Amyloidosis

Complex MONDO:0019065 Pathograph 24 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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1
Inheritance
5
Pathophys.
8
Phenotypes
2
Gaps
24
Pathograph
2
Genes
9
Medical Actions
5
Subtypes
2
Differentials
4
Datasets
4
Trials
1
Models
8
References
1
Deep Research
🏷

Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY CARDIOVASCULAR KIDNEY URINARY TRACT NEUROLOGIC
Mechanistic Nosology
proteotoxic disease
👪

Inheritance

1
Autosomal dominant inheritance of ATTRv amyloidosis HP:0000006
Pathogenic TTR variants cause hereditary ATTR amyloidosis with autosomal dominant transmission and variable penetrance and age at onset.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:25604431 SUPPORT Other
"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"
The review explicitly identifies the inherited ATTRv mechanism and autosomal dominant transmission.
◆

Subtypes

5
AL (Immunoglobulin Light Chain) Amyloidosis MONDO:0019438
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 Other
"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 MONDO:0018018
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 Other
"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 MONDO:0019439
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 Other
"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
Amyloid deposition confined to one anatomic site rather than distributed systemically. Localized amyloid is etiologically heterogeneous, so this umbrella entry does not assume that every localized deposit is light-chain derived or produced by a local plasma-cell clone.
Show evidence (1 reference)
PMID:33100054 SUPPORT Other
"It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins."
The ISA nomenclature update establishes that localized amyloid forms exist and gives AEFEMP1 portal-vein amyloid as one example; it does not imply a single precursor or clonal mechanism for all localized amyloidoses.
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Discussions and Knowledge Gaps

2
How should precursor-specific epidemiology, organ tropism, and treatment effects be compared without treating amyloidosis as one homogeneous disease?
KNOWLEDGE GAP OPEN amyloidosis_precursor_specificity_and_umbrella_scope
Attached to
pathophysiology#Amyloid Fibril Formation and Extracellular Deposition
Amyloid fibril formation is shared, but AL, ATTRv, ATTRwt, AA, hereditary non-TTR, and localized forms differ in precursor supply, affected populations, organ distribution, prognosis, and therapy. This umbrella record therefore retains subtype qualifiers and defers subtype-level detail to dedicated entries.
Show evidence (1 reference)
PMID:33100054 SUPPORT Other
"Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid..."
The ISA update demonstrates precursor and localization heterogeneity and continuing candidate discovery, supporting the need to avoid a homogeneous umbrella interpretation.
Which model systems reproduce human peripheral and autonomic nerve deposition closely enough to test neuropathy-directed clearance and repair strategies?
HUMAN MODEL MISMATCH OPEN attr_mouse_neuropathy_model_mismatch
Attached to
pathophysiology#Amyloid Fibril Formation and Extracellular Deposition
The classic human TTR Met30 transgenic mouse develops systemic deposits but lacks deposition in the peripheral and autonomic nervous systems, so it cannot alone establish treatment effects on the defining human neuropathy.
Show evidence (1 reference)
PMID:8086125 SUPPORT Model Organism
"The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues."
The model directly demonstrates the human-model mismatch.
⚙

