Amyloidosis

Complex MONDO:0019065 Pathograph 2 Proteostasis Deficiency Protein Misfolding Disease

Amyloidosis is a heterogeneous group of protein-misfolding disorders defined by the extracellular deposition of insoluble fibrillar aggregates of an abnormally folded precursor protein in tissues. More than 30 distinct precursor proteins are known to give rise to systemic or localized amyloid, each producing characteristic cross-beta-sheet fibrils that resist proteolysis and disrupt the architecture and function of affected organs. The major clinical entities are AL amyloidosis (immunoglobulin light chain, secondary to a plasma cell dyscrasia), ATTR amyloidosis (transthyretin, either hereditary from TTR mutations or acquired wild-type/senile disease), and AA amyloidosis (serum amyloid A, secondary to chronic inflammatory conditions). Disease phenotype is determined by the specific precursor and its tissue tropism, with common targets including the heart, peripheral and autonomic nervous system, kidneys, liver, and gastrointestinal tract.

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2
Pathophys.
6
Phenotypes
2
Pathograph
1
Genes
2
Medical Actions
5
Subtypes
◆

Subtypes

5
AL (Immunoglobulin Light Chain) Amyloidosis
Systemic amyloidosis caused by a clonal plasma cell dyscrasia in which misfolded monoclonal immunoglobulin light chains deposit as amyloid in multiple organs, most commonly the heart and kidneys.
Show evidence (1 reference)
PMID:26858336 SUPPORT Human Clinical
"Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs."
This trial publication explicitly defines AL amyloidosis as misfolded light chain accumulation causing organ dysfunction.
ATTRv (Hereditary Transthyretin) Amyloidosis
Autosomal dominant amyloidosis caused by pathogenic variants in the TTR gene that destabilize the transthyretin tetramer, leading to monomer dissociation, misfolding, and amyloid fibril deposition predominantly in peripheral nerve and heart.
Show evidence (1 reference)
PMID:25604431 SUPPORT Human Clinical
"TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis"
Sekijima review describes the autosomal-dominant tetramer-dissociation mechanism of hereditary ATTR.
ATTRwt (Wild-Type Transthyretin) Amyloidosis
Age-related, non-hereditary amyloidosis in which native wild-type transthyretin progressively deposits as amyloid in the myocardium of older adults, causing restrictive cardiomyopathy (formerly senile systemic amyloidosis).
Show evidence (2 references)
PMID:26048914 SUPPORT Human Clinical
"The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis."
Dubrey 2015 review defines wild-type ATTR as the non-hereditary, native TTR form previously called senile systemic amyloidosis.
PMID:31731233 SUPPORT Human Clinical
"Wild-type ATTR amyloidosis (ATTR-wt) is characterized by the accumulation of amyloid in the heart, leading to fatal heart failure and arrhythmia."
Shiozaki 2019 forensic autopsy series confirms cardiac-predominant amyloid in ATTRwt.
AA (Serum Amyloid A) Amyloidosis
Reactive systemic amyloidosis in which the acute-phase reactant serum amyloid A protein, chronically elevated in sustained inflammation (autoinflammatory syndromes, rheumatoid arthritis, chronic infection), is deposited as amyloid, typically targeting the kidneys.
Show evidence (1 reference)
PMID:18514052 SUPPORT Human Clinical
"A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis."
Stankovic and Grateau identify chronic acute-phase elevation of SAA as the precursor mechanism for AA amyloidosis.
Localized Amyloidosis
Organ-restricted amyloid deposition (e.g., bladder, larynx, skin, tracheobronchial tree) usually formed from light chains produced by a local clonal B-cell or plasma cell population, without systemic involvement.
⚙

