Fabry disease

name: Fabry disease
creation_date: '2026-01-08T17:12:45Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
disease_term:
  preferred_term: Fabry disease
  term:
    id: MONDO:0010526
    label: Fabry disease

parents:
- "Lysosomal storage diseases"
- "X-linked genetic disorders"

description: >
  Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in GLA that reduce or abolish
  α-galactosidase A activity, leading to lysosomal accumulation of glycosphingolipids, principally globotriaosylceramide
  (Gb3) and its deacylated derivative globotriaosylsphingosine (lyso-Gb3). Substrate accumulation initiates a network of
  cellular stress responses including endoplasmic reticulum stress, autophagy impairment, mitochondrial dysfunction, and
  activation of innate immune pathways, leading to progressive organ damage in kidney, heart, vasculature, and nervous system.

pathophysiology:
- name: Lysosomal alpha-galactosidase A deficiency and Gb3 accumulation
  description: >
    GLA mutations reduce or abolish α-galactosidase A enzyme activity, causing accumulation of globotriaosylceramide (Gb3)
    and its deacylated form lyso-Gb3 in lysosomes. Lyso-Gb3 is closely associated with disease severity and exerts direct
    cytotoxic effects on podocytes, neurons, and other cell types. Substrate accumulation initiates lysosomal dysfunction
    with impaired autophagy and reduced ATP production.
  evidence:
  - reference: PMID:31939530
    supports: PARTIAL
    snippet: "Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system"
    explanation: "Supports the core GLA deficiency/Gb3 accumulation mechanism, but not the full lyso-Gb3 cytotoxicity and autophagy-ATP details."
  biological_processes:
  - preferred_term: glycosphingolipid metabolic process
    term:
      id: GO:0006681
      label: glycosphingolipid metabolic process
  - preferred_term: lysosomal catabolic process
    term:
      id: GO:0090487
      label: lysosomal catabolic process
  genes:
  - preferred_term: GLA
    term:
      id: hgnc:4296
      label: GLA

- name: Endoplasmic reticulum stress and unfolded protein response
  description: >
    Misfolded α-Gal A variants trigger endoplasmic reticulum stress and activate the unfolded protein response (UPR).
    Persistent UPR activation causes apoptosis and inflammatory signaling through NF-κB and MAPK pathways, contributing
    to cell death and tissue injury.
  evidence:
  - reference: PMID:39978321
    supports: PARTIAL
    snippet: "Missense variants in the coding sequence of the GLA gene would generate the misfolding of the altered protein alpha-galactosidase A. Emergence of misfolded proteins may generate stress of the endoplasmic reticulum, leading to induction of the unfolded protein response (UPR)"
    explanation: "Supports ER stress/UPR induction from misfolded GLA variants, but does not fully establish all downstream pathway details stated."
  biological_processes:
  - preferred_term: response to unfolded protein
    term:
      id: GO:0006986
      label: response to unfolded protein
  - preferred_term: NF-kappaB signaling pathway
    term:
      id: GO:0007249
      label: NF-kappaB signaling pathway

- name: Mitochondrial dysfunction and oxidative stress
  description: >
    Gb3 and lyso-Gb3 accumulation impairs mitochondrial function with reduced ATP production, complex I/III impairment,
    and elevated reactive oxygen species (ROS) production. Oxidative damage correlates with cardiac hypertrophy and
    contributes to cell death and inflammation.
  evidence:
  - reference: PMID:29530533
    supports: NO_EVIDENCE
    snippet: "Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications"
    explanation: "Snippet is general disease background and does not directly support mitochondrial dysfunction or oxidative stress mechanisms."
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  - preferred_term: regulation of mitochondrial membrane potential
    term:
      id: GO:0051881
      label: regulation of mitochondrial membrane potential