Pathophysiology

5
Clonal Immunoglobulin Light-Chain Precursor Excess
In AL amyloidosis, a clonal CD38-positive plasma-cell population produces an amyloidogenic immunoglobulin light chain. This is an acquired clonal precursor-supply mechanism and is not the mechanism of ATTR or AA disease.
plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
Downstream
Protein Misfolding and Beta-Sheet Oligomerization Amyloidogenic light chains misfold and self-associate into aggregation-prone species.
Show evidence (1 reference)
PMID:34192431 SUPPORT Other
"Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells."
ANDROMEDA directly identifies the clonal plasma-cell source and light-chain precursor.
TTR Tetramer Destabilization and Monomer Release
In ATTRv, pathogenic TTR variants destabilize the circulating tetramer; in ATTRwt, age-associated destabilization occurs without a pathogenic coding variant. Tetramer dissociation releases monomers that can misfold.
TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee.
protein folding GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Protein Misfolding and Beta-Sheet Oligomerization Dissociated TTR monomers enter the misfolding and aggregation pathway.
Show evidence (1 reference)
PMID:25604431 SUPPORT Other
"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"
The review directly supports the variant-TTR tetramer-dissociation sequence; the description separately bounds this evidence to ATTRv.
Sustained Serum Amyloid A Precursor Production
In AA amyloidosis, persistent inflammation maintains the hepatic acute-phase response and chronically elevates serum amyloid A, supplying the precursor from which AA fibrils are formed.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
SAA1 hgnc:10513 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SAA1 (hgnc:10513). hgnc:10513 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Protein Misfolding and Beta-Sheet Oligomerization Sustained SAA supply permits cleavage, misfolding, and aggregation into AA amyloid.
Show evidence (1 reference)
PMID:18514052 SUPPORT Other
"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."
The review directly identifies persistent acute-phase SAA production as the AA precursor mechanism.
Protein Misfolding and Beta-Sheet Oligomerization
Disease-specific precursors leave their native conformations and self-associate into beta-sheet-rich oligomeric and prefibrillar species. Soluble species can be proteotoxic, but the magnitude and organ specificity of that toxicity vary by precursor and are not assumed to be uniform.
protein folding GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Amyloid Fibril Formation and Extracellular Deposition Beta-sheet-rich oligomers nucleate and elongate into insoluble extracellular amyloid fibrils.
Show evidence (2 references)
PMID:25604431 SUPPORT Other
"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."
The trial report's background supports the AL misfolding paradigm but is not primary mechanistic evidence for every oligomerization step.
Amyloid Fibril Formation and Extracellular Deposition
Misfolded precursors polymerize into cross-beta-sheet amyloid fibrils that accumulate extracellularly in precursor-specific target tissues. Progressive deposits disrupt tissue architecture; precursor-specific soluble species may add direct cellular toxicity. The downstream organ effects are therefore modeled separately and retain subtype-specific evidence.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
amyloid fibril formation GO:1990000 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased amyloid fibril formation (GO:1990000). GO:1990000 is a biological process from the Gene Ontology. ↑ 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.
Carpal Tunnel Syndrome Tenosynovial amyloid deposition can produce median-nerve compression and carpal tunnel syndrome in hereditary ATTR amyloidosis.
Proteinuria Glomerular amyloid deposition disrupts filtration and produces nephrotic-range proteinuria in AA amyloidosis.
Show evidence (3 references)
PMID:40649158 SUPPORT Other
"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.
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Phenotypes

8
Cardiovascular 1
Cardiomyopathy Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723), qualified as course progressive. HP:0001723 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:34518987 SUPPORT Other
"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 Other
"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.
Genitourinary 2
Nephrotic Syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18514052 SUPPORT Other
"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.
Proteinuria VERY_FREQUENT HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
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 HP:0000158 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macroglossia (HP:0000158). HP:0000158 is a phenotype from the Human Phenotype Ontology.
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 HP:0011034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amyloid deposition (HP:0011034). HP:0011034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33787019 SUPPORT Other
"Confirmation in the tissue by biopsy and Congo red staining with the characteristic green birefringence under polarized light is recommended."
The diagnostic guideline identifies tissue Congo-red positivity with characteristic birefringence as confirmatory evidence of amyloid deposition.
Nervous System 3
Peripheral Neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830), qualified as course progressive. HP:0009830 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22094129 SUPPORT Other
"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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autonomic dysfunction, annotated with Abnormal autonomic nervous system physiology (HP:0012332), qualified as course progressive. HP:0012332 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22094129 SUPPORT Other
"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.
Carpal Tunnel Syndrome FREQUENT Constrictive median neuropathy HP:0012185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal tunnel syndrome, annotated with Constrictive median neuropathy (HP:0012185). HP:0012185 is a phenotype from the Human Phenotype Ontology.
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 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:22094129 SUPPORT Other
"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 Other
"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 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SAA1 (hgnc:10513). hgnc:10513 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
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

