pages 1-2)

Laboratory abnormalities - Markedly increased DMG in serum and urine (quantified in Table 1 of discovery report). (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine media 773767bc) - Persistently increased serum/plasma creatine kinase (~4× upper limit of normal). (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2)

Phenotype timing and severity - Age of onset: childhood for odor complaint (age ~5). (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2) - Course: chronic/lifelong in the index patient. (walker2012trimethylaminuriaanddimethylglycine pages 3-5) - Severity: described as mild/non‑fatal in later mechanistic literature. (augustin2016structureandbiochemical pages 7-9)

3.2 Suggested HPO terms (mapping based on described features)

(These are ontology suggestions for curation; HPO IDs not retrieved in this run.) - Fishy body odor / abnormal body odor: Abnormal body odor - Fatigue: Fatigue - Muscle weakness: Muscle weakness - Elevated creatine kinase: Elevated circulating creatine kinase concentration - Increased dimethylglycine: Abnormal circulating metabolite concentration (specific metabolite annotation may require custom term)

3.3 Quantitative phenotype-associated data

Table 1 in the original Clinical Chemistry report provides the key quantitative biochemical phenotype: - Serum DMG: 221 (reported as mmol/L in excerpt) vs reference 1–5 (moolenaar1999defectindimethylglycine pages 4-5) - Urine DMG: 457 and 441 mmol/mol creatinine vs reference 1–26 (for age >2 months) (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine media 773767bc) - Creatine kinase: 1066 U/L (ref 30–270 U/L) (moolenaar1999defectindimethylglycine pages 1-2)

Visual evidence: Table 1/Figure 5 showing these abnormalities and age-related urine DMG reference distribution are captured as cropped images. (moolenaar1999defectindimethylglycine media 773767bc, moolenaar1999defectindimethylglycine media 214a655b)

3.4 Quality of life impact

The index case reported severe psychosocial impact from persistent odor (qualitative description in follow-on NMR paper). (moolenaar2001invivoand pages 94-98)

4. Genetic / molecular information

4.1 Causal gene

DMGDH encodes mitochondrial dimethylglycine dehydrogenase, a covalently flavinylated enzyme requiring THF. (augustin2016structureandbiochemical pages 1-3, moolenaar1999defectindimethylglycine pages 1-2)

4.2 Pathogenic variant(s)

Index disease variant: c.326A>G; p.His109Arg (H109R), homozygous in the reported patient. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, mcandrew2008molecularbasisof pages 1-3)

4.3 Functional consequences (variant-level)

Two independent functional analyses support pathogenicity: - H109R shows reduced flavin incorporation/cofactor saturation, markedly impaired substrate affinity and/or catalytic efficiency, and reduced stability—mechanistic routes to decreased enzymatic flux and DMG accumulation. (mcandrew2008molecularbasisof pages 4-6, augustin2016structureandbiochemical pages 7-9, augustin2016structureandbiochemical pages 1-3) - Quantitatively, one study reports the H109R mutant as having a ~65‑fold increase in Km and ~27‑fold decrease in activity, with overall ~1800‑fold loss in catalytic efficiency (after accounting for flavination), consistent with a severe hypomorphic/LOF allele. (mcandrew2008molecularbasisof pages 4-6)

4.4 Population frequency context

The H109R allele was observed in ExAC at 58/118,656 alleles (0.049%), predominantly in individuals of African descent, highlighting that population presence does not exclude pathogenicity for autosomal recessive disease when homozygosity is rare. (augustin2016structureandbiochemical pages 1-3)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic findings, or chromosomal abnormalities were reported for DMGDH deficiency in the retrieved sources.

5. Environmental information

No established environmental toxins, lifestyle factors, or infectious triggers are reported as causal. Symptom fluctuation with stress/exertion (odor worsening) is noted in the index case. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2)

6. Mechanism / pathophysiology

6.1 Molecular pathway and causal chain

Upstream: Dietary choline → betaine → DMG (as part of choline catabolism / methyl group metabolism).

