Amyloidosis

Complex MONDO:0019065 Pathograph 8 Show in embeddings browser 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.
8
Phenotypes
8
Pathograph
2
Genes
8
Medical Actions
5
Subtypes
1
Deep Research
◆

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
Downstream
Amyloid Deposition Extracellular amyloid fibril deposition is the defining histopathologic phenotype of amyloidosis.
Cardiomyopathy Myocardial amyloid accumulation can produce infiltrative cardiomyopathy.
Peripheral Neuropathy Amyloid deposition in hereditary ATTR can produce length-dependent peripheral polyneuropathy.
Nephrotic Syndrome Renal amyloid deposition can progress through nephropathy and nephrotic-range proteinuria to nephrotic syndrome.
Macroglossia Amyloid infiltration can produce tongue enlargement, especially in AL amyloidosis.
Autonomic Dysfunction Hereditary ATTR amyloid polyneuropathy can include life-threatening autonomic dysfunction.
Show evidence (3 references)
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.
DOI:10.1038/s41580-023-00647-2 SUPPORT Other
"Multiple lines of evidence suggest that small soluble species are responsible for the observed toxicity. These species have been associated with numerous detrimental effects, such as permeabilization of cellular membranes, impairment of degradation pathways, disruption of synaptic signalling and..."
Louros et al. establish that soluble oligomeric species, not only mature fibrils, drive amyloid cytotoxicity via membrane permeabilization, impaired protein degradation, and mitochondrial dysfunction.
DOI:10.1002/ana.26965 SUPPORT Other
"Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils"
Chompoopong et al. localize amyloid fibril deposition to the endoneurium and dorsal root/sympathetic ganglia, causing Schwann cell atrophy, the substrate of amyloid neuropathy.
⬡

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

8
Genitourinary 1
Proteinuria VERY_FREQUENT Proteinuria HP:0000093
Show evidence (1 reference)
DOI:10.1007/s11926-024-01147-8 SUPPORT Other
"emergence of proteinuria and gradual reduction in kidney function, apparent in over 90% of patients upon their initial presentation"
Mirioglu et al. report proteinuria with declining renal function in over 90% of AA amyloidosis patients at presentation, supporting a VERY_FREQUENT band.
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 3
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.
Carpal Tunnel Syndrome FREQUENT Constrictive median neuropathy HP:0012185
Show evidence (1 reference)
DOI:10.3389/fneur.2023.1242815 SUPPORT Other
"CTS occurred in two-thirds of patients with ATTRv"
Poli et al. (citing Karam 2019) report carpal tunnel syndrome in two-thirds of ATTRv patients, supporting both the association and a FREQUENT band.
🧬

Genetic Associations

2
TTR (Pathogenic Variants)
Gene: TTR hgnc:12405
Show evidence (3 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.
DOI:10.1001/jamacardio.2024.2190 SUPPORT Human Clinical
"The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry."
Aung et al. quantify the strong ancestry skew of pathogenic TTR variants (driven by Val142Ile) in UK Biobank, 4.3% in African-ancestry participants versus 0.02% in European-ancestry.
SAA1 (Susceptibility/Precursor)
Gene: SAA1 hgnc:10513
Show evidence (1 reference)
DOI:10.1007/s11926-024-01147-8 SUPPORT Other
"serum AA (SAA) protein, through a long process including cleavage, misfolding, and aggregation into an insoluble beta-sheet form"
Mirioglu et al. identify serum amyloid A (SAA) protein as the acute-phase precursor that is cleaved, misfolds, and aggregates into AA amyloid fibrils.
💊

Medical Actions

8
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.
Acoramidis
Action: Pharmacotherapy NCIT:C15986
Agent: acoramidis NCIT:C170791
Oral high-affinity transthyretin tetramer stabilizer, FDA-approved disease-modifying therapy for ATTR cardiomyopathy; binds TTR and prevents dissociation into amyloidogenic monomers.
Show evidence (1 reference)
DOI:10.1007/s10741-025-10502-5 SUPPORT Other
"While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches."
Ang et al. identify acoramidis (with tafamidis) as one of the FDA-approved TTR stabilizers for ATTR cardiomyopathy.
Vutrisiran
Action: Pharmacotherapy NCIT:C15986
Agent: vutrisiran NCIT:C152919
Subcutaneous GalNAc-conjugated small interfering RNA that silences hepatic TTR mRNA; licensed for hereditary ATTR polyneuropathy and studied in ATTR cardiomyopathy.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN"
Ioannou et al. document vutrisiran as a licensed siRNA gene silencer for ATTR polyneuropathy.
Inotersen
Action: Pharmacotherapy NCIT:C15986
Agent: inotersen NCIT:C121667
2'-O-methoxyethyl-modified antisense oligonucleotide that triggers RNase H1-mediated degradation of TTR mRNA, lowering both wild-type and mutant transthyretin; licensed for hereditary ATTR polyneuropathy.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN"
Ioannou et al. document inotersen as a licensed antisense oligonucleotide gene silencer for ATTR polyneuropathy.
Eplontersen
Action: Pharmacotherapy NCIT:C15986
Agent: eplontersen NCIT:C175062
GalNAc-conjugated, RNase H-dependent antisense oligonucleotide targeting TTR mRNA; an FDA-approved RNA-lowering therapy for hereditary ATTR amyloidosis (polyneuropathy) with cardiomyopathy trials.
Show evidence (1 reference)
DOI:10.7759/cureus.62981 SUPPORT Other
"Four FDA-approved RNAi medications for ATTR polyneuropathy are patisiran, vutrisiran, inotersen, and eplontersen."
Dave et al. list eplontersen among the four FDA-approved RNA-lowering medications for ATTR polyneuropathy.
Daratumumab
Action: Pharmacotherapy NCIT:C15986
Agent: daratumumab NCIT:C74007
Anti-CD38 monoclonal antibody added to bortezomib-cyclophosphamide-dexamethasone (Dara-CyBorD/D-VCd); standard-of-care induction for newly diagnosed AL amyloidosis that depletes the amyloidogenic clonal plasma cells (ANDROMEDA trial).
Show evidence (1 reference)
DOI:10.18632/oncotarget.28415 SUPPORT Other
"the hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%)"
Bou Zerdan et al. report that daratumumab-CyBorD nearly tripled the hematologic complete response rate over CyBorD alone in newly diagnosed AL amyloidosis (ANDROMEDA).
Tocilizumab
Action: Pharmacotherapy NCIT:C15986
Agent: tocilizumab NCIT:C84217
Anti-interleukin-6 receptor monoclonal antibody used in AA amyloidosis to suppress the inflammatory drive of serum amyloid A production, lowering SAA and improving renal function.
Show evidence (1 reference)
DOI:10.1007/s11926-024-01147-8 SUPPORT Other
"tocilizumab was superior to anti-TNFs in terms of obtaining a decrease in SAA"
Mirioglu et al. report that tocilizumab (anti-IL-6 receptor) reduced SAA in AA amyloidosis, superior to anti-TNF therapy.
{ }