9
Tafamidis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tafamidis CHEBI:78538 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tafamidis (CHEBI:78538). CHEBI:78538 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral transthyretin tetramer stabilizer that binds the thyroxine-binding sites of TTR and prevents dissociation into amyloidogenic monomers. The pivotal ATTR-ACT trial established benefit in ATTR cardiomyopathy; regulatory indications for polyneuropathy vary by jurisdiction.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — Kinetic tetramer stabilization reduces release of aggregation-prone TTR monomers.
Show evidence (1 reference)
PMID:25604431 SUPPORT Other
"the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials"
The review identifies tafamidis as a TTR tetramer stabilizer; the upstream node defines why stabilization inhibits monomer release.
Show evidence (1 reference)
PMID:30145929 SUPPORT Human Clinical
"In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo."
ATTR-ACT directly demonstrates clinical benefit in ATTR cardiomyopathy without extending the claim to other amyloid types.
Patisiran
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: patisiran NCIT:C116792 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses patisiran (NCIT:C116792). NCIT:C116792 is a therapeutic agent from the NCI Thesaurus.
Platform: siRNA RNAi knockdown Delivery: Lipid nanoparticle Targeting: Unconjugated
RNA target: TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee. TTR mRNA
Dosing: once every 3 weeks every 21 days
Lipid-nanoparticle-formulated small interfering RNA that silences hepatic TTR mRNA, lowering circulating transthyretin and slowing hereditary ATTR polyneuropathy progression.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — Hepatic TTR mRNA silencing lowers the circulating precursor pool upstream of tetramer dissociation.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"Binding triggers activation of the Argonaute slicer protein, which degrades the mRNA, thereby inhibiting TTR synthesis"
The review directly describes patisiran-mediated TTR mRNA degradation and synthesis inhibition in hepatocytes.
Show evidence (1 reference)
PMID:29972753 SUPPORT Human Clinical
"In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis."
The randomized APOLLO trial directly supports benefit in hereditary ATTR amyloidosis with polyneuropathy.
Acoramidis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acoramidis NCIT:C170791 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses acoramidis (NCIT:C170791). NCIT:C170791 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Oral high-affinity transthyretin tetramer stabilizer, FDA-approved disease-modifying therapy for ATTR cardiomyopathy; binds TTR and prevents dissociation into amyloidogenic monomers.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — High-affinity tetramer stabilization reduces monomer dissociation.
Show evidence (1 reference)
PMID:38197816 SUPPORT Human Clinical
"(also called AG10) is a novel TTR stabilizer that is designed to mimic the action of the T119M variant."
In context, the pivotal trial report directly identifies acoramidis (AG10) as a rationally designed TTR stabilizer; the snippet begins after a PDF line-break artifact in the drug name.
Show evidence (1 reference)
PMID:38197816 SUPPORT Human Clinical
"In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo."
ATTRibute-CM directly demonstrates clinical benefit in ATTR cardiomyopathy.
Vutrisiran
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vutrisiran NCIT:C152919 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses vutrisiran (NCIT:C152919). NCIT:C152919 is a therapeutic agent from the NCI Thesaurus.
Platform: siRNA RNAi knockdown Delivery: Ligand conjugate Targeting: GalNAc
RNA target: TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee. TTR mRNA
Dosing: once every 3 months every 90 days
Subcutaneous GalNAc-conjugated small interfering RNA that silences hepatic TTR mRNA. It lowers variant and wild-type TTR and has randomized phase III outcome evidence in ATTR cardiomyopathy as well as an indication for hereditary ATTR polyneuropathy.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — Hepatocyte-directed RNA interference lowers the circulating TTR precursor pool.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"Vutrisiran achieved a dose-dependent TTR knockdown; a single 25 mg subcutaneous dose resulted in a maximum TTR reduction of 80%, which was sustained for 90 days"
The review reports sustained, dose-dependent TTR lowering after vutrisiran.
Show evidence (1 reference)
PMID:39213194 SUPPORT Human Clinical
"Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life."
HELIOS-B directly demonstrates benefit in the ATTR-CM trial population.
NTLA-2001 in vivo TTR gene editing