- name: Autophagy impairment
  description: >
    Lysosomal Gb3 accumulation impairs autophagic flux, leading to accumulation of damaged proteins and organelles.
    Persistent podocyte injury despite enzyme replacement therapy is mediated in part by α-synuclein accumulation,
    implicating lysosomal toxicity as a disease driver beyond Gb3 storage.
  evidence:
  - reference: PMID:37014703
    supports: PARTIAL
    snippet: "Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT"
    explanation: "Shows that α-synuclein accumulation impairs lysosomal function and autophagy in Fabry podocytes, and that SNCA is a key driver of injury beyond Gb3 accumulation"
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  genes:
  - preferred_term: SNCA
    term:
      id: hgnc:11138
      label: SNCA

- name: Innate immune activation and inflammation
  description: >
    Substrate accumulation activates NLRP3 inflammasome and NF-κB-mediated inflammatory responses, leading to elevation
    of IL-1β, IL-6, IL-18, and TNF-α. Complement cascade is activated with elevated C3a and C5a, particularly in patients
    with anti-drug antibodies. These inflammatory mediators propagate endothelial dysfunction and tissue injury.
  evidence:
  - reference: PMID:38304433
    supports: SUPPORT
    snippet: "we demonstrate strong activation of the complement system in 17 classical male FD patients with either missense or nonsense mutations before and after ERT as evidenced by high C3a and C5a serum levels"
    explanation: "Demonstrates that complement system is strongly activated in Fabry disease patients, supporting the role of innate immune activation in pathogenesis"
  - reference: PMID:38932991
    supports: PARTIAL
    snippet: "Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms"
    explanation: "Confirms inflammation as a key pathogenic mechanism in Fabry disease, with emphasis on innate immune response"
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response

- name: Endothelial dysfunction and vascular remodeling
  description: >
    Gb3/lyso-Gb3 accumulation in endothelial cells leads to upregulation of adhesion molecules (VCAM1, ICAM1), eNOS uncoupling,
    and reduced nitric oxide availability. Vascular smooth muscle proliferation and remodeling occur, contributing to
    microvascular dysfunction and increased thrombotic risk.
  evidence:
  - reference: PMID:31939530
    supports: NO_EVIDENCE
    snippet: "Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency"
    explanation: "Snippet lists clinical manifestations but does not directly support the specific endothelial dysfunction/vascular remodeling mechanisms stated."
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: leukocyte adhesion to endothelial cells
    term:
      id: GO:0007107
      label: leukocyte adhesion to endothelial cells

- name: Fibrosis and extracellular matrix remodeling
  description: >
    TGF-β-driven profibrotic signaling leads to extracellular matrix deposition in kidney and heart. This fibrotic process
    becomes partially independent of Gb3 substrate levels and contributes to progressive organ dysfunction through epithelial-to-mesenchymal
    transition and myofibroblast activation.
  evidence:
  - reference: PMID:38304433
    supports: PARTIAL
    snippet: "we found increased IL-6, IL-10 and TGF-ß1 serum levels in FD patients"
    explanation: "Supports elevated profibrotic cytokine signaling (TGF-β1), but not the full extracellular matrix remodeling cascade described."
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: transforming growth factor beta signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta signaling pathway
  genes:
  - preferred_term: TGFB1
    term:
      id: hgnc:11766
      label: TGFB1

phenotypes:
- name: Acrodystrophic neuropathic pain
  category: Neurological
  description: >
    Severe, burning pain affecting the extremities, particularly hands and feet, often the earliest clinical manifestation.
    Pain crises can be disabling. Pathophysiology involves neuronal sensitization from lyso-Gb3 effects and lysosomal dysfunction.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31939530
    supports: SUPPORT
    snippet: "The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain"
    explanation: "Establishes acroparesthesia and neuropathic pain as early clinical manifestations in Fabry disease"
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain

- name: Angiokeratomas
  category: Cutaneous
  description: >
    Small, dark red skin lesions that cluster in the lower trunk and genital region. These are pathognomonic cutaneous
    manifestations of Fabry disease resulting from vascular dilatation with epidermal hyperkeratosis.
  frequency: FREQUENT
  evidence:
  - reference: PMID:31939530
    supports: SUPPORT
    snippet: "Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency"
    explanation: "Identifies angiokeratomas as a characteristic progressive clinical manifestation of Fabry disease"
  phenotype_term:
    preferred_term: Angiokeratoma
    term:
      id: HP:0001014
      label: Angiokeratoma