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.
  - reference: DOI:10.1038/s41580-023-00647-2
    reference_title: "Mechanisms and pathology of protein misfolding and aggregation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple lines of evidence suggest that small soluble species are responsible for the observed toxicity. These species have been associated with numerous detrimental effects, such as permeabilization of cellular membranes, impairment of degradation pathways, disruption of synaptic signalling and mitochondrial dysfunction"
    explanation: Louros et al. establish that soluble oligomeric species, not only mature fibrils, drive amyloid cytotoxicity via membrane permeabilization, impaired protein degradation, and mitochondrial dysfunction.
  - reference: DOI:10.1002/ana.26965
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils"
    explanation: Chompoopong et al. localize amyloid fibril deposition to the endoneurium and dorsal root/sympathetic ganglia, causing Schwann cell atrophy, the substrate of amyloid neuropathy.
  downstream:
  - target: Amyloid Deposition
    causal_link_type: DIRECT
    description: >-
      Extracellular amyloid fibril deposition is the defining histopathologic
      phenotype of amyloidosis.
    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: >-
        The review supports extracellular amyloid fibril deposition as the
        disease-defining tissue phenotype.
  - target: Cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Myocardial amyloid accumulation can produce infiltrative cardiomyopathy.
    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: >-
        Cardiac amyloidosis evidence directly links myocardial misfolded TTR
        accumulation to ATTR cardiomyopathy.
  - target: Peripheral Neuropathy
    causal_link_type: DIRECT
    description: >-
      Amyloid deposition in hereditary ATTR can produce length-dependent
      peripheral polyneuropathy.
    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: >-
        Familial amyloid polyneuropathy evidence supports length-dependent
        peripheral neuropathy as a direct amyloidosis manifestation.
  - target: Nephrotic Syndrome
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - renal amyloid nephropathy with heavy proteinuria
    description: >-
      Renal amyloid deposition can progress through nephropathy and
      nephrotic-range proteinuria to 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: >-
        AA amyloidosis evidence supports renal nephropathy as a major clinical
        manifestation.
  - target: Macroglossia
    causal_link_type: DIRECT
    description: >-
      Amyloid infiltration can produce tongue enlargement, especially in AL
      amyloidosis.
    evidence:
    - reference: PMID:8115892
      reference_title: "Gastrointestinal manifestations of amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Gastrointestinal symptoms included anorexia, macroglossia, intestinal"
      explanation: >-
        The clinical case series directly lists macroglossia among
        gastrointestinal manifestations of amyloidosis.
  - target: Autonomic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Hereditary ATTR amyloid polyneuropathy can include life-threatening
      autonomic dysfunction.
    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: >-
        Familial amyloid polyneuropathy evidence supports autonomic dysfunction
        as a direct amyloidosis manifestation.
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.
- name: Carpal Tunnel Syndrome
  category: Neurological
  subtype: ATTRv
  description: >-
    Bilateral carpal tunnel syndrome from amyloid deposition in the flexor
    retinaculum/tenosynovium is a common early and often presenting sign of
    ATTR amyloidosis, frequently predating systemic diagnosis by years.
  phenotype_term:
    preferred_term: Carpal tunnel syndrome
    term:
      id: HP:0012185
      label: Constrictive median neuropathy
  frequency: FREQUENT
  evidence:
  - reference: DOI:10.3389/fneur.2023.1242815
    reference_title: "Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTS occurred in two-thirds of patients with ATTRv"
    explanation: Poli et al. (citing Karam 2019) report carpal tunnel syndrome in two-thirds of ATTRv patients, supporting both the association and a FREQUENT band.
- name: Proteinuria
  category: Renal
  subtype: AA
  description: >-
    Glomerular amyloid deposition in AA amyloidosis produces proteinuria and
    progressive decline in renal function, the dominant clinical presentation.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  frequency: VERY_FREQUENT
  evidence:
  - reference: DOI:10.1007/s11926-024-01147-8
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "emergence of proteinuria and gradual reduction in kidney function, apparent in over 90% of patients upon their initial presentation"
    explanation: Mirioglu et al. report proteinuria with declining renal function in over 90% of AA amyloidosis patients at presentation, supporting a VERY_FREQUENT band.
genetic:
- name: TTR
  gene_term:
    preferred_term: TTR
    term:
      id: hgnc:12405
      label: 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.
  - reference: DOI:10.1001/jamacardio.2024.2190
    reference_title: "Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry."
    explanation: Aung et al. quantify the strong ancestry skew of pathogenic TTR variants (driven by Val142Ile) in UK Biobank, 4.3% in African-ancestry participants versus 0.02% in European-ancestry.
- name: SAA1
  association: Susceptibility/Precursor
  subtype: AA
  gene_term:
    preferred_term: SAA1
    term:
      id: hgnc:10513
      label: SAA1
  notes: >-
    SAA1 encodes serum amyloid A1, the acute-phase apolipoprotein that is the
    fibril precursor in AA amyloidosis. Sustained inflammatory overproduction
    of SAA drives fibril deposition, and SAA1 genotype (e.g., SAA1.1
    homozygosity) modifies AA amyloidosis risk in some populations.
  evidence:
  - reference: DOI:10.1007/s11926-024-01147-8
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "serum AA (SAA) protein, through a long process including cleavage, misfolding, and aggregation into an insoluble beta-sheet form"
    explanation: Mirioglu et al. identify serum amyloid A (SAA) protein as the acute-phase precursor that is cleaved, misfolds, and aggregates into AA amyloid fibrils.
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.
- name: Acoramidis
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Oral high-affinity transthyretin tetramer stabilizer, FDA-approved
    disease-modifying therapy for ATTR cardiomyopathy; binds TTR and prevents
    dissociation into amyloidogenic monomers.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acoramidis
      term:
        id: NCIT:C170791
        label: Acoramidis
  evidence:
  - reference: DOI:10.1007/s10741-025-10502-5
    reference_title: "Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches."
    explanation: Ang et al. identify acoramidis (with tafamidis) as one of the FDA-approved TTR stabilizers for ATTR cardiomyopathy.
- name: Vutrisiran
  therapeutic_modality: SIRNA
  description: >-
    Subcutaneous GalNAc-conjugated small interfering RNA that silences hepatic
    TTR mRNA; licensed for hereditary ATTR polyneuropathy and studied in ATTR
    cardiomyopathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vutrisiran
      term:
        id: NCIT:C152919
        label: Vutrisiran
  evidence:
  - reference: DOI:10.1007/s40259-023-00577-7
    reference_title: "RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN"
    explanation: Ioannou et al. document vutrisiran as a licensed siRNA gene silencer for ATTR polyneuropathy.
- name: Inotersen
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  description: >-
    2'-O-methoxyethyl-modified antisense oligonucleotide that triggers RNase
    H1-mediated degradation of TTR mRNA, lowering both wild-type and mutant
    transthyretin; licensed for hereditary ATTR polyneuropathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: inotersen
      term:
        id: NCIT:C121667
        label: Inotersen
  evidence:
  - reference: DOI:10.1007/s40259-023-00577-7
    reference_title: "RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN"
    explanation: Ioannou et al. document inotersen as a licensed antisense oligonucleotide gene silencer for ATTR polyneuropathy.
- name: Eplontersen
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: GALNAC
  description: >-
    GalNAc-conjugated, RNase H-dependent antisense oligonucleotide targeting
    TTR mRNA; an FDA-approved RNA-lowering therapy for hereditary ATTR
    amyloidosis (polyneuropathy) with cardiomyopathy trials.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eplontersen
      term:
        id: NCIT:C175062
        label: Eplontersen
  evidence:
  - reference: DOI:10.7759/cureus.62981
    reference_title: "RNA Interference Therapeutics for Hereditary Amyloidosis: A Narrative Review of Clinical Trial Outcomes and Future Directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Four FDA-approved RNAi medications for ATTR polyneuropathy are patisiran, vutrisiran, inotersen, and eplontersen."
    explanation: Dave et al. list eplontersen among the four FDA-approved RNA-lowering medications for ATTR polyneuropathy.
- name: Daratumumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-CD38 monoclonal antibody added to
    bortezomib-cyclophosphamide-dexamethasone (Dara-CyBorD/D-VCd);
    standard-of-care induction for newly diagnosed AL amyloidosis that depletes
    the amyloidogenic clonal plasma cells (ANDROMEDA trial).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: daratumumab
      term:
        id: NCIT:C74007
        label: Daratumumab
  evidence:
  - reference: DOI:10.18632/oncotarget.28415
    reference_title: "Systemic AL amyloidosis: current approach and future direction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%)"
    explanation: Bou Zerdan et al. report that daratumumab-CyBorD nearly tripled the hematologic complete response rate over CyBorD alone in newly diagnosed AL amyloidosis (ANDROMEDA).
- name: Tocilizumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-interleukin-6 receptor monoclonal antibody used in AA amyloidosis to
    suppress the inflammatory drive of serum amyloid A production, lowering SAA
    and improving renal function.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  evidence:
  - reference: DOI:10.1007/s11926-024-01147-8
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "tocilizumab was superior to anti-TNFs in terms of obtaining a decrease in SAA"
    explanation: Mirioglu et al. report that tocilizumab (anti-IL-6 receptor) reduced SAA in AA amyloidosis, superior to anti-TNF therapy.
diagnosis:
- name: Cardiac Radionuclide Scintigraphy
  description: >-
    Bone-avid radionuclide (e.g., technetium-pyrophosphate/DPD/HMDP)
    scintigraphy enables accurate non-invasive diagnosis of transthyretin
    cardiac amyloidosis (ATTR-CM) in patients with a negative monoclonal
    protein screen, obviating endomyocardial biopsy.
  diagnosis_term:
    preferred_term: cardiac radionuclide scintigraphy
    term:
      id: NCIT:C62667
      label: Radionuclide Imaging
  evidence:
  - reference: PMID:41171219
    reference_title: "Transthyretin Cardiac Amyloidosis Evaluation and Management: 2025 ACC Concise Clinical Guidance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There have also been substantial advances in diagnosis, including the ability to perform accurate noninvasive diagnosis using radionuclide scintigraphy in individuals with a negative monoclonal protein screen."
    explanation: The 2025 ACC guidance establishes radionuclide scintigraphy as an accurate non-invasive diagnostic test for transthyretin cardiac amyloidosis when the monoclonal protein screen is negative.
- name: Early Diagnosis of AL Amyloidosis
  description: >-
    Prompt recognition of AL amyloidosis across haematology, cardiology,
    neurology, renal, and general clinics, because early-stage diagnosis before
    advanced organ involvement markedly improves survival with contemporary
    treatment.
  evidence:
  - reference: PMID:42099096
    reference_title: "Early diagnosis of AL amyloidosis in haematology, cardiology, neurology, renal and general clinics: A British Society for Haematology Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with early-stage disease can expect approximately 80% survival at 5 years with contemporary treatment, compared to less than 30% for those with advanced disease."
    explanation: The British Society for Haematology guideline motivates early cross-specialty AL amyloidosis diagnosis by quantifying the large survival advantage of early-stage detection.
prevalence:
- population: United States
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.61
  notes: >-
    ATTR amyloidosis point prevalence 6.1 per million in the US in a systematic
    review (range up to 232 per million in endemic Portugal).
  evidence:
  - reference: DOI:10.1186/s13023-025-03547-0
    reference_title: "Epidemiology of transthyretin (ATTR) amyloidosis: a systematic literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ATTR prevalence ranged from 6.1/million in the US to 232/million in Portugal with very limited data on ATTR-PN."
    explanation: Delgado et al. systematic review reports ATTR prevalence of 6.1 per million in the US.
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  notes: >-
    Systemic AL amyloidosis estimated incidence ~10 cases per million persons
    per year (= 1.0 per 100,000).
  evidence:
  - reference: DOI:10.18632/oncotarget.28415
    reference_title: "Systemic AL amyloidosis: current approach and future direction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an estimated incidence of 10 cases per million persons a year"
    explanation: Bou Zerdan et al. state AL amyloidosis has an estimated incidence of 10 cases per million persons a year.
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 56 citations 2026-07-05T19:21:25.261434