Category: Therapeutic Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Agent: NTLA-2001 NCIT:C204942 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses NTLA-2001, annotated with Lipid Nanoparticle Encapsulating mRNA Encoding Cas9 Protein and TTR-targeting Single Guide RNA NTLA-2001 (NCIT:C204942). NCIT:C204942 is a therapeutic agent from the NCI Thesaurus.
Platform: Gene editing
NTLA-2001 (nexiguran ziclumeran) is an investigational, single-infusion lipid-nanoparticle CRISPR-Cas9 therapy designed to disrupt TTR in hepatocytes and durably lower circulating TTR. First-in-human evidence establishes target engagement in a very small cohort, not clinical efficacy.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — In vivo CRISPR-Cas9 knockout of hepatic TTR reduces the circulating precursor available for tetramer formation, misfolding, and deposition.
Show evidence (1 reference)
PMID:34215024 SUPPORT Human Clinical
"NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum."
The first-in-human report directly defines the therapeutic platform and TTR-lowering mechanism.
Show evidence (1 reference)
PMID:34215024 SUPPORT Human Clinical
"In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR."
The six-patient early-phase study demonstrates target engagement but not clinical benefit or long-term safety.
Inotersen
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: inotersen NCIT:C121667 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses inotersen (NCIT:C121667). NCIT:C121667 is a therapeutic agent from the NCI Thesaurus.
Platform: Antisense oligonucleotide RNase H knockdown Delivery: Unformulated (free uptake) Targeting: Unconjugated Chemistry: 2′-MOE
RNA target: TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee. TTR mRNA
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.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — RNase H1-mediated TTR mRNA degradation lowers the circulating precursor pool.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"Inotersen is a 2´-O-methoxyethyl-modified ASO that binds to the 3´ untranslated portion of the complementary mRNA, promoting ribonuclease H1-mediated mRNA degradation."
The review directly describes inotersen's TTR-directed RNase H1 degradation mechanism.
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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: eplontersen NCIT:C175062 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses eplontersen (NCIT:C175062). NCIT:C175062 is a therapeutic agent from the NCI Thesaurus.
Platform: Antisense oligonucleotide RNase H knockdown Delivery: Ligand conjugate Targeting: GalNAc Chemistry: 2′-MOE
RNA target: TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee. TTR mRNA
GalNAc-conjugated, RNase H-dependent antisense oligonucleotide targeting TTR mRNA; an FDA-approved RNA-lowering therapy for hereditary ATTR amyloidosis (polyneuropathy) with cardiomyopathy trials.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization and Monomer Release — GalNAc-directed hepatocyte delivery of the ASO lowers TTR expression upstream of tetramer release.
Show evidence (1 reference)
DOI:10.1007/s40259-023-00577-7 SUPPORT Other
"eplontersen induced a 28-fold more potent TTR knockdown than inotersen"
The review reports potent TTR knockdown by eplontersen in a transgenic model.
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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: daratumumab NCIT:C74007 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses daratumumab (NCIT:C74007). NCIT:C74007 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
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).
Mechanism Target:
INHIBITS Clonal Immunoglobulin Light-Chain Precursor Excess — CD38-directed plasma-cell depletion suppresses production of amyloidogenic light chains.
Show evidence (1 reference)
PMID:34192431 SUPPORT Human Clinical
"Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease."
The trial report identifies both the CD38-positive clonal plasma-cell source and daratumumab's CD38 target; precursor suppression is the resulting therapeutic inference.
Show evidence (1 reference)
PMID:34192431 SUPPORT Human Clinical
"The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%)"
ANDROMEDA directly supports the response advantage of daratumumab-CyBorD in newly diagnosed systemic AL amyloidosis.
Tocilizumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tocilizumab NCIT:C84217 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tocilizumab (NCIT:C84217). NCIT:C84217 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
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.
Mechanism Target:
INHIBITS Sustained Serum Amyloid A Precursor Production — IL-6 receptor blockade suppresses the inflammatory acute-phase drive and lowers SAA precursor concentrations.
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"
The AA review directly reports reduction of the SAA precursor with tocilizumab.
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.
🔬