Pathophysiology

2
Precursor Protein Destabilization and Misfolding
A disease-specific precursor protein (immunoglobulin light chain in AL, transthyretin in ATTR, serum amyloid A in AA) becomes destabilized through mutation, post-translational modification, sustained overproduction, or age-related conformational change, populating partially unfolded monomeric intermediates that escape proteostasis surveillance and assemble into oligomeric and pre-fibrillar species.
plasma cell CL:0000786 hepatocyte CL:0000182
protein folding GO:0006457 ↓ DECREASED response to unfolded protein GO:0006986 ↑ INCREASED
Downstream
Amyloid Fibril Deposition and Organ Dysfunction Partially unfolded monomeric intermediates assemble into oligomers and cross-beta-sheet amyloid fibrils that deposit in target tissues.
Show evidence (2 references)
PMID:25604431 SUPPORT Human Clinical
"TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils"
Sekijima exemplifies the general precursor-destabilization-and-misfolding paradigm using transthyretin.
PMID:26858336 SUPPORT Human Clinical
"Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs."
Same precursor-misfolding paradigm demonstrated for AL amyloidosis (immunoglobulin light chain).
Amyloid Fibril Deposition and Organ Dysfunction
Misfolded precursors polymerize into cross-beta-sheet amyloid fibrils that accumulate in the extracellular space of target organs. Fibrillar and oligomeric species cause organ dysfunction by mechanical disruption of tissue architecture, direct cytotoxicity to resident cells (notably cardiomyocytes and Schwann cells), and impairment of microvascular flow, producing progressive cardiomyopathy, neuropathy, and nephropathy.
cardiac muscle cell CL:0000746 Schwann cell CL:0002573
amyloid fibril formation GO:1990000 ↑ INCREASED
Show evidence (1 reference)
PMID:40649158 SUPPORT Human Clinical
"Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils."
This 2025 review explicitly states that extracellular deposition of misfolded monomers as insoluble amyloid fibrils causes progressive multisystem disease.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Amyloidosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Head and Neck 1
Macroglossia Macroglossia HP:0000158
Show evidence (1 reference)
PMID:8115892 SUPPORT Human Clinical
"Gastrointestinal symptoms included anorexia, macroglossia, intestinal"
Lee et al. document macroglossia as a recognized manifestation of amyloidosis in a clinical case series.
Metabolism 1
Amyloid Deposition Amyloid deposition HP:0011034
Nervous System 2
Peripheral Neuropathy Peripheral neuropathy HP:0009830
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22094129 SUPPORT Human Clinical
"TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction"
Planté-Bordeneuve and Said establish length-dependent peripheral polyneuropathy as the hallmark neurological manifestation of TTR-FAP.
Autonomic Dysfunction Abnormal autonomic nervous system physiology HP:0012332
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22094129 SUPPORT Human Clinical
"TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death"
Planté-Bordeneuve and Said establish life-threatening autonomic dysfunction as a hallmark of TTR-FAP.
Other 2
Cardiomyopathy Restrictive cardiomyopathy HP:0001723
Course: PROGRESSIVE
Show evidence (2 references)
PMID:34518987 SUPPORT Human Clinical
"It results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM)."
This genetics-of-cardiac-amyloidosis review establishes myocardial misfolded TTR accumulation as the cause of ATTR cardiomyopathy.
PMID:40649158 SUPPORT Human Clinical
"Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes."
2025 update confirms cardiomyopathy as a principal manifestation of ATTR amyloidosis.
Nephrotic Syndrome Nephrotic syndrome HP:0000100
Show evidence (2 references)
PMID:18514052 SUPPORT Human Clinical
"Nephropathy is the main clinical manifestation of amyloidosis."
Stankovic and Grateau identify nephropathy (with proteinuria progressing to nephrotic syndrome) as the dominant clinical manifestation of AA amyloidosis.
PMID:23548761 SUPPORT Human Clinical
"Mean serum creatinine and proteinuria at diagnosis were 4.65±4.89 mg/dl and 8.04±6.09 g/day"
Yilmaz et al. document nephrotic-range proteinuria (mean 8 g/day) in a biopsy-proven AA amyloidosis cohort, supporting nephrotic syndrome as a typical phenotype.
🧬

Genetic Associations

1
TTR (Pathogenic Variants)
Show evidence (2 references)
PMID:22094129 SUPPORT Human Clinical
"The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide."
Planté-Bordeneuve and Said establish TTR Val30Met as the most common of >100 amyloidogenic TTR mutations causing familial amyloid polyneuropathy.
PMID:34518987 SUPPORT Human Clinical
"Over 150 different pathologic point mutations within the transthyretin gene have been identified, each carrying variable clinical phenotypes and penetrance."
Arno and Cowger document the breadth and phenotypic heterogeneity of pathogenic TTR variants in cardiac amyloidosis.
💊