Core defect: DMGDH is a mitochondrial FAD- and THF-dependent enzyme that demethylates DMG to sarcosine; THF accepts the methyl group (preventing release of formaldehyde). (augustin2016structureandbiochemical pages 1-3)

Downstream biochemical consequence: DMGDH deficiency results in marked accumulation of DMG in serum and urine, and absent/undetectable sarcosine in the original biochemical profile. (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 1-2)

Clinical consequence (known): fish‑like odor (likely from volatile DMG), fatigue/weakness, and elevated CK. However, because the phenotype is based on very few individuals, links beyond metabolite accumulation remain uncertain. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 5-5)

6.2 Suggested GO biological process / cellular component terms

(ontology suggestions) - GO: one‑carbon metabolic process - GO: choline metabolic process / betaine metabolic process - GO: glycine metabolic process - GO cellular component: mitochondrial matrix (DMGDH is mitochondrial) (augustin2016structureandbiochemical pages 1-3)

6.3 Suggested cell types (Cell Ontology)

No specific cell type pathology is described; enzyme is liver‑relevant in catabolism. For curation, consider: - Hepatocyte (primary site of choline metabolism; inferred, not directly evidenced here) - Skeletal muscle cell (given CK and fatigue; speculative)

7. Anatomical structures affected

7.1 Organ/system level (evidence-based)

Muscle involvement: suggested by fatigue/weakness and persistently elevated CK. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-2)

7.2 Suggested UBERON terms

Skeletal muscle tissue (UBERON suggestion)
Liver (UBERON suggestion; diagnostic enzyme assay discussion implies liver relevance) (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

7.3 Subcellular localization

Mitochondrial enzyme (matrix-associated) consistent with biochemical characterization. (augustin2016structureandbiochemical pages 1-3)

8. Temporal development

Onset: childhood for odor (age ~5). (walker2012trimethylaminuriaanddimethylglycine pages 3-5)
Course: chronic/lifelong; no defined staging described. (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

9. Inheritance and population

9.1 Inheritance

Inferred autosomal recessive (chapter source: “likely autosomal recessive”; index patient homozygous). (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

9.2 Epidemiology

Extremely rare; as of the chapter publication, “only one case has been reported.” (walker2012trimethylaminuriaanddimethylglycine pages 3-5)
No robust incidence/prevalence estimates were identified in the retrieved sources.

9.3 Population/ancestry

Index case: described as a man of African ancestry. (moolenaar1999defectindimethylglycine pages 1-2)
H109R allele: enriched in ExAC African ancestry subset. (augustin2016structureandbiochemical pages 1-3)

10. Diagnostics

10.1 Core diagnostic biomarker

Elevated DMG in plasma/serum and urine is the defining biochemical abnormality. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 4-5)

10.2 Laboratory methods (real-world implementations)

^1H NMR spectroscopy of urine and serum was a key diagnostic approach in the discovery study; DMG displayed characteristic singlets (2.93 and 3.80 ppm) and was confirmed by spiking experiments. (moolenaar1999defectindimethylglycine pages 4-5)
GC‑MS confirmation can be performed, but the discovery paper notes DMG can be missed by routine organic-acid workflows using solvent extraction (lost during ethyl acetate extraction). (moolenaar1999defectindimethylglycine pages 3-4, walker2012trimethylaminuriaanddimethylglycine pages 3-5)
Fish‑challenge testing and urinary trimethylamine measures were used to exclude trimethylaminuria in the presenting “fish odor” complaint. (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 3-4)

10.3 Enzyme assay

A chapter notes DMGDH activity is not normally detectable in blood cells/fibroblasts, so confirmatory enzyme testing would require liver tissue (biopsy)—a major practical limitation. (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

10.4 Genetic testing

Confirmatory diagnosis is via DMGDH sequencing to identify biallelic pathogenic variants (e.g., A326G/H109R). (moolenaar1999defectindimethylglycine pages 1-1, walker2012trimethylaminuriaanddimethylglycine pages 3-5)

10.5 Differential diagnosis

Given the presenting symptom of fish-like odor, differential considerations include trimethylaminuria; DMGDH deficiency can be distinguished by massively elevated DMG and low trimethylamine after fish challenge. (moolenaar1999defectindimethylglycine pages 4-5, moolenaar1999defectindimethylglycine pages 3-4)

11. Outcome / prognosis

Later biochemical/structural literature describes the disorder as non‑fatal and typically mild. (augustin2016structureandbiochemical pages 7-9)
No survival statistics, long-term organ outcomes, or standardized quality-of-life metrics were identified, due to limited case ascertainment.

