Barth syndrome

name: Barth syndrome
creation_date: '2026-04-12T00:00:00Z'
updated_date: '2026-04-12T22:52:33Z'
category: Mendelian
synonyms:
- BTHS
- TAFAZZIN-related Barth syndrome
description: >-
  Barth syndrome is an ultra-rare X-linked recessive mitochondrial disorder
  caused by hemizygous pathogenic variants in TAFAZZIN, which encodes the
  cardiolipin remodeling enzyme tafazzin. Defective tafazzin activity increases
  monolysocardiolipin, decreases mature cardiolipin, and destabilizes
  mitochondrial membrane structure, oxidative phosphorylation, and metabolic
  flexibility in high-energy tissues. The core phenotype includes
  cardiomyopathy, left ventricular noncompaction, neutropenia, skeletal
  myopathy, exercise intolerance, growth delay, recurrent bacterial infections,
  and 3-methylglutaconic aciduria, with lactic acidosis and arrhythmia risk in a
  subset of affected boys.
disease_term:
  preferred_term: Barth syndrome
  term:
    id: MONDO:0010543
    label: Barth syndrome
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
  - classification_value: cardiovascular disorder
  mechanistic_category:
  - classification_value: mitochondrial disease
parents: []
prevalence:
- notes: >-
    Ultra-rare. Published review literature in 2019 described fewer than 200
    reported cases worldwide, while emphasizing likely underdiagnosis.
  evidence:
  - reference: PMID:31239752
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although Barth syndrome is still an orphan disease, with fewer than 200
      cases described so far, there is extensive ongoing research with regard to
      its pathomechanism and new therapeutic approaches.
    explanation: >-
      This review directly supports that Barth syndrome is ultra-rare and had
      fewer than 200 described cases at the time of publication.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Barth syndrome is inherited in an X-linked recessive manner and primarily
    affects hemizygous males, while heterozygous females are typically
    asymptomatic carriers.
  evidence:
  - reference: PMID:31239752
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Objectives: Barth syndrome is an ultra-rare, infantile-onset, X-linked
      recessive mitochondrial disorder, primarily affecting males, due to
      variants in TAZ encoding for the cardiolipin transacylase tafazzin.
    explanation: >-
      The review abstract explicitly identifies Barth syndrome as an X-linked
      recessive disorder affecting males.
genetic:
- name: TAFAZZIN
  gene_term:
    preferred_term: TAFAZZIN
    term:
      id: hgnc:11577
      label: TAFAZZIN
  association: Loss-of-function
  presence: Positive
  features: >-
    Hemizygous pathogenic variants in TAFAZZIN disrupt tafazzin-mediated
    cardiolipin remodeling. Reported disease alleles include missense, nonsense,
    frameshift, splice-site, and larger rearrangement variants, with substantial
    inter-individual phenotypic variability and no robust genotype-phenotype
    correlation.
  evidence:
  - reference: PMID:23409742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by mutations in the TAZ gene encoding tafazzin, a protein
      involved in the metabolism of cardiolipin, a mitochondrial-specific
      phospholipid involved in mitochondrial energy production.
    explanation: >-
      This clinical series directly identifies TAZ/TAFAZZIN mutation as the
      molecular cause of Barth syndrome.
pathophysiology:
- name: Tafazzin deficiency impairs cardiolipin remodeling
  description: >-
    Loss of tafazzin activity disrupts remodeling of mitochondrial cardiolipin,
    producing the signature increase in monolysocardiolipin and reduction in
    mature cardiolipin. Because cardiolipin is essential for inner-membrane
    architecture and energy transduction, this lipid-remodeling defect is the
    initiating lesion for downstream mitochondrial dysfunction in Barth syndrome.
  genes:
  - preferred_term: TAFAZZIN
    term:
      id: hgnc:11577
      label: TAFAZZIN
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiolipin metabolic process
    term:
      id: GO:0032048
      label: cardiolipin metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23409742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by mutations in the TAZ gene encoding tafazzin, a protein
      involved in the metabolism of cardiolipin, a mitochondrial-specific
      phospholipid involved in mitochondrial energy production.
    explanation: >-
      This directly links TAFAZZIN mutation to defective cardiolipin metabolism,
      the primary molecular lesion in Barth syndrome.
  downstream:
  - target: Mitochondrial respiratory chain dysfunction
    causal_link_type: DIRECT
  - target: Myocardial metabolic substrate shift
    causal_link_type: DIRECT
- name: Mitochondrial respiratory chain dysfunction
  description: >-
    Cardiolipin deficiency destabilizes the mitochondrial inner membrane,
    lowering membrane potential and impairing respiratory chain function. In
    patient-derived cells and affected tissues, this is accompanied by abnormal
    reactive oxygen species handling and reduced ATP-generating capacity.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:23361305
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An examination of the patients' fibroblast cultures revealed that
      extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the
      control value) dominated other unspecific mitochondrial changes detected
      (respiratory chain dysfunction, abnormal ROS production and depressed
      antioxidant defense).
    explanation: >-
      Patient-derived fibroblasts demonstrate markedly impaired membrane
      potential together with respiratory chain dysfunction, supporting a core
      mitochondrial bioenergetic defect.