Medical Actions

2
Tafamidis
Action: Pharmacotherapy NCIT:C15986
Agent: tafamidis CHEBI:78538
Oral transthyretin tetramer stabilizer that binds the thyroxine-binding sites of TTR, preventing dissociation into amyloidogenic monomers; approved for ATTR cardiomyopathy and polyneuropathy.
Show evidence (1 reference)
PMID:25604431 SUPPORT Human Clinical
"the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis"
Sekijima review documents that tafamidis is an approved TTR tetramer stabilizer with proven clinical benefit in hereditary ATTR amyloidosis.
Patisiran
Action: Pharmacotherapy NCIT:C15986
Agent: patisiran NCIT:C116792
Lipid-nanoparticle-formulated small interfering RNA that silences hepatic TTR mRNA, lowering circulating transthyretin and slowing hereditary ATTR polyneuropathy progression.
Show evidence (2 references)
PMID:30480471 SUPPORT Human Clinical
"Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein."
Kristen et al. describe patisiran as an RNAi therapeutic that lowers wild-type and mutant TTR, the mechanism of action used in hereditary ATTR amyloidosis.
PMID:30480471 SUPPORT Human Clinical
"In Phase II, III and long-term extension studies in patients with hereditary transthyretin-mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy."
Phase II/III/extension data show patisiran slows or improves ATTRv neuropathy progression.
{ }