Diagnosis

5
Tissue Confirmation With Congo Red
When tissue confirmation is required, biopsy demonstrates amyloid by Congo red staining with characteristic green birefringence under polarized light. A positive stain establishes amyloid deposition but does not identify the precursor protein.
Histopathologic examination NCIT:C18190 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33787019 SUPPORT Other
"Confirmation in the tissue by biopsy and Congo red staining with the characteristic green birefringence under polarized light is recommended."
The guideline directly supports tissue confirmation and the defining optical finding.
Proteomic Amyloid Typing
Amyloid deposits should be biochemically typed because therapies are precursor-specific. Mass-spectrometry proteomics can identify established and uncommon amyloid types in a single assay and avoids inferring AL solely from an incidental monoclonal gammopathy.
Mass spectrometry-based amyloid typing
Show evidence (1 reference)
PMID:32861330 SUPPORT Human Clinical
"Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice."
The 16,175-specimen clinical series supports proteomic typing across amyloid types.
Monoclonal Protein Evaluation
Serum free light chains plus serum and urine immunofixation evaluate a monoclonal plasma-cell process. This screen is essential before accepting a non-biopsy ATTR-CM diagnosis and does not by itself prove that a deposit is AL.
Laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33787019 SUPPORT Other
"Measurement of serum free light chains is recommended for evaluation of a monoclonal plasma cell proliferative disorder."
The guideline supports serum free-light-chain testing for a monoclonal plasma-cell disorder.
Cardiac Radionuclide Scintigraphy
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.
cardiac radionuclide scintigraphy NCIT:C62667 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41171219 SUPPORT Other
"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."
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.
Early Diagnosis of AL Amyloidosis
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.
Show evidence (1 reference)
PMID:42099096 SUPPORT Other
"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."
The British Society for Haematology guideline motivates early cross-specialty AL amyloidosis diagnosis by quantifying the large survival advantage of early-stage detection.
📊

Prevalence

2
United States
Point Prevalence 0.61 per 100,000 1–9 per 1,000,000
ATTR amyloidosis point prevalence 6.1 per million in the US in a systematic review (range up to 232 per million in endemic Portugal).
Show evidence (1 reference)
DOI:10.1186/s13023-025-03547-0 SUPPORT Other
"ATTR prevalence ranged from 6.1/million in the US to 232/million in Portugal with very limited data on ATTR-PN."
Delgado et al. systematic review reports ATTR prevalence of 6.1 per million in the US.
Worldwide
Annual Incidence 1.0 per 100,000 1–9 per 100,000 per year AL
Systemic AL amyloidosis estimated incidence ~10 cases per million persons per year (= 1.0 per 100,000).
Show evidence (1 reference)
DOI:10.18632/oncotarget.28415 SUPPORT Other
"an estimated incidence of 10 cases per million persons a year"
Bou Zerdan et al. state AL amyloidosis has an estimated incidence of 10 cases per million persons a year.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Amyloidosis:

Hypertrophic cardiomyopathy MONDO:0005045
Overlapping Features Sarcomeric hypertrophic cardiomyopathy can resemble cardiac amyloidosis by producing increased ventricular wall thickness and heart failure symptoms.
Distinguishing Features
  • Dynamic outflow-tract obstruction or systolic anterior motion favors sarcomeric hypertrophic cardiomyopathy.
  • Amyloid evaluation integrates monoclonal-protein testing, bone scintigraphy, cardiac imaging, and tissue typing when needed.
Show evidence (1 reference)
PMID:41463072 SUPPORT Other
"numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases."
The review places amyloidosis among the major nonsarcomeric hypertrophic phenocopies that require differentiation from sarcomeric HCM.
Fabry disease MONDO:0010526
Overlapping Features Fabry cardiomyopathy is a metabolic phenocopy that can also present with ventricular wall thickening; correct identification matters because the amyloidosis and Fabry treatment pathways are different.
Distinguishing Features
  • Fabry disease is evaluated with alpha-galactosidase A activity, GLA testing, and characteristic extracardiac findings rather than amyloid typing.
Show evidence (1 reference)
PMID:41463072 SUPPORT Other
"numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases."
The review places amyloidosis and Fabry disease among the major nonsarcomeric hypertrophic phenocopies.
📊