  downstream:
  - target: Myocardial metabolic substrate shift
    causal_link_type: DIRECT
  - target: Abnormal cardiomyocyte calcium handling
    causal_link_type: DIRECT
- name: Myocardial metabolic substrate shift
  description: >-
    Tafazzin-deficient cardiomyocytes show reduced mitochondrial fatty-acid
    utilization and compensatory reliance on glucose and alternative anaplerotic
    fuels. This metabolic rewiring reflects impaired mitochondrial substrate
    handling and contributes to contractile inefficiency in the Barth heart.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:31861102
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also demonstrate that TAZ517delG induces metabolic alterations in
      pathways related to energy production as reflected by high glucose uptake,
      an increase in glycolytic lactate production and a decrease in palmitate
      uptake.
    explanation: >-
      Patient-derived and genome-edited iPSC cardiomyocytes show a shift away
      from fatty-acid use toward glucose-reliant metabolism.
  - reference: PMID:37930434
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice with an inducible knockdown (KD) of TAFAZZIN,
    explanation: >-
      The abstract explicitly identifies an inducible Tafazzin-knockdown mouse
      model as one of the systems used to demonstrate the reported metabolic
      rewiring in Barth syndrome.
  - reference: PMID:37930434
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial
      uptake and oxidation of fatty acids was strongly decreased, while glucose
      uptake was increased.
    explanation: >-
      iPSC-derived cardiac myocytes independently show decreased mitochondrial
      fatty-acid utilization with compensatory glucose uptake.
  downstream:
  - target: Abnormal cardiomyocyte calcium handling
    causal_link_type: DIRECT
- name: Abnormal cardiomyocyte calcium handling
  description: >-
    In Barth syndrome cardiomyocytes, excess mitochondrial and cellular reactive
    oxygen species activates the CaMKII-RYR2 axis, increasing sarcoplasmic
    reticulum calcium leak. The result is abnormal diastolic calcium handling,
    reduced calcium transient amplitude, impaired contractility, and greater
    arrhythmia vulnerability.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:33793303
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared with wild-type controls, BTHS-induced pluripotent stem
      cell-derived cardiomyocytes had increased diastolic Ca2+ and decreased
      Ca2+ transient amplitude.
    explanation: >-
      This directly demonstrates abnormal calcium homeostasis in
      Barth-syndrome iPSC-derived cardiomyocytes.
  - reference: PMID:33793303
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Inhibition of this reactive oxygen species-CaMKII-RYR2 pathway through
      pharmacological inhibitors or genome editing normalized aberrant Ca2+
      handling in BTHS-induced pluripotent stem cell-derived cardiomyocytes and
      improved their contractile function.
    explanation: >-
      Rescue of calcium handling and contractility identifies ROS-CaMKII-RYR2
      signaling as a causal mechanism rather than a bystander abnormality.
- name: Impaired myeloid maturation
  description: >-
    Barth-syndrome neutropenia reflects impaired granulocytic maturation rather
    than a pure peripheral destruction phenotype. Bone-marrow studies show
    reduced maturation of the myeloid lineage, providing a mechanistic basis for
    intermittent or chronic neutropenia and recurrent infection risk.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: myeloid cell differentiation
    term:
      id: GO:0030099
      label: myeloid cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:30451719
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pretreatment bone marrow evaluations predominantly showed reduced myeloid
      maturation which normalized on G-CSF therapy in seven of 13 examined.
    explanation: >-
      Bone-marrow findings in affected patients support impaired myeloid
      maturation as a direct mechanism of Barth-syndrome neutropenia.
phenotypes:
- name: Cardiomyopathy
  description: >-
    Cardiomyopathy is the central clinical manifestation of Barth syndrome and
    may be dilated, hypertrophic, or mixed with endocardial fibroelastosis or
    noncompaction features.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:25299040
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiomyopathy, which is almost always present before age five years, is
      typically dilated cardiomyopathy with or without endocardial
      fibroelastosis or left ventricular noncompaction; hypertrophic
      cardiomyopathy can also occur.
    explanation: >-
      GeneReviews summarizes cardiomyopathy as the dominant early-life Barth
      syndrome phenotype and defines its major structural subtypes.
- name: Left ventricular noncompaction
  description: >-
    Prominent ventricular trabeculation and noncompaction morphology are common
    cardiac features and may be present even when overall disease severity
    differs between affected individuals.
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: PMID:23361305
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both brothers, 2D-echocardiography revealed some features of left
      ventricular noncompaction (LVNC) despite marked differences in the course
      of the disease;
    explanation: >-
      This affected-sibling report directly documents LVNC as a Barth syndrome
      cardiac phenotype.
- name: Neutropenia
  description: >-
    Neutropenia may be chronic, intermittent, or cyclic, and contributes
    substantially to infection risk and aphthous ulceration.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:30451719
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Major features include neutropenia, dilated cardiomyopathy, motor delay
      and proximal myopathy, feeding problems, and constitutional growth delay.
    explanation: >-
      This large Barth syndrome neutropenia review identifies neutropenia as one
      of the defining disease manifestations.