1. Disease Information

Overview

Amyloidosis is a heterogeneous group of diseases characterized by the pathological extracellular deposition of insoluble misfolded protein material called "amyloid" in tissues and organs (poli2023hereditarytransthyretinamyloidosis pages 1-2). These amyloid fibrils are ordered structures of 7–13 nm diameter with cross-β-sheet secondary structure that damage tissue organization and induce progressive organ dysfunction (ajmal2023proteinmisfoldingand pages 4-6). Over 30 types of amyloid fibrils have been identified in humans, but the clinically most important systemic forms are immunoglobulin light-chain (AL) amyloidosis, transthyretin (ATTR) amyloidosis (both hereditary/variant [ATTRv] and wild-type [ATTRwt]), and serum amyloid A (AA) amyloidosis (fontana2025thelastdecade pages 1-3, zanwar2023immunoglobulinlightchain pages 1-2).

Key Identifiers

  • MONDO ID: MONDO:0019065 (amyloidosis); MONDO:0018634 (hereditary amyloidosis); MONDO:0019438 (AL amyloidosis) (OpenTargets Search: amyloidosis)
  • ICD-10: E85 (Amyloidosis), with subtypes E85.0–E85.9
  • OMIM: #105210 (Amyloidosis, hereditary, transthyretin-related); #204900 (Amyloidosis, primary/AL)
  • MeSH: D000686
  • Orphanet: ORPHA:69 (Amyloidosis); ORPHA:85443 (AL amyloidosis); ORPHA:271861 (ATTR amyloidosis)

Synonyms

Common alternative names include: amyloid disease, systemic amyloidosis, primary amyloidosis (AL), secondary amyloidosis (AA), senile systemic amyloidosis (ATTRwt), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and transthyretin-related hereditary amyloidosis.