- name: Proteinuria
  category: Renal
  description: >
    Urinary protein excretion, often the earliest sign of Fabry nephropathy. Progresses from microalbuminuria to overt
    proteinuria. Results from podocyte injury due to Gb3/lyso-Gb3 accumulation, autophagy impairment, and inflammatory signaling.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39100494
    supports: PARTIAL
    snippet: "This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction"
    explanation: "Supports podocyte dysfunction mechanisms, but does not directly report clinical proteinuria frequency."
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: proteinuria

- name: Chronic kidney disease
  category: Renal
  description: >
    Progressive renal dysfunction leading to end-stage renal disease. Driven by podocyte loss, glomerulosclerosis,
    tubulointerstitial fibrosis, and persistent inflammation.
  frequency: FREQUENT
  evidence:
  - reference: PMID:31939530
    supports: SUPPORT
    snippet: "Subsequently, symptoms related to progressive impairment appear...proteinuria, and renal insufficiency. The latter being the main cause of death in FD"
    explanation: "Identifies progressive renal failure as the primary cause of death in Fabry disease"
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease

- name: Left ventricular hypertrophy
  category: Cardiac
  description: >
    Concentric hypertrophy of the left ventricle resulting from cardiomyocyte lipid accumulation, oxidative stress,
    inflammation, and fibrosis. Increases arrhythmia risk and may progress to heart failure.
  frequency: FREQUENT
  evidence:
  - reference: PMID:33602475
    supports: SUPPORT
    snippet: "Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death"
    explanation: "Confirms that left ventricular hypertrophy is a major cardiac manifestation of Fabry disease"
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: cardiomyopathy

- name: Cardiac arrhythmia
  category: Cardiac
  description: >
    Atrial fibrillation and ventricular arrhythmias result from cardiomyocyte hypertrophy, fibrosis, and inflammatory
    remodeling that create arrhythmogenic substrate.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31939530
    supports: NO_EVIDENCE
    snippet: "Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency"
    explanation: "Snippet supports myocardial fibrosis but does not directly report arrhythmia as a phenotype."
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia

- name: Stroke
  category: Neurological
  description: >
    Increased risk of ischemic stroke and transient ischemic attacks due to cerebrovascular dysfunction from endothelial
    dysfunction, microvascular remodeling, and pro-thrombotic state.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35652398
    supports: NO_EVIDENCE
    snippet: "A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity"
    explanation: "Snippet discusses treatment approach and does not directly support stroke frequency/risk."
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: stroke

biochemical:
- name: Lyso-Gb3
  presence: Increased
  context: Diagnostic and therapeutic biomarker closely associated with disease severity and organ damage
  synonyms:
  - globotriaosylsphingosine
  evidence:
  - reference: PMID:37207471
    supports: PARTIAL
    snippet: "Disease-specific biomarkers are useful in the diagnosis of Fabry disease; non-disease-specific biomarkers may be useful to assess organ damage"
    explanation: "Supports biomarker use in Fabry disease broadly, but does not specifically name lyso-Gb3 in the quoted text."