12. Treatment

12.1 Evidence-based interventions (limited)

No established disease-modifying therapy exists.

Riboflavin trial (index case): The original report states the patient received riboflavin 10 mg/day for 3 months without clinical improvement. (moolenaar1999defectindimethylglycine pages 3-4)

Supportive/empiric measures (expert opinion from authoritative chapter): - Counseling - Dietary choline restriction and avoidance of excessive sweating (odor management) - Antibiotics to alter intestinal microflora “not indicated” - Suggested trial of folate with riboflavin (hypothesis-driven, not proven) (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

12.2 Suggested MAXO terms

(ontology suggestions) - Dietary modification / dietary choline restriction - Vitamin supplementation (riboflavin; folate) - Genetic counseling

12.3 Clinical trials

No DMGDH deficiency–specific trials were retrieved.

13. Prevention

Primary prevention: not applicable in the usual sense for an autosomal recessive condition.
Secondary prevention: early biochemical/genetic diagnosis may reduce psychosocial morbidity by explaining odor and guiding supportive measures. (walker2012trimethylaminuriaanddimethylglycine pages 3-5)
Genetic counseling: indicated for families once a causative DMGDH genotype is identified (inferred from AR inheritance and chapter guidance). (walker2012trimethylaminuriaanddimethylglycine pages 3-5)

14. Other species / natural disease

No naturally occurring veterinary disease analogs were identified in the retrieved sources.

15. Model organisms / experimental systems

15.1 Human protein functional models

Functional evidence is largely derived from recombinant enzyme studies and structural biology (including a reported PDB structure for human DMGDH in one study). (augustin2016structureandbiochemical pages 1-3)

15.2 Need for in vivo models

The molecular basis paper notes that additional DMGDH‑deficient humans or an appropriate mouse model would be needed to resolve genotype–phenotype questions. (mcandrew2008molecularbasisof pages 8-8)

Recent developments (prioritizing 2023–2024)

Direct 2023–2024 primary case expansions were not available in the retrievable corpus for this run. As a proxy for “latest research” relevant to real‑world implementation, the most concrete near‑term development is the continued mainstreaming of broad metabolomics and sequencing for rare disease diagnosis (with older but still relevant metabolomics evidence in this run). For example, DI‑HRMS metabolomics has been evaluated for inborn errors using dried blood spots and plasma; one limitation noted is that some workflows may fail to recognize DMGDH deficiency depending on feature detection/annotation. (moolenaar2001invivoand pages 98-101)

Key primary sources (URLs and publication dates)

Moolenaar SH et al. “Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study.” Clinical Chemistry (Apr 1999). https://doi.org/10.1093/clinchem/45.4.459 (moolenaar1999defectindimethylglycine pages 1-1)
McAndrew R et al. “Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R.” Journal of Inherited Metabolic Disease (Oct 2008). https://doi.org/10.1007/s10545-008-0999-2 (mcandrew2008molecularbasisof pages 1-3)
Walker V, Wevers RA. “Trimethylaminuria and Dimethylglycine Dehydrogenase Deficiency.” In Inborn Metabolic Diseases (Jan 2012). https://doi.org/10.1007/978-3-540-28785-8_31 (walker2012trimethylaminuriaanddimethylglycine pages 3-5)
Augustin P et al. “Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant.” FEBS Journal (Oct 2016). https://doi.org/10.1111/febs.13828 (augustin2016structureandbiochemical pages 1-3)

Clinical trials / registries relevant to real-world implementation

CoRDS (Coordination of Rare Diseases at Sanford) observational registry / natural history infrastructure: NCT01793168 (first posted Feb 2013, recruiting; last update posted May 2025). https://clinicaltrials.gov/study/NCT01793168 (NCT01793168 chunk 2, NCT01793168 chunk 1)