Source YAML

click to show 
name: Amyloidosis
creation_date: "2026-05-13T10:00:00Z"
updated_date: "2026-05-13T14:00:00Z"
category: Complex
description: >-
  Amyloidosis is a heterogeneous group of protein-misfolding disorders defined
  by the extracellular deposition of insoluble fibrillar aggregates of an
  abnormally folded precursor protein in tissues. More than 30 distinct
  precursor proteins are known to give rise to systemic or localized amyloid,
  each producing characteristic cross-beta-sheet fibrils that resist proteolysis
  and disrupt the architecture and function of affected organs. The major
  clinical entities are AL amyloidosis (immunoglobulin light chain, secondary to
  a plasma cell dyscrasia), ATTR amyloidosis (transthyretin, either hereditary
  from TTR mutations or acquired wild-type/senile disease), and AA amyloidosis
  (serum amyloid A, secondary to chronic inflammatory conditions). Disease
  phenotype is determined by the specific precursor and its tissue tropism, with
  common targets including the heart, peripheral and autonomic nervous system,
  kidneys, liver, and gastrointestinal tract.
disease_term:
  preferred_term: amyloidosis
  term:
    id: MONDO:0019065
    label: amyloidosis
synonyms:
- amyloid disease
- amyloid deposition disease
- systemic amyloidosis
parents:
- Proteostasis Deficiency
- Protein Misfolding Disease
has_subtypes:
- name: AL
  display_name: AL (Immunoglobulin Light Chain) Amyloidosis
  description: >-
    Systemic amyloidosis caused by a clonal plasma cell dyscrasia in which
    misfolded monoclonal immunoglobulin light chains deposit as amyloid in
    multiple organs, most commonly the heart and kidneys.
  evidence:
  - reference: PMID:26858336
    reference_title: "First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs."
    explanation: This trial publication explicitly defines AL amyloidosis as misfolded light chain accumulation causing organ dysfunction.
- name: ATTRv
  display_name: ATTRv (Hereditary Transthyretin) Amyloidosis
  description: >-
    Autosomal dominant amyloidosis caused by pathogenic variants in the TTR
    gene that destabilize the transthyretin tetramer, leading to monomer
    dissociation, misfolding, and amyloid fibril deposition predominantly in
    peripheral nerve and heart.
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis"
    explanation: Sekijima review describes the autosomal-dominant tetramer-dissociation mechanism of hereditary ATTR.
- name: ATTRwt
  display_name: ATTRwt (Wild-Type Transthyretin) Amyloidosis
  description: >-
    Age-related, non-hereditary amyloidosis in which native wild-type
    transthyretin progressively deposits as amyloid in the myocardium of older
    adults, causing restrictive cardiomyopathy (formerly senile systemic
    amyloidosis).
  evidence:
  - reference: PMID:26048914
    reference_title: "The transthyretin amyloidoses: advances in therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis."
    explanation: Dubrey 2015 review defines wild-type ATTR as the non-hereditary, native TTR form previously called senile systemic amyloidosis.
  - reference: PMID:31731233
    reference_title: "Wild-type ATTR amyloidosis may be associated with unexpected death among the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wild-type ATTR amyloidosis (ATTR-wt) is characterized by the accumulation of amyloid in the heart, leading to fatal heart failure and arrhythmia."
    explanation: Shiozaki 2019 forensic autopsy series confirms cardiac-predominant amyloid in ATTRwt.
- name: AA
  display_name: AA (Serum Amyloid A) Amyloidosis
  description: >-
    Reactive systemic amyloidosis in which the acute-phase reactant serum
    amyloid A protein, chronically elevated in sustained inflammation
    (autoinflammatory syndromes, rheumatoid arthritis, chronic infection),
    is deposited as amyloid, typically targeting the kidneys.
  evidence:
  - reference: PMID:18514052
    reference_title: "[Amyloidosis AA]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis."
    explanation: Stankovic and Grateau identify chronic acute-phase elevation of SAA as the precursor mechanism for AA amyloidosis.
- name: Localized
  display_name: Localized Amyloidosis
  description: >-
    Organ-restricted amyloid deposition (e.g., bladder, larynx, skin,
    tracheobronchial tree) usually formed from light chains produced by a local
    clonal B-cell or plasma cell population, without systemic involvement.
pathophysiology:
- name: Precursor Protein Destabilization and Misfolding
  description: >-
    A disease-specific precursor protein (immunoglobulin light chain in AL,
    transthyretin in ATTR, serum amyloid A in AA) becomes destabilized through
    mutation, post-translational modification, sustained overproduction, or
    age-related conformational change, populating partially unfolded monomeric
    intermediates that escape proteostasis surveillance and assemble into
    oligomeric and pre-fibrillar species.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  - preferred_term: response to unfolded protein
    term:
      id: GO:0006986
      label: response to unfolded protein
    modifier: INCREASED
  downstream:
  - target: Amyloid Fibril Deposition and Organ Dysfunction
    description: Partially unfolded monomeric intermediates assemble into oligomers and cross-beta-sheet amyloid fibrils that deposit in target tissues.
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils"
    explanation: Sekijima exemplifies the general precursor-destabilization-and-misfolding paradigm using transthyretin.
  - reference: PMID:26858336
    reference_title: "First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs."
    explanation: Same precursor-misfolding paradigm demonstrated for AL amyloidosis (immunoglobulin light chain).
- name: Amyloid Fibril Deposition and Organ Dysfunction
  description: >-
    Misfolded precursors polymerize into cross-beta-sheet amyloid fibrils that
    accumulate in the extracellular space of target organs. Fibrillar and
    oligomeric species cause organ dysfunction by mechanical disruption of
    tissue architecture, direct cytotoxicity to resident cells (notably
    cardiomyocytes and Schwann cells), and impairment of microvascular flow,
    producing progressive cardiomyopathy, neuropathy, and nephropathy.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  evidence:
  - reference: PMID:40649158
    reference_title: "Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils."
    explanation: This 2025 review explicitly states that extracellular deposition of misfolded monomers as insoluble amyloid fibrils causes progressive multisystem disease.
phenotypes:
- name: Amyloid Deposition
  category: Histological