The following table summarizes the four major systemic amyloidosis types:

Type Precursor Protein Gene(s) Etiology Main Organs Affected Typical Age of Onset Inheritance Key Epidemiology Primary Treatment Approaches
AL amyloidosis Monoclonal immunoglobulin light chains (κ or λ) Immunoglobulin light-chain loci; recurrent plasma-cell cytogenetic abnormalities include t(11;14), 1q21 gain Clonal plasma-cell disorder with misfolded light-chain production and extracellular fibril deposition; often arises from MGUS/smoldering myeloma and ~10% also meet criteria for multiple myeloma (zanwar2023immunoglobulinlightchain pages 1-2, zerdan2023systemicalamyloidosis pages 1-2, zanwar2023immunoglobulinlightchain pages 6-7) Heart, kidney, liver, GI tract, peripheral/autonomic nerves, soft tissue; ~70% have multiorgan involvement at diagnosis (zerdan2023systemicalamyloidosis pages 1-2, zanwar2023immunoglobulinlightchain pages 1-2) Usually adult/older adult; age >65–70 years is adverse prognostic factor (zanwar2023immunoglobulinlightchain pages 6-7, zanwar2023immunoglobulinlightchain pages 1-2) Not classically inherited; acquired clonal hematologic disease Incidence ≈1 per 100,000 person-years; ~3,500–4,500 new US cases/year; also reported as ~10 per million/year (zanwar2023immunoglobulinlightchain pages 1-2, zerdan2023systemicalamyloidosis pages 1-2) First-line daratumumab + bortezomib/cyclophosphamide/dexamethasone (D-VCd); bortezomib-based regimens; selected patients receive autologous stem-cell transplantation; supportive organ care (chompoopong2024amyloidneuropathyfrom pages 10-11, chompoopong2024amyloidneuropathyfrom pages 11-11, dima2023diagnosticandtreatment pages 2-3)
ATTR variant (ATTRv, hereditary transthyretin amyloidosis) Mutant transthyretin TTR (chromosome 18); >140–150 pathogenic variants; key variants include p.Val50Met/Val30Met and p.Val142Ile/Val122Ile (poli2023hereditarytransthyretinamyloidosis pages 2-3, poli2023hereditarytransthyretinamyloidosis pages 1-2, ioannou2023rnatargetingand pages 1-2) Destabilizing missense TTR variants reduce tetramer stability, causing monomer misfolding and amyloid fibril deposition; phenotype may be neuropathic, cardiac, or mixed (poli2023hereditarytransthyretinamyloidosis pages 2-3, poli2023hereditarytransthyretinamyloidosis pages 1-2, ioannou2023rnatargetingand pages 1-2) Peripheral/autonomic nerves, heart, GI tract, kidneys, eyes, leptomeninges/CNS (poli2023hereditarytransthyretinamyloidosis pages 4-6, chompoopong2024amyloidneuropathyfrom pages 6-6) Early-onset in endemic areas often 2nd–5th decade; late-onset usually after 50 years and often 7th–8th decade in non-endemic regions (poli2023hereditarytransthyretinamyloidosis pages 4-6, poli2023hereditarytransthyretinamyloidosis pages 2-3) Autosomal dominant with incomplete/variable penetrance; parent-of-origin effects reported for Val30Met/Val50Met (poli2023hereditarytransthyretinamyloidosis pages 2-3, chompoopong2024amyloidneuropathyfrom pages 6-6, bhatt2024hereditarytransthyretinamyloidosis pages 1-2) Global prevalence estimated ~10,186 affected persons (range 5,000–38,000); endemic clusters in Portugal, Sweden, Brazil, Japan; Val122Ile present in ~3–4% of African Americans (poli2023hereditarytransthyretinamyloidosis pages 2-3, bhatt2024hereditarytransthyretinamyloidosis pages 1-2, ioannou2023rnatargetingand pages 1-2) TTR stabilizers (tafamidis; diflunisal off-label; acoramidis for cardiomyopathy), gene silencers (patisiran, vutrisiran, inotersen, eplontersen), emerging CRISPR gene editing (NTLA-2001), supportive multidisciplinary care (anan2025advancesinthe pages 4-5, dave2024rnainterferencetherapeutics pages 4-5, ioannou2023rnatargetingand pages 1-2)
ATTR wild-type (ATTRwt) Wild-type transthyretin TTR (wild-type sequence) Age-related destabilization/misfolding of native TTR without pathogenic coding mutation; predominantly cardiac deposition (fontana2025thelastdecade pages 1-3, kim2026autotacmediatedtargeteddegradation pages 4-8, ishida2026crispr–cas3basededitingfor pages 1-2) Heart (restrictive/infiltrative cardiomyopathy), conduction system; can be associated with carpal tunnel syndrome and other musculoskeletal manifestations in broader ATTR spectrum (fontana2025thelastdecade pages 1-3, chompoopong2024amyloidneuropathyfrom pages 7-7) Older adults, predominantly elderly men; often >70–80 years (fontana2025thelastdecade pages 1-3, delgado2025epidemiologyoftransthyretin pages 4-6, delgado2025epidemiologyoftransthyretin pages 2-4) Non-Mendelian; no inherited pathogenic variant required US ATTR prevalence reported as 6.1/million overall in systematic review; 2-year mortality in wild-type ATTR-CM ~10–30%; autopsy deposits in ~25% of people aged ≥85 years (delgado2025epidemiologyoftransthyretin pages 4-6, delgado2025epidemiologyoftransthyretin pages 1-2, kim2026autotacmediatedtargeteddegradation pages 4-8) Tafamidis is established disease-modifying therapy; acoramidis now approved for ATTR-CM; investigational/expanding roles for gene silencers and gene editing in cardiomyopathy; supportive HF care/diuretics (anan2025advancesinthe pages 4-5, ang2025emergingnovelgenemodulating pages 10-10, ioannou2023rnatargetingand pages 1-2)
AA amyloidosis Serum amyloid A (SAA) protein SAA1 and related SAA loci as susceptibility modifiers; SAA1.1 homozygosity increases risk in some populations (mirioglu2024aaamyloidosisa pages 1-2) Chronic inflammatory states drive sustained SAA overproduction and secondary fibril deposition; causes include chronic infection, inflammatory arthritis, FMF, immunodeficiency; ~20% idiopathic/unknown cause (mirioglu2024aaamyloidosisa pages 1-2, mirioglu2024aaamyloidosisa pages 4-6) Kidney predominates; also liver, GI tract, heart less commonly, and other organs depending on inflammatory burden (mirioglu2024aaamyloidosisa pages 1-2, mirioglu2024aaamyloidosisa pages 4-6) Usually adults, median diagnosis age ~50–70 years (mirioglu2024aaamyloidosisa pages 1-2) Not usually Mendelian; underlying inflammatory disorders may be genetic (e.g., FMF), and SAA genotype modifies risk (mirioglu2024aaamyloidosisa pages 1-2) Incidence ~1–2 cases per million person-years in developed countries; now ~2.9% of all amyloidosis cases; slight male predominance (mirioglu2024aaamyloidosisa pages 1-2) Control underlying inflammation and reduce SAA: biologics such as IL-6 inhibition (tocilizumab), IL-1 inhibition (anakinra), other anti-inflammatory therapy; kidney transplantation for ESRD in selected patients (mirioglu2024aaamyloidosisa pages 1-2, mirioglu2024aaamyloidosisa pages 4-6)

Table: This table compares the four major systemic amyloidosis categories across precursor protein, genetics, etiology, organ involvement, onset, epidemiology, and current treatment strategy. It is useful as a compact disease-knowledge-base reference grounded in the gathered evidence.

2. Etiology

Disease Causal Factors

AL Amyloidosis: Caused by a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin light chains (κ or λ) misfold and deposit as amyloid fibrils in tissues. It often arises from pre-malignant conditions such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma, and approximately 10% of patients also meet criteria for multiple myeloma (zerdan2023systemicalamyloidosis pages 1-2).