genetic:
- name: GLA gene mutations
  presence: Pathogenic
  association: X-linked recessive
  notes: >
    Loss-of-function mutations in GLA cause deficiency of α-galactosidase A. Disease shows X-linked inheritance with
    hemizygous males severely affected and heterozygous females showing variable phenotypes due to X-inactivation.
    Genetic testing is the gold standard for diagnosis and can identify a wide spectrum of variants including point mutations,
    insertions, deletions, and deep intronic variants. Long-read sequencing approaches enable comprehensive variant detection.
  evidence:
  - reference: PMID:39100494
    supports: SUPPORT
    snippet: "Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A)"
    explanation: "Confirms that Fabry disease is X-linked and caused by deficiency of alpha-galactosidase A enzyme"
  - reference: PMID:39609713
    supports: SUPPORT
    snippet: "Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications"
    explanation: "Establishes genetic testing as diagnostic gold standard and highlights need for comprehensive sequencing approaches to detect all variant types"
  inheritance:
  - name: X-linked recessive
    description: Males are hemizygous and severely affected; females are heterozygous carriers with variable presentation. In males, diagnosis is based on enzyme activity testing showing very low or absent α-galactosidase A activity in classical forms (near zero) or reduced activity (under 30%) in late-onset forms.
    evidence:
    - reference: PMID:31939530
      supports: SUPPORT
      snippet: "Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene"
      explanation: "Confirms X-linked recessive inheritance pattern of Fabry disease"
    - reference: PMID:32723516
      supports: SUPPORT
      snippet: "In male, diagnosis is made with alpha-galactosidase A enzyme activity dosage in leukocyte, that is very low or null in classical forms and under 30 percent in late-onset forms"
      explanation: "Describes enzyme activity testing thresholds for diagnosis in males based on disease form severity"

treatments:
- name: Enzyme replacement therapy
  description: >
    Recombinant α-galactosidase A (agalsidase alfa/beta and pegunigalsidase alfa) restores enzyme activity and reduces Gb3
    accumulation. Early initiation improves outcomes but cannot reverse established organ damage or fibrosis.
  evidence:
  - reference: PMID:37014703
    supports: PARTIAL
    snippet: "long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury"
    explanation: "Shows that ERT reduces substrate accumulation but cannot fully reverse organ damage in Fabry nephropathy"
  treatment_term:
    preferred_term: enzyme replacement therapy
    term:
      id: MAXO:0000933
      label: enzyme replacement or supplementation therapy
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: proteinuria
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease

- name: Pharmacological chaperone therapy
  description: >
    Migalastat stabilizes GLA mutant variants and improves lysosomal trafficking. Useful for approximately 35-50% of patients
    with amenable mutations.
  evidence:
  - reference: PMID:40310476
    supports: SUPPORT
    snippet: "if a responding ('amenable') α-galactosidase A mutation is present, oral pharmacological chaperone therapy (migalastat 123 mg, every other day)"
    explanation: "Confirms migalastat is an approved oral chaperone therapy for amenable GLA mutations"
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy

- name: Gene therapy
  description: >
    AAV and lentiviral-based therapies deliver functional GLA gene for sustained enzyme expression. Shows promise for achieving
    durable Gb3 clearance and reduced need for repeated infusions.
  evidence:
  - reference: PMID:40310476
    supports: PARTIAL
    snippet: "Future therapeutic options may include substrate reduction therapy, gene therapy, messenger RNA therapy, and/or vesicle-packaged enzyme replacement therapy"
    explanation: "Supports gene therapy as a future option, but not established clinical efficacy outcomes."
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy

- name: Supportive care
  description: >
    Management of complications including pain control, renal protection with ACE inhibitors, cardiac monitoring, and stroke prevention.
    Pain management and cardiovascular monitoring are essential for quality of life.
  evidence:
  - reference: PMID:32183665
    supports: NO_EVIDENCE
    snippet: "The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone"
    explanation: "Snippet supports disease-specific therapy standards, not the supportive-care interventions described in this item."
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia

notes: >
  Early diagnosis and treatment initiation are critical for improving outcomes. Progressive organ damage despite enzyme replacement
  therapy suggests ongoing pathogenic mechanisms beyond lipid substrate, including persistent inflammation, oxidative stress, fibrosis,
  and α-synuclein-mediated lysosomal toxicity. Multi-targeted therapeutic approaches may be needed to address these diverse mechanisms.
differential_diagnoses:
- name: Hypertrophic Cardiomyopathy (HCM)
  disease_term:
    preferred_term: Hypertrophic Cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  description: >
    HCM is the most common cardiac differential diagnosis for Fabry disease, as both conditions present with left ventricular hypertrophy,
    cardiomyocyte dysfunction, and arrhythmias. Both can cause sudden cardiac death and progressive heart failure. The cardiac phenotype
    of Fabry disease (apical involvement, LGE pattern, reduced ejection fraction) overlaps significantly with HCM. Systemic manifestations
    including neuropathic pain, renal disease, and skin lesions are distinguishing features of Fabry disease absent in HCM.
  distinguishing_features:
  - Prominent basal inferolateral late gadolinium enhancement (LGE) pattern (~50% of Fabry patients)
  - Acrodystrophic neuropathic pain and pain crises (absent in HCM)
  - Angiokeratomas and cornea verticillata (pathognomonic for Fabry disease)
  - Progressive renal disease with proteinuria and decline in GFR (rare in HCM)
  - X-linked inheritance pattern (HCM typically autosomal dominant)
  - Elevated lyso-Gb3 biomarker (diagnostic for Fabry disease)
  - Prominent papillary muscles are characteristic of Fabry disease
  evidence:
  - reference: PMID:33922740
    supports: PARTIAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is the main cardiac manifestation of FD"
    explanation: "Establishes HCM as the primary cardiac differential diagnosis for Fabry disease"

- name: Cardiac Amyloidosis
  disease_term:
    preferred_term: Amyloidosis
    term:
      id: MONDO:0019065
      label: amyloidosis
  description: >
    Cardiac amyloidosis presents with heart failure, arrhythmias, and LGE patterns similar to Fabry disease. Both conditions can cause
    concentric or apical hypertrophy, conduction abnormalities, and restrictive physiology. Systolic dysfunction may occur in both.
    The apical sparing pattern seen on imaging can occur in both amyloidosis and Fabry disease, making differentiation challenging
    without additional diagnostic markers.
  distinguishing_features:
  - Extracardiac systemic manifestations (neuropathic pain, angiokeratomas, renal disease) are typical of Fabry disease but absent in cardiac amyloidosis
  - Distinctive cornea verticillata ("cherry red spot" on ophthalmology) is specific to Fabry disease
  - Young age of symptom onset is characteristic of Fabry disease (often in childhood); cardiac amyloidosis is more common in elderly
  - Male predominance with severe phenotype indicates X-linked inheritance typical of Fabry disease
  - Elevated lyso-Gb3 biomarker is diagnostic for Fabry disease
  - Skin or conjunctival biopsy showing amyloid (amyloidosis) versus genetic testing for GLA mutations (Fabry disease) provides definitive diagnosis
  evidence:
  - reference: PMID:33922740
    supports: PARTIAL
    snippet: "An apical sparing pattern on longitudinal strain has also been described in FD, similarly to amyloidosis"
    explanation: "Identifies cardiac amyloidosis as an important differential diagnosis based on overlapping imaging patterns"

- name: Myocarditis
  disease_term:
    preferred_term: Myocarditis
    term:
      id: MONDO:0004496
      label: myocarditis
  description: >
    Myocarditis frequently occurs in Fabry disease (reported in 56% of patients) and can also present as an independent disorder.
    Both can cause acute or subacute cardiac dysfunction, ventricular dysfunction, arrhythmias, and myocardial inflammation on imaging.
    Myocarditis in Fabry disease results from chronic Gb3 accumulation in cardiomyocytes, while primary myocarditis is typically triggered
    by viral infections, autoimmune mechanisms, or drug reactions. The distinction is critical for treatment planning.
  distinguishing_features:
  - Myocarditis in Fabry disease is chronic and progressive (from lysosomal substrate accumulation), whereas primary myocarditis is acute/subacute
  - Extracardiac features including neuropathic pain, angiokeratomas, renal disease, and cornea verticillata are absent in isolated myocarditis
  - Elevated lyso-Gb3 biomarker is diagnostic for Fabry disease
  - Family history showing X-linked inheritance pattern indicates Fabry disease, whereas primary myocarditis typically presents sporadically
  - Left ventricular hypertrophy pattern is characteristic of Fabry disease, while acute myocarditis presents with dilated cardiomyopathy
  - Prodromal viral illness preceding acute myocarditis is typically absent in Fabry disease
  evidence:
  - reference: PMID:33922740
    supports: PARTIAL
    snippet: "Endomyocardial biopsies have shown myocarditis in 56% of FD patients"
    explanation: "Establishes the high prevalence of myocardial inflammation in Fabry disease and importance of differential diagnosis"