  description: >-
    Extracellular deposition of Congo-red-positive, apple-green-birefringent
    fibrillar amyloid in affected tissues is the defining histopathological
    hallmark of all amyloidoses.
  phenotype_term:
    preferred_term: Amyloid deposition
    term:
      id: HP:0011034
      label: Amyloid deposition
- name: Cardiomyopathy
  category: Cardiovascular
  description: >-
    Infiltrative cardiomyopathy from amyloid deposition in the myocardium
    causes wall thickening, restrictive physiology, and progressive heart
    failure; prominent in AL and ATTR amyloidosis.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34518987
    reference_title: "The genetics of cardiac amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM)."
    explanation: This genetics-of-cardiac-amyloidosis review establishes myocardial misfolded TTR accumulation as the cause of ATTR cardiomyopathy.
  - reference: PMID:40649158
    reference_title: "Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes."
    explanation: 2025 update confirms cardiomyopathy as a principal manifestation of ATTR amyloidosis.
- name: Peripheral Neuropathy
  category: Neurological
  description: >-
    Length-dependent sensorimotor and small-fiber peripheral neuropathy is a
    hallmark of hereditary ATTR amyloidosis and can also occur in AL disease.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22094129
    reference_title: "Familial amyloid polyneuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction"
    explanation: Planté-Bordeneuve and Said establish length-dependent peripheral polyneuropathy as the hallmark neurological manifestation of TTR-FAP.
- name: Nephrotic Syndrome
  category: Renal
  description: >-
    Glomerular amyloid deposition produces heavy proteinuria, hypoalbuminemia,
    edema, and nephrotic syndrome, typical of AL and AA amyloidosis.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:18514052
    reference_title: "[Amyloidosis AA]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephropathy is the main clinical manifestation of amyloidosis."
    explanation: Stankovic and Grateau identify nephropathy (with proteinuria progressing to nephrotic syndrome) as the dominant clinical manifestation of AA amyloidosis.
  - reference: PMID:23548761
    reference_title: "Renal involvement in AA amyloidosis: clinical outcomes and survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mean serum creatinine and proteinuria at diagnosis were 4.65±4.89 mg/dl and 8.04±6.09 g/day"
    explanation: Yilmaz et al. document nephrotic-range proteinuria (mean 8 g/day) in a biopsy-proven AA amyloidosis cohort, supporting nephrotic syndrome as a typical phenotype.
- name: Macroglossia
  category: Head and Neck
  description: >-
    Tongue enlargement from amyloid infiltration is a relatively specific
    physical finding for AL amyloidosis.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:8115892
    reference_title: "Gastrointestinal manifestations of amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal symptoms included anorexia, macroglossia, intestinal"
    explanation: Lee et al. document macroglossia as a recognized manifestation of amyloidosis in a clinical case series.
- name: Autonomic Dysfunction
  category: Neurological
  description: >-
    Length-dependent autonomic neuropathy from amyloid deposition in autonomic
    fibers and ganglia produces orthostatic hypotension, gastrointestinal
    dysmotility, neurogenic bladder, and sexual dysfunction; a life-threatening
    hallmark of ATTRv amyloidosis.
  phenotype_term:
    preferred_term: Autonomic dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22094129
    reference_title: "Familial amyloid polyneuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death"
    explanation: Planté-Bordeneuve and Said establish life-threatening autonomic dysfunction as a hallmark of TTR-FAP.
genetic:
- name: TTR
  association: Pathogenic Variants
  subtype: ATTRv
  notes: >-
    Primary amyloid precursor gene encoding transthyretin, a liver-derived
    homotetrameric transport protein for thyroxine and retinol. Pathogenic
    variants destabilize the native tetramer, predisposing to monomer
    dissociation, misfolding, and amyloid fibril formation. More than 100 TTR
    point mutations have been identified worldwide, with Val30Met being the most
    common.
  evidence:
  - reference: PMID:22094129
    reference_title: "Familial amyloid polyneuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide."
    explanation: Planté-Bordeneuve and Said establish TTR Val30Met as the most common of >100 amyloidogenic TTR mutations causing familial amyloid polyneuropathy.
  - reference: PMID:34518987
    reference_title: "The genetics of cardiac amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 150 different pathologic point mutations within the transthyretin gene have been identified, each carrying variable clinical phenotypes and penetrance."
    explanation: Arno and Cowger document the breadth and phenotypic heterogeneity of pathogenic TTR variants in cardiac amyloidosis.
treatments:
- name: Tafamidis
  description: >-
    Oral transthyretin tetramer stabilizer that binds the thyroxine-binding
    sites of TTR, preventing dissociation into amyloidogenic monomers; approved
    for ATTR cardiomyopathy and polyneuropathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tafamidis
      term:
        id: CHEBI:78538
        label: tafamidis
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis"
    explanation: Sekijima review documents that tafamidis is an approved TTR tetramer stabilizer with proven clinical benefit in hereditary ATTR amyloidosis.
- name: Patisiran
  therapeutic_modality: SIRNA
  description: >-
    Lipid-nanoparticle-formulated small interfering RNA that silences hepatic
    TTR mRNA, lowering circulating transthyretin and slowing hereditary ATTR
    polyneuropathy progression.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: patisiran
      term:
        id: NCIT:C116792
        label: Patisiran
  evidence:
  - reference: PMID:30480471
    reference_title: "Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein."
    explanation: Kristen et al. describe patisiran as an RNAi therapeutic that lowers wild-type and mutant TTR, the mechanism of action used in hereditary ATTR amyloidosis.
  - reference: PMID:30480471
    reference_title: "Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Phase II, III and long-term extension studies in patients with hereditary transthyretin-mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy."
    explanation: Phase II/III/extension data show patisiran slows or improves ATTRv neuropathy progression.
datasets: []