ATTR Amyloidosis (Hereditary): Caused by autosomal dominant mutations in the TTR gene (chromosome 18q11.2–q12.1), which destabilize the transthyretin tetramer, promoting dissociation into monomers that misfold and aggregate into amyloid fibrils (poli2023hereditarytransthyretinamyloidosis pages 2-3, poli2023hereditarytransthyretinamyloidosis pages 1-2).

ATTR Amyloidosis (Wild-type): Results from age-related destabilization of native wild-type TTR protein without pathogenic coding mutations, predominantly causing cardiac deposition in elderly individuals. Autopsy studies revealed myocardial ATTR deposits in approximately 25% of individuals aged ≥85 years (kim2026autotacmediatedtargeteddegradation pages 4-8).

AA Amyloidosis: A complication of chronic inflammatory disorders where sustained overproduction of serum amyloid A (SAA) protein leads to fibril deposition. Common causes include chronic infections, inflammatory arthritis, familial Mediterranean fever (FMF), and primary immunodeficiencies. Approximately 20% of cases are idiopathic (mirioglu2024aaamyloidosisa pages 1-2).

Risk Factors

Genetic risk factors: - TTR gene mutations: Over 150 pathogenic variants identified, predominantly missense. Val30Met (p.Val50Met) is probably the most common worldwide, and Val122Ile (p.Val142Ile) is carried by 3–4% of African Americans (poli2023hereditarytransthyretinamyloidosis pages 2-3, ioannou2023rnatargetingand pages 1-2). - SAA1.1 homozygosity increases risk for AA amyloidosis in European populations (mirioglu2024aaamyloidosisa pages 1-2). - Cytogenetic abnormalities in AL amyloidosis: t(11;14) occurs in 40–60% of patients; 1q21 gain in ~50%; trisomies in up to 30% (zanwar2023immunoglobulinlightchain pages 6-7).

Environmental/demographic risk factors: - Advanced age (particularly for ATTRwt and late-onset ATTRv) - Male sex predominates in ATTR-CM and AA amyloidosis (mirioglu2024aaamyloidosisa pages 1-2, delgado2025epidemiologyoftransthyretin pages 2-4) - African ancestry (Val122Ile variant prevalence 3.8% in African-descent populations in UK Biobank) (aung2024prevalencecardiacphenotype pages 11-15) - Sustained chronic inflammation for AA amyloidosis (mirioglu2024aaamyloidosisa pages 1-2)

3. Phenotypes and Clinical Manifestations

Cardiac Involvement

Cardiac amyloidosis is the key determinant of survival across all types. In AL amyloidosis, cardiac involvement occurs in approximately 70% of cases, presenting with heart failure, biventricular hypertrophy, restrictive filling pattern, arrhythmias (atrial fibrillation, ventricular tachycardia), AV conduction delays, low voltage on ECG, and poor R-wave progression (dima2023diagnosticandtreatment pages 1-2). Echocardiographic findings include concentric hypertrophy, small LV cavity, diastolic dysfunction, reduced global longitudinal strain with preserved apical strain, and biatrial dilatation (chompoopong2024amyloidneuropathyfrom pages 7-7, zanwar2023immunoglobulinlightchain pages 2-4). Untreated advanced cardiac AL amyloidosis has a median survival of 6 months (fontana2025thelastdecade pages 1-3).

Suggested HPO terms: HP:0001638 (Cardiomyopathy); HP:0001635 (Congestive heart failure); HP:0004749 (Atrial flutter/fibrillation); HP:0001712 (Left ventricular hypertrophy)

Renal Involvement

The kidney is the major affected organ in AA amyloidosis, manifesting as nephrotic-range proteinuria and progressive renal failure (mirioglu2024aaamyloidosisa pages 1-2). In AL amyloidosis, renal involvement presents as nephrotic syndrome without obvious etiology (zanwar2023immunoglobulinlightchain pages 1-2). In ATTRv, approximately one-third of endemic and 6% of non-endemic cases develop nephrotic syndrome (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0000100 (Nephrotic syndrome); HP:0000093 (Proteinuria); HP:0003774 (Stage 5 chronic kidney disease)

Neurological Manifestations

Amyloid neuropathy is manifested as a length-dependent sensory-predominant neuropathy associated with generalized autonomic failure (chompoopong2024amyloidneuropathyfrom pages 6-6). Small unmyelinated nerves are involved early in early-onset Val30Met ATTRv, whereas other variants and AL amyloidosis present with large- and small-fiber involvement. Carpal tunnel syndrome occurs in two-thirds of ATTRv patients, sometimes preceding diagnosis by 10 years (poli2023hereditarytransthyretinamyloidosis pages 4-6). Neurogenic orthostatic hypotension occurs in 40–60% of ATTRv patients (chompoopong2024amyloidneuropathyfrom pages 6-6). CNS involvement (leptomeningeal amyloidosis) can cause stroke, hemorrhage, cognitive impairment, ataxia, and epilepsy (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0009830 (Peripheral neuropathy); HP:0002459 (Dysautonomia); HP:0012185 (Orthostatic hypotension); HP:0012531 (Pain); HP:0001324 (Muscle weakness)

Gastrointestinal and Other Manifestations

GI symptoms include premature satiety, gastric distension, nausea, vomiting, diarrhea from malabsorption, and constipation (poli2023hereditarytransthyretinamyloidosis pages 4-6, zanwar2023immunoglobulinlightchain pages 2-4). Hepatomegaly with elevated alkaline phosphatase is common in AL amyloidosis. Classic pathognomonic findings in AL include macroglossia, periorbital ecchymoses ("raccoon eyes"), and musculoskeletal pathologies (zanwar2023immunoglobulinlightchain pages 2-4). Ocular involvement in ATTRv (10% of patients) includes vitreous opacities, glaucoma, and keratoconjunctivitis sicca (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0002240 (Hepatomegaly); HP:0000158 (Macroglossia); HP:0002014 (Diarrhea); HP:0001824 (Weight loss)

4. Genetic/Molecular Information

Causal Genes

TTR (Transthyretin): HGNC:12405; ENSG00000118271; chromosome 18q12.1. The TTR gene encodes a 127-amino acid protein that functions as a transporter of thyroxine and retinol-binding protein, primarily synthesized in the liver, choroid plexus, and retinal pigment epithelium (poli2023hereditarytransthyretinamyloidosis pages 1-2). Over 140–150 pathogenic variants have been identified, predominantly single-nucleotide substitutions producing missense mutations (poli2023hereditarytransthyretinamyloidosis pages 2-3, kim2026autotacmediatedtargeteddegradation pages 1-4, bhatt2024hereditarytransthyretinamyloidosis pages 1-2).

Key Pathogenic Variants: - p.Val50Met (Val30Met): Probably the most common disease-causing variant worldwide; associated with familial amyloid polyneuropathy. Can manifest as early-onset (age <50) with predominant polyneuropathy or late-onset with mixed phenotype. Higher penetrance in Portuguese families versus French and Swedish families (chompoopong2024amyloidneuropathyfrom pages 6-6, ioannou2023rnatargetingand pages 1-2). - p.Val142Ile (Val122Ile): Carried by 3–4% of African Americans and associated with predominant cardiomyopathy. In UK Biobank, prevalence was 4.3% in participants with African ancestry, associated with HR 2.68 for heart failure (ioannou2023rnatargetingand pages 1-2, aung2024prevalencecardiacphenotype pages 11-15). - p.Thr80Ala: Cardiac-predominant or mixed phenotype with earlier onset (~10 years earlier than Val142Ile) (aung2024prevalencecardiacphenotype pages 11-15).