Limitations of the current evidence base

The human phenotype and natural history remain weakly defined because the core evidence is dominated by a single well-described individual and secondary summaries. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 1-1)
Standard disease identifiers beyond OMIM (e.g., MONDO, Orphanet, ICD, MeSH) were not found in the retrieved set and must be added via direct ontology database queries.
Therapeutic guidance is largely expert opinion and hypothesis-driven supplementation trials rather than controlled clinical evidence. (walker2012trimethylaminuriaanddimethylglycine pages 3-5, moolenaar1999defectindimethylglycine pages 3-4)

References

(augustin2016structureandbiochemical pages 7-9): Peter Augustin, Altijana Hromic, Tea Pavkov‐Keller, Karl Gruber, and Peter Macheroux. Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease‐related h109r variant. The Febs Journal, 283:3587-3603, Oct 2016. URL: https://doi.org/10.1111/febs.13828, doi:10.1111/febs.13828. This article has 27 citations.
(augustin2016structureandbiochemical pages 1-3): Peter Augustin, Altijana Hromic, Tea Pavkov‐Keller, Karl Gruber, and Peter Macheroux. Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease‐related h109r variant. The Febs Journal, 283:3587-3603, Oct 2016. URL: https://doi.org/10.1111/febs.13828, doi:10.1111/febs.13828. This article has 27 citations.
(walker2012trimethylaminuriaanddimethylglycine pages 3-5): Valerie Walker and Ron A. Wevers. Trimethylaminuria and dimethylglycine dehydrogenase deficiency. Inborn Metabolic Diseases, pages 381-385, Jan 2012. URL: https://doi.org/10.1007/978-3-540-28785-8_31, doi:10.1007/978-3-540-28785-8_31. This article has 3 citations.
(mcandrew2008molecularbasisof pages 1-3): Ryan McAndrew, Jerry Vockley, and Jung-Ja P. Kim. Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant h109r. Journal of Inherited Metabolic Disease, 31:761-768, Oct 2008. URL: https://doi.org/10.1007/s10545-008-0999-2, doi:10.1007/s10545-008-0999-2. This article has 14 citations and is from a peer-reviewed journal.
(moolenaar1999defectindimethylglycine pages 4-5): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(moolenaar1999defectindimethylglycine pages 1-1): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(moolenaar2001invivoand pages 89-94): Sytske H. Moolenaar, Marjo S. van der Knaap, Udo F. H. Engelke, Petra J. W. Pouwels, Fokje S. M. Janssen‐Zijlstra, Nanda M. Verhoeven, Cornelis Jakobs, and Ron A. Wevers. In vivo and in vitro nmr spectroscopy reveal a putative novel inborn error involving polyol metabolism. NMR in Biomedicine, 14:167-176, May 2001. URL: https://doi.org/10.1002/nbm.690, doi:10.1002/nbm.690. This article has 58 citations and is from a peer-reviewed journal.
(moolenaar2001invivoand pages 94-98): Sytske H. Moolenaar, Marjo S. van der Knaap, Udo F. H. Engelke, Petra J. W. Pouwels, Fokje S. M. Janssen‐Zijlstra, Nanda M. Verhoeven, Cornelis Jakobs, and Ron A. Wevers. In vivo and in vitro nmr spectroscopy reveal a putative novel inborn error involving polyol metabolism. NMR in Biomedicine, 14:167-176, May 2001. URL: https://doi.org/10.1002/nbm.690, doi:10.1002/nbm.690. This article has 58 citations and is from a peer-reviewed journal.
(moolenaar1999defectindimethylglycine pages 1-2): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(moolenaar1999defectindimethylglycine pages 3-4): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(moolenaar1999defectindimethylglycine pages 5-5): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(moolenaar2001invivoand pages 98-101): Sytske H. Moolenaar, Marjo S. van der Knaap, Udo F. H. Engelke, Petra J. W. Pouwels, Fokje S. M. Janssen‐Zijlstra, Nanda M. Verhoeven, Cornelis Jakobs, and Ron A. Wevers. In vivo and in vitro nmr spectroscopy reveal a putative novel inborn error involving polyol metabolism. NMR in Biomedicine, 14:167-176, May 2001. URL: https://doi.org/10.1002/nbm.690, doi:10.1002/nbm.690. This article has 58 citations and is from a peer-reviewed journal.
(moolenaar1999defectindimethylglycine media 773767bc): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(mcandrew2008molecularbasisof pages 4-6): Ryan McAndrew, Jerry Vockley, and Jung-Ja P. Kim. Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant h109r. Journal of Inherited Metabolic Disease, 31:761-768, Oct 2008. URL: https://doi.org/10.1007/s10545-008-0999-2, doi:10.1007/s10545-008-0999-2. This article has 14 citations and is from a peer-reviewed journal.
(mcandrew2008molecularbasisof pages 6-8): Ryan McAndrew, Jerry Vockley, and Jung-Ja P. Kim. Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant h109r. Journal of Inherited Metabolic Disease, 31:761-768, Oct 2008. URL: https://doi.org/10.1007/s10545-008-0999-2, doi:10.1007/s10545-008-0999-2. This article has 14 citations and is from a peer-reviewed journal.
(moolenaar1999defectindimethylglycine media 214a655b): Sytske H Moolenaar, Jo Poggi-Bach, Udo FH Engelke, Jacqueline MB Corstiaensen, Arend Heerschap, Jan GN de Jong, Barbara A Binzak, Jerry Vockley, and Ron A Wevers. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: nmr spectroscopy study. Clinical chemistry, 45 4:459-64, Apr 1999. URL: https://doi.org/10.1093/clinchem/45.4.459, doi:10.1093/clinchem/45.4.459. This article has 100 citations and is from a highest quality peer-reviewed journal.
(mcandrew2008molecularbasisof pages 8-8): Ryan McAndrew, Jerry Vockley, and Jung-Ja P. Kim. Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant h109r. Journal of Inherited Metabolic Disease, 31:761-768, Oct 2008. URL: https://doi.org/10.1007/s10545-008-0999-2, doi:10.1007/s10545-008-0999-2. This article has 14 citations and is from a peer-reviewed journal.
(NCT01793168 chunk 2): Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford. Sanford Health. 2010. ClinicalTrials.gov Identifier: NCT01793168
(NCT01793168 chunk 1): Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford. Sanford Health. 2010. ClinicalTrials.gov Identifier: NCT01793168