- name: Growth delay
  description: >-
    Constitutional growth impairment begins in childhood and is a common
    component of the multisystem phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:23409742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: Barth syndrome (BS) is an X-linked infantile-onset
      cardioskeletal disease characterized by cardiomyopathy, hypotonia, growth
      delay, neutropenia and 3-methylglutaconic aciduria.
    explanation: >-
      This clinical series explicitly lists growth delay among the core Barth
      syndrome manifestations.
- name: Proximal muscle weakness
  description: >-
    Skeletal myopathy predominantly involves proximal musculature and contributes
    to motor delay and reduced physical performance.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:25299040
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Skeletal myopathy predominantly affects the proximal muscles, and results
      in delays in development of early motor skills.
    explanation: >-
      GeneReviews directly supports proximal-predominant skeletal muscle
      involvement in Barth syndrome.
- name: Exercise intolerance
  description: >-
    Profound exercise limitation reflects the combined effect of impaired cardiac
    reserve and reduced skeletal-muscle oxygen extraction/utilization.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:21873497
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, severe exercise intolerance in BTHS is due to both cardiac
      and skeletal muscle impairments that are consistent with cardiac and
      skeletal mitochondrial myopathy.
    explanation: >-
      This exercise-physiology study directly attributes exercise intolerance to
      combined cardiac and skeletal-muscle dysfunction in Barth syndrome.
- name: Recurrent bacterial infections
  description: >-
    Recurrent bacterial infection is a major downstream consequence of Barth
    syndrome neutropenia and includes pneumonia, sepsis, cellulitis, and oral
    ulcer-associated infection.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:25299040
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neutropenia is most often associated with bacterial infections and
      aphthous ulcers, pneumonia, and sepsis.
    explanation: >-
      GeneReviews links Barth syndrome neutropenia to recurrent bacterial
      infectious complications.
biochemical:
- name: Increased monolysocardiolipin:cardiolipin ratio
  presence: INCREASED
  notes: >-
    The MLCL:CL ratio is the key biochemical signature of Barth syndrome and is
    sufficiently robust for dried-blood-spot screening.
  evidence:
  - reference: PMID:18070816
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All BTHS patients (n = 31) had monolysocardiolipin:cardiolipin ratios
      >0.40 and all controls (n = 215) had monolysocardiolipin:cardiolipin
      ratios <0.23.
    explanation: >-
      This bloodspot assay study establishes an increased MLCL:CL ratio as the
      defining Barth syndrome biomarker.
- name: Elevated urinary 3-methylglutaconic acid
  presence: INCREASED
  notes: >-
    Increased urinary 3-methylglutaconic acid is a classic metabolic marker,
    although it may be absent in some neonatal presentations.
  evidence:
  - reference: PMID:23409742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited 3-methylglutaconic aciduria and neutropenia, when
      tested and five of them also had lactic acidosis.
    explanation: >-
      This case series directly documents 3-methylglutaconic aciduria as a
      common biochemical abnormality in Barth syndrome.
- name: Lactic acidosis
  presence: INCREASED
  notes: >-
    Lactic acidosis accompanies the mitochondrial energy defect in a substantial
    subset of affected patients and may be particularly prominent in severe
    infantile presentations.
  evidence:
  - reference: PMID:23409742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited 3-methylglutaconic aciduria and neutropenia, when
      tested and five of them also had lactic acidosis.
    explanation: >-
      This cohort directly reports lactic acidosis in most evaluated patients.
treatments:
- name: Heart failure pharmacotherapy
  description: >-
    Standard heart-failure medications are used to manage Barth cardiomyopathy,
    with careful attention to volume status because affected patients are
    vulnerable to overdiuresis and dehydration.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:25299040
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      for heart failure, careful fluid and volume management and avoidance of
      overdiuresis and dehydration, standard heart failure medications, and
      cardiac transplantation when heart failure is severe and intractable.
    explanation: >-
      GeneReviews supports standard heart-failure pharmacotherapy as core
      management for Barth cardiomyopathy.
- name: Granulocyte colony-stimulating factor (G-CSF)
  description: >-
    G-CSF is used prophylactically in neutropenic Barth syndrome patients to
    reduce severe bacterial infection risk and improve marrow neutrophil
    maturation.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:30451719
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections
      in the more severe neutropenic patients although infections remain a
      threat even in patients who are very compliant with therapy, especially in
      those with indwelling devices.
    explanation: >-
      This review directly supports G-CSF prophylaxis as effective management
      for severe Barth-syndrome neutropenia.
- name: Elamipretide
  description: >-
    Elamipretide is a cardiolipin-directed mitochondrial therapy used to improve
    muscle strength in Barth syndrome.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: elamipretide
      term:
        id: CHEBI:233331
        label: elamipretide
  evidence:
  - reference: PMID:25299040
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Targeted therapy: Elamipretide is indicated for the improvement of muscle
      strength in individuals with Barth syndrome.
    explanation: >-
      The updated GeneReviews management section identifies elamipretide as a
      Barth syndrome-targeted therapy for muscle weakness.
datasets: []