Inheritance: Autosomal dominant with incomplete and variable penetrance. Genetic anticipation has been reported in Val30Met families, with shorter disease intervals in mother-to-son transmission (chompoopong2024amyloidneuropathyfrom pages 6-6). Maternal inheritance of Val30Met shows earlier disease onset in offspring, suggesting parental imprinting and possible mitochondrial genome involvement (poli2023hereditarytransthyretinamyloidosis pages 2-3).

Other Amyloidogenic Genes (from OpenTargets): - APP (amyloid beta precursor protein; score 0.86) - GSN (gelsolin; score 0.85) — causes Finnish-type amyloidosis - ITM2B (integral membrane protein 2B; score 0.84) - FGA (fibrinogen alpha chain; score 0.79) — causes hereditary renal amyloidosis - APOA1 (apolipoprotein A1; score 0.78) — causes hereditary systemic amyloidosis - CST3 (cystatin C; score 0.73) — causes Icelandic-type cerebral amyloid angiopathy - LYZ (lysozyme; score 0.72) — causes hereditary systemic amyloidosis - B2M (beta-2-microglobulin; score 0.67) — causes dialysis-related amyloidosis - SAA1 (serum amyloid A1) — precursor protein in AA amyloidosis (OpenTargets Search: amyloidosis)

5. Mechanism / Pathophysiology

Protein Misfolding and Amyloid Formation

The fundamental pathological process in all amyloidoses involves protein misfolding and aggregation. Under normal conditions, molecular chaperones guide proteins through energy landscapes to facilitate productive folding and prevent aggregation (louros2023mechanismsandpathology pages 1-4). In amyloidosis, precursor proteins become trapped in local energy minima with non-native structures, exposing hydrophobic patches that promote self-assembly into oligomers, protofibrils, and ultimately insoluble amyloid fibrils (ajmal2023proteinmisfoldingand pages 4-6).

Specific Mechanisms by Subtype

In ATTR amyloidosis, TTR tetramer destabilization (caused by mutations in ATTRv or aging in ATTRwt) leads to dissociation into monomers that misfold, aggregate abnormally, and deposit in extracellular locations, leading to progressive multiorgan damage (poli2023hereditarytransthyretinamyloidosis pages 2-3). Current therapies include tetramer stabilizers and RNA interference agents, but they do not eliminate pre-existing aggregates, underscoring the need for disease-modifying therapeutics capable of removing pathogenic TTR species (kim2026autotacmediatedtargeteddegradation pages 4-8).

Toxicity Mechanisms

Toxicity is attributed to both small soluble oligomeric species and fibrillar aggregates. Soluble oligomers cause permeabilization of cellular membranes, impairment of degradation pathways, disruption of synaptic signaling, and mitochondrial dysfunction. Fibrillar toxicity results from mechanical perturbations, sequestration of cellular factors, and inflammatory responses (louros2023mechanismsandpathology pages 16-19). Amyloid fibrils deposit in the endoneurium of peripheral nerves, extensively in dorsal root ganglia and sympathetic ganglia, leading to Schwann cell atrophy and blood–nerve barrier disruption (chompoopong2024amyloidneuropathyfrom pages 6-6).

Cellular Quality Control

Cells employ the ubiquitin-proteasome system (UPS) as the first-line mechanism for degrading soluble misfolded proteins, while autophagy-lysosome pathways clear insoluble aggregates (ajmal2023proteinmisfoldingand pages 9-11, ajmal2023proteinmisfoldingand pages 8-9, kim2026autotacmediatedtargeteddegradation pages 4-8). When these quality control systems are overwhelmed, accumulation of protein aggregates causes proteotoxicity and cell death (ajmal2023proteinmisfoldingand pages 9-11).

Suggested GO terms: GO:0006986 (Response to unfolded protein); GO:0006914 (Autophagy); GO:0030163 (Protein catabolic process); GO:0051082 (Unfolded protein binding); GO:0070841 (Inclusion body assembly)

6. Anatomical Structures Affected

Organ Level

  • Heart (UBERON:0000948): Primary organ in ATTR-CM and frequently in AL. Amyloid fibril deposition in the myocardium causes restrictive cardiomyopathy. Cardiac involvement is the single most important prognostic marker in AL amyloidosis (zanwar2023immunoglobulinlightchain pages 1-2, fontana2025thelastdecade pages 1-3).
  • Kidney (UBERON:0002113): Major target organ in AA amyloidosis and frequently in AL. Manifests as nephrotic syndrome and progressive renal failure (mirioglu2024aaamyloidosisa pages 1-2, zanwar2023immunoglobulinlightchain pages 1-2).
  • Peripheral nervous system (UBERON:0000010): Predominantly in ATTRv and AL. Length-dependent sensorimotor polyneuropathy and autonomic neuropathy (poli2023hereditarytransthyretinamyloidosis pages 4-6, chompoopong2024amyloidneuropathyfrom pages 6-6).
  • Liver (UBERON:0002107): Hepatomegaly in AL amyloidosis; primary source of TTR and SAA synthesis (zanwar2023immunoglobulinlightchain pages 2-4).
  • Gastrointestinal tract (UBERON:0001555): Motility disorders, malabsorption (poli2023hereditarytransthyretinamyloidosis pages 4-6).
  • Eye (UBERON:0000970): Vitreous opacities, glaucoma in ATTRv (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Cell Types Involved

  • Cardiomyocytes (CL:0000746): Direct fibril toxicity causes sarcomere disruption and electromechanical uncoupling
  • Plasma cells (CL:0000786): Clonal source of amyloidogenic light chains in AL
  • Hepatocytes (CL:0000182): Primary site of TTR and SAA synthesis
  • Schwann cells (CL:0002573): Atrophy in proximity to amyloid fibrils in nerves
  • Macrophages (CL:0000235): Inflammatory response to amyloid deposits

7. Epidemiology and Population

Prevalence and Incidence

  • AL amyloidosis: Incidence approximately 1 per 100,000 person-years (3,500–4,500 new cases annually in the US), also reported as ~10 per million/year (zanwar2023immunoglobulinlightchain pages 1-2, zerdan2023systemicalamyloidosis pages 1-2).
  • ATTR amyloidosis: Prevalence varies dramatically by geography: 6.1 per million in the US to 232 per million in Portugal (delgado2025epidemiologyoftransthyretin pages 1-2). In endemic sub-regions, prevalence reaches up to 1,631 per million (poli2023hereditarytransthyretinamyloidosis pages 2-3). ATTRwt estimated to affect ~500,000 individuals worldwide (ishida2026crispr–cas3basededitingfor pages 1-2). In the US, 2018 incidence was 3.9 per million person-years overall, rising to 36.6 PMPY in elderly individuals (delgado2025epidemiologyoftransthyretin pages 4-6).
  • AA amyloidosis: Incidence 1–2 cases per million person-years in developed countries; now represents only ~2.9% of all amyloidosis cases (mirioglu2024aaamyloidosisa pages 1-2).