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Differential Diagnoses

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References & Deep Research

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Dimethylglycine Dehydrogenase Deficiency (DMGDH deficiency; hyperdimethylglycinemia): Comprehensive Disease Characteristics Report

Target disease

Executive summary

1. Disease information

1.1 What is the disease?

1.2 Common synonyms / alternative names (from primary literature)

1.3 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes

3.1 Reported human phenotypes (best-described index case)

3.2 Suggested HPO terms (mapping based on described features)

3.3 Quantitative phenotype-associated data

3.4 Quality of life impact

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variant(s)

4.3 Functional consequences (variant-level)

4.4 Population frequency context

4.5 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Molecular pathway and causal chain

6.2 Suggested GO biological process / cellular component terms

6.3 Suggested cell types (Cell Ontology)

7. Anatomical structures affected

7.1 Organ/system level (evidence-based)

7.2 Suggested UBERON terms

7.3 Subcellular localization

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology

9.3 Population/ancestry

10. Diagnostics

10.1 Core diagnostic biomarker

10.2 Laboratory methods (real-world implementations)

10.3 Enzyme assay

10.4 Genetic testing

10.5 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Evidence-based interventions (limited)

12.2 Suggested MAXO terms

12.3 Clinical trials

13. Prevention

14. Other species / natural disease

15. Model organisms / experimental systems

15.1 Human protein functional models

15.2 Need for in vivo models

Recent developments (prioritizing 2023–2024)

Key primary sources (URLs and publication dates)

Clinical trials / registries relevant to real-world implementation

Limitations of the current evidence base