- name: Chagas Disease
  disease_term:
    preferred_term: Chagas disease
    term:
      id: MONDO:0001444
      label: Chagas disease
  description: >
    Chagas disease, caused by Trypanosoma cruzi, can present with cardiac manifestations including cardiomyopathy, arrhythmias, and
    sudden cardiac death, overlapping with Fabry disease cardiac phenotypes. Both can cause left ventricular dysfunction and conduction
    abnormalities. Chronic Chagas disease produces cardiomyopathy with LGE patterns that can mimic Fabry disease. However, systemic
    manifestations differ significantly.
  distinguishing_features:
  - Acrodystrophic neuropathic pain and pain crises are characteristic of Fabry disease but not seen in Chagas disease
  - Angiokeratomas and cornea verticillata are pathognomonic for Fabry disease
  - Renal involvement with progressive proteinuria and chronic kidney disease is typical of Fabry disease but absent in Chagas disease
  - Geographic/epidemiological risk differs (Chagas disease endemic to Central/South America; Fabry disease worldwide with X-linked inheritance)
  - Gastrointestinal involvement (megaesophagus, megacolon) is typical of Chagas disease but not seen in Fabry disease
  - Serological testing for Trypanosoma cruzi antibodies versus genetic testing for GLA mutations provides definitive diagnosis
  evidence:
  - reference: PMID:33922740
    supports: PARTIAL
    snippet: "This LGE pattern is not exclusive of FD and may also be found in myocarditis, Chagas disease, and sarcoidosis"
    explanation: "Highlights the imaging overlap between Fabry disease and Chagas disease as cardiac differentials"

- name: Sarcoidosis
  disease_term:
    preferred_term: Sarcoidosis
    term:
      id: MONDO:0019338
      label: sarcoidosis
  description: >
    Sarcoidosis is a multisystem granulomatous disorder that can involve heart (cardiac sarcoidosis), kidneys, nervous system, and skin,
    creating potential overlap with Fabry disease systemic manifestations. Both can cause cardiomyopathy, arrhythmias, conduction abnormalities,
    renal disease, and neuropathy. Cardiac sarcoidosis with LGE on imaging can superficially resemble Fabry disease cardiomyopathy.
    Neurological involvement (stroke, neuropathy) occurs in both conditions.
  distinguishing_features:
  - Acrodystrophic neuropathic pain with pain crises is characteristic of Fabry disease, whereas sarcoidosis causes other neuropathy types
  - Angiokeratomas and cornea verticillata are pathognomonic for Fabry disease and absent in sarcoidosis
  - Pulmonary involvement with hilar lymphadenopathy is typical of sarcoidosis but absent in Fabry disease
  - Cutaneous manifestations differ (angiokeratomas in Fabry disease versus erythema nodosum or lupus pernio in sarcoidosis)
  - Calcium metabolism abnormalities (hypercalcemia, hypercalciuria) are typical of sarcoidosis but absent in Fabry disease
  - Elevated lyso-Gb3 biomarker is diagnostic for Fabry disease, while elevated ACE and serum calcium suggest sarcoidosis
  - Skin or conjunctival biopsy showing granulomas versus genetic testing for GLA mutations provides definitive diagnosis
  evidence:
  - reference: PMID:33922740
    supports: PARTIAL
    snippet: "This LGE pattern is not exclusive of FD and may also be found in myocarditis, Chagas disease, and sarcoidosis"
    explanation: "Establishes sarcoidosis as a multisystem differential diagnosis for Fabry disease with overlapping imaging patterns"