Population Demographics

  • ATTRwt predominantly affects older males (>70–80 years) (fontana2025thelastdecade pages 1-3, delgado2025epidemiologyoftransthyretin pages 2-4).
  • ATTRv Val122Ile: 4.3% prevalence in UK Biobank participants with African ancestry; represents the fourth most common cause of heart failure (11%) in Afro-Caribbeans (aung2024prevalencecardiacphenotype pages 11-15).
  • Study populations are predominantly male (56–94%), with mean ages ranging from 52.3 to 83 years (delgado2025epidemiologyoftransthyretin pages 2-4).
  • Endemic ATTRv clusters exist in Portugal, Sweden, Brazil, and Japan (poli2023hereditarytransthyretinamyloidosis pages 2-3).

Mortality

  • Two-year mortality risk: 10–30% for wild-type ATTR-CM; 10–50% for variant ATTR-CM (delgado2025epidemiologyoftransthyretin pages 1-2).
  • Median survival times across ATTR studies: 12–80 months (delgado2025epidemiologyoftransthyretin pages 4-6).
  • AL amyloidosis: Median OS 48.8 months in the European EMN23 study; early mortality 13.4%; stage IIIb patients had median OS of only 4.5–5.0 months (zanwar2023immunoglobulinlightchain pages 6-7).
  • Untreated advanced cardiac AL: median survival 6 months (fontana2025thelastdecade pages 1-3).

8. Diagnostics

Histopathological Diagnosis

Congo red staining with characteristic apple-green birefringence under polarized light microscopy is the primary diagnostic method. Alternative stains include thioflavin T and sulfated alcian blue (zerdan2023systemicalamyloidosis pages 1-2, zanwar2023immunoglobulinlightchain pages 2-4, mirioglu2024aaamyloidosisa pages 4-6). Electron microscopy reveals rigid, unbranched fibrils of 8–12 nm diameter (mirioglu2024aaamyloidosisa pages 4-6).

Tissue Sources and Sensitivity

Bone marrow biopsy (56–70% sensitivity) and fat pad aspiration (70–80% sensitivity) performed concurrently achieve 80–90% sensitivity for AL amyloidosis diagnosis (zanwar2023immunoglobulinlightchain pages 2-4). Salivary gland biopsy and periumbilical fat aspiration with Congo red staining show 77–89% sensitivity for AA amyloidosis (mirioglu2024aaamyloidosisa pages 4-6).

Amyloid Typing

Mass spectrometry-based proteomic assay (laser microdissection/mass spectrometry) is the gold standard for amyloid typing, offering high sensitivity and specificity (zanwar2023immunoglobulinlightchain pages 2-4).

Cardiac Imaging

  • Bone scintigraphy: Technetium-99m pyrophosphate (99mTc-PYP) SPECT demonstrates excellent sensitivity (85–97%) and specificity (97–100%) for diagnosing TTR cardiac amyloidosis non-invasively (zanwar2023immunoglobulinlightchain pages 2-4, fontana2025thelastdecade pages 4-6).
  • Cardiac MRI: Provides tissue characterization with late gadolinium enhancement, native T1 mapping, and extracellular volume (ECV) measurement serving as a surrogate for interstitial amyloid burden (fontana2025thelastdecade pages 4-6).
  • Echocardiography: Cornerstone first-line imaging showing concentric hypertrophy, restrictive filling, and apical sparing of longitudinal strain (chompoopong2024amyloidneuropathyfrom pages 7-7).

Staging Systems

The Mayo/Boston staging system for AL amyloidosis uses cardiac biomarkers: troponin I (>0.1 ng/mL) and BNP (>81 pg/mL), with further substratification of stage III based on BNP >700 pg/mL (stage IIIb) (dima2023diagnosticandtreatment pages 2-3, chompoopong2024amyloidneuropathyfrom pages 8-9).

Genetic Testing

TTR gene sequencing (single-gene or multigene panel) identifies missense, nonsense, and splice-site variants. Testing is recommended for all patients with suspected ATTR amyloidosis and for family members of known carriers (chompoopong2024amyloidneuropathyfrom pages 6-6).

9. Treatment

AL Amyloidosis Treatment

First-line therapy: Daratumumab (anti-CD38 monoclonal antibody) combined with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) is now standard based on the landmark ANDROMEDA trial. In Asian patients, overall hematologic complete response rate was 58.6% vs. 9.7% with VCd alone (chompoopong2024amyloidneuropathyfrom pages 11-11). Daratumumab achieved clinical remission in 59% of patients, with cardiac improvement in 57% and renal improvement in 57% (chompoopong2024amyloidneuropathyfrom pages 11-11). Real-world UK data with daratumumab-bortezomib-thalidomide-dexamethasone showed 97% overall hematologic response rate and 65% complete response.

Autologous stem cell transplantation (ASCT): Effective strategy after high-dose melphalan, improving survival to 48 months in up to 77% of eligible patients, though only ~20% meet eligibility criteria due to frailty, old age, or multiorgan involvement (chompoopong2024amyloidneuropathyfrom pages 10-11).

Emerging therapies in clinical trials: - Teclistamab (bispecific antibody): Phase 2 trials for relapsed/refractory AL (NCT06649695, NCT06935162, NCT07079423) - Elranatamab: Phase 1/2 trial (NCT06569147) - CAR-T cell therapy targeting CD19 and BCMA: Phase 1b/2 (NCT07081646) - Belantamab mafodotin: Phase 1/2 (NCT05145816) - Dara-VCd plus ASCT vs. Dara-VCd alone: Phase 3 (NCT06022939)

Suggested MAXO terms: MAXO:0001001 (Chemotherapy); MAXO:0000068 (Transplantation)

ATTR Amyloidosis Treatment

TTR Stabilizers: - Tafamidis: First FDA-approved disease-modifying therapy for ATTR-CM; demonstrated significant reductions in all-cause mortality and cardiovascular hospitalizations in the ATTR-ACT trial (anan2025advancesinthe pages 4-5). - Acoramidis: FDA-approved TTR stabilizer for ATTR-CM; outperformed placebo in clinical trials (ang2025emergingnovelgenemodulating pages 10-10, dave2024rnainterferencetherapeutics pages 4-5).

Gene Silencers (RNA-based therapies): - Patisiran (siRNA): Licensed for ATTR polyneuropathy; early data suggest cardiac benefit (ioannou2023rnatargetingand pages 1-2). - Vutrisiran (siRNA): Licensed for ATTR polyneuropathy (ioannou2023rnatargetingand pages 1-2). - Inotersen (ASO): Significant improvements in neurological function (mNIS+7 difference −19.7, P<0.001) and quality of life; sustained benefits over 5.2 years (dave2024rnainterferencetherapeutics pages 4-5, chompoopong2024amyloidneuropathyfrom pages 11-11). - Eplontersen (ASO): Well-tolerated with significant TTR reduction; improved LVEF by 4.3% in cardiomyopathy subgroup (dave2024rnainterferencetherapeutics pages 4-5).

Gene Editing: - NTLA-2001 (CRISPR-Cas9): In Phase 3 clinical trials; has demonstrated durable reductions in serum TTR, with up to 90% sustained plasma TTR reduction over 24 months (ishida2026crispr–cas3basededitingfor pages 1-2). - ART001 (CRISPR-Cas9): A single injection achieved >80% TTR knock-down at doses >0.5 mg/kg, lasting at least 72 weeks without serious adverse events. - CRISPR-Cas3: A mechanistically distinct approach generating long-range deletions; achieved 48.7% hepatic editing and 80.1% serum TTR reduction in mice (ishida2026crispr–cas3basededitingfor pages 1-2).

Emerging approaches: - AUTOTAC-mediated targeted degradation of TTR aggregates (ATC201): Novel bifunctional degrader that reduces intracellular TTR aggregates and improves neuromuscular function in hATTR mouse models (kim2026autotacmediatedtargeteddegradation pages 4-8). - Anti-amyloid monoclonal antibodies (PRX004, NI006): In Phase 1 trials, designed to clear existing amyloid deposits (anan2025advancesinthe pages 4-5, dave2024rnainterferencetherapeutics pages 7-8).

AA Amyloidosis Treatment

Management primarily aims to reduce SAA levels by controlling underlying inflammation. Anti-inflammatory biologics including tocilizumab (IL-6 inhibitor) and anakinra (IL-1 receptor antagonist) have dramatically expanded the therapeutic armamentarium (mirioglu2024aaamyloidosisa pages 1-2). Long-term tocilizumab treatment has been associated with disappearance of amyloid deposits from tissues. Kidney transplantation is preferred in patients with kidney failure, with recurrence in allografts becoming rare due to new anti-inflammatory agents (mirioglu2024aaamyloidosisa pages 1-2).

10. Prognosis and Outcomes

Prognostic Factors

  • Cardiac involvement is the single most important prognostic marker in AL amyloidosis (zanwar2023immunoglobulinlightchain pages 1-2).
  • Cardiac biomarkers (NT-proBNP, troponin) drive staging systems (dima2023diagnosticandtreatment pages 2-3, chompoopong2024amyloidneuropathyfrom pages 8-9).
  • Cytogenetic abnormalities: t(11;14) associated with poor bortezomib response; 1q21 gain associated with shorter OS (zanwar2023immunoglobulinlightchain pages 6-7).
  • Hematologic response: Complete response (negative immunofixation, normal FLC ratio) achieved in 65–80% with first-line therapy is associated with superior outcomes (zanwar2023immunoglobulinlightchain pages 6-7).
  • Age >65–70, poor performance status (ECOG >2), and autonomic involvement are adverse prognostic factors (zanwar2023immunoglobulinlightchain pages 6-7).

Survival

  • AL amyloidosis median OS: 48.8 months overall; stage IIIb median OS only 4.5–5.0 months with no improvement despite newer therapies (zanwar2023immunoglobulinlightchain pages 6-7).
  • Early mortality in AL: 13.4% and did not improve over time; remained >39% for stage IIIb patients.
  • ATTR-CM: 2-year mortality 10–30% (wild-type) and 10–50% (variant) (delgado2025epidemiologyoftransthyretin pages 1-2).
  • TTR LP/P variant carriers: HR 2.68 for heart failure; HR 1.98 for all-cause mortality with non-Val142Ile variants (aung2024prevalencecardiacphenotype pages 11-15).

11. Prevention

Primary Prevention

For AA amyloidosis, primary prevention involves effective control of underlying inflammatory conditions using biological therapies to suppress SAA production (mirioglu2024aaamyloidosisa pages 1-2).

Secondary Prevention / Screening

  • Cascade genetic screening of family members of ATTRv patients is recommended, given autosomal dominant inheritance and availability of effective therapies (chompoopong2024amyloidneuropathyfrom pages 6-6, poli2023hereditarytransthyretinamyloidosis pages 1-2).
  • Screening for ATTR-CM in patients with HFpEF and left ventricular wall thickness ≥12 mm using 99mTc-PYP scintigraphy has been evaluated but faces cost-effectiveness challenges primarily due to high treatment costs (zanwar2023immunoglobulinlightchain pages 2-4).
  • Carpal tunnel syndrome tissue screening for amyloid has been proposed as an early detection strategy.

Genetic Counseling

Genetic counseling is essential for ATTRv families, addressing risk assessment, reproductive planning, and presymptomatic testing. The hATTR Compass Genetic Testing Program identified pathogenic TTR variants in 6.6% of 22,886 referred patients, with only 32% reporting known family history (bhatt2024hereditarytransthyretinamyloidosis pages 1-2).

12. Animal Models

Transgenic Mouse Models

  • HM30 transgenic mice: Mouse TTR knocked out with ectopic overexpression of human TTR V30M; used for studying hereditary ATTR amyloidosis pathogenesis and therapeutic interventions (kim2026autotacmediatedtargeteddegradation pages 4-8).
  • TTR exon-humanized mice: Used for evaluating CRISPR-Cas3 gene editing approaches; a single LNP-based treatment achieved 48.7% hepatic editing and 80.1% serum TTR reduction (ishida2026crispr–cas3basededitingfor pages 1-2).
  • Mouse models carrying human TTR transgenes: Used for evaluation of highly modified sgRNA for CRISPR-based TTR knockdown.

In Vitro Models

  • Human iPSC-derived cardiomyocytes, endothelial cells, and fibroblasts seeded on TTR fibrils (WT, V122I, V30M) provide cell-type-specific disease phenotypes including sarcomere disruption, altered calcium handling, and reduced cell viability.
  • Choroid plexus organoids model amyloid uptake at the blood-CSF barrier.

13. Disease-Target Associations (OpenTargets)

OpenTargets analysis identified 12 primary targets associated with amyloidosis (MONDO:0019065), with the highest association scores for: 1. TTR (transthyretin) — score 0.90; approved therapies targeting this gene 2. APP (amyloid beta precursor protein) — score 0.87 3. GSN (gelsolin) — score 0.85 4. ITM2B (integral membrane protein 2B) — score 0.84 5. FGA (fibrinogen alpha chain) — score 0.79 6. APOA1 (apolipoprotein A1) — score 0.78 7. CST3 (cystatin C) — score 0.73 8. LYZ (lysozyme) — score 0.72 9. B2M (beta-2-microglobulin) — score 0.67 10. APOE (apolipoprotein E) — score 0.62

For AL amyloidosis specifically, additional associated targets include CCND1 (cyclin D1), CALCA, INS, NPPA, and SAA1 (OpenTargets Search: amyloidosis).

14. Summary and Future Directions

Amyloidosis has undergone a dramatic transformation in the past decade, from an underdiagnosed and universally fatal condition to one with expanding diagnostic and therapeutic options. Key advances include non-invasive cardiac scintigraphy for ATTR diagnosis, daratumumab-based regimens revolutionizing AL amyloidosis treatment, and RNA-based gene silencing and CRISPR gene editing therapies fundamentally altering the ATTR treatment landscape (ioannou2023rnatargetingand pages 1-2, ishida2026crispr–cas3basededitingfor pages 1-2). Despite these advances, critical unmet needs remain: early mortality in advanced cardiac AL amyloidosis has not improved (zanwar2023immunoglobulinlightchain pages 6-7), comprehensive epidemiological data from Africa and South America are lacking (delgado2025epidemiologyoftransthyretin pages 8-8), and therapies capable of clearing pre-existing amyloid deposits are still investigational (kim2026autotacmediatedtargeteddegradation pages 4-8). Novel approaches including AUTOTAC-mediated targeted protein degradation, anti-amyloid monoclonal antibodies, bispecific antibodies, and CAR-T cell therapy represent the next frontier in amyloidosis management.

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