Related Datasets

4
Gene expression and V(D)J profiles of B-lineage cells from bone marrow samples of healthy adults (HA) and patients with multiple myeloma (MM) and light-chain amyloidosis (AL). geo:GSE293872
We employed single-cell RNA sequencing combined with BCR sequencing (scRNA/BCR-seq) to identify transcriptional differences between clonal B cells and non-clonal B cells from MM and AL patients versus their healthy counterparts.
human SINGLE CELL RNA SEQ n=38
PMID:41812162
Identified by GEO DataSets index search for Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Exome Sequencing to Define the Landscape of Plasma Cells in Systemic Light chain Amyloidosis ega:EGAS00001001418
Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, but limited whole exome data are available. We report the findings of an exome sequencing study in AL to define a plasma cell signature and compare this to monoclonal gammopathy of undefined significance (MGUS) and myeloma (MM). Twenty-four samples from unselected newly diagnosed untreated AL patients were analysed. CD138+ cells were isolated from bone marrow cells using MACSorting (Miltenyi Biotech, Bisley, UK).
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D) ega:EGAS00001002730
HCHWA-D is an early onset hereditary form of Cerebral Amyloid Angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the Amyloid Precursor Protein (APP). Post-mortem brain tissue (9 patients and 9 age-related controls; frontal and occipital cortex) was used for next generation sequencing of RNA (RNA-Seq with ribosomal RNA depletion).
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Analysis of exonic somatic variants in light-chain amyloidosis (ALA) and ALA concomitant with multiple myeloma ega:EGAS00001004214
We aim to provide the very first insight into ALA+MM molecular profiles and compare the results with ALA and with MM. Our detailed study of ALA and ALA+MM represents an important step towards improved understanding of their genetic and transcriptomic background, which is a prerequisite for development of optimal treatment strategies in the future.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
🔬

Clinical Trials

4
NCT03201965 PHASE_III COMPLETED
ANDROMEDA compared daratumumab plus cyclophosphamide, bortezomib, and dexamethasone with CyBorD alone in newly diagnosed systemic AL amyloidosis.
Target Phenotypes: Amyloid deposition HP:0011034 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Amyloid deposition (HP:0011034). HP:0011034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03201965 SUPPORT Human Clinical
"The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants."
The registry summary identifies the population, intervention, comparator, and purpose.
NCT01994889 PHASE_III COMPLETED
ATTR-ACT compared two daily tafamidis meglumine doses with placebo in hereditary or wild-type transthyretin amyloid cardiomyopathy.
Target Phenotypes: Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT01994889 SUPPORT Human Clinical
"This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy."
The registry summary directly states the intervention and ATTR-CM population.
NCT04153149 PHASE_III ACTIVE_NOT_RECRUITING
HELIOS-B evaluates quarterly subcutaneous vutrisiran versus placebo in patients with ATTR amyloidosis with cardiomyopathy; the randomized outcomes have been published while registry follow-up remains active.
Target Phenotypes: Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04153149 SUPPORT Human Clinical
"This study will evaluate the efficacy and safety of vutrisiran 25 mg administered subcutaneously (SC) once every 3 months (q3M) compared to placebo in participants with ATTR amyloidosis with cardiomyopathy."
The registry summary directly states the intervention and ATTR-CM population.
NCT04601051 PHASE_I COMPLETED
First-in-human single-dose NTLA-2001 in vivo CRISPR-Cas9 editing evaluated safety and pharmacodynamic TTR lowering in ATTRv polyneuropathy and ATTR cardiomyopathy; early evidence establishes target engagement, not clinical efficacy.
Target Phenotypes: Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology. Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04601051 SUPPORT Human Clinical
"This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001"
The registry summary establishes the early-phase safety and pharmacodynamic scope.
🐁

Animal Models

1
Human mutant TTR Met30 transgene Mus musculus
Transgenic mice expressing human mutant TTR Met30 develop age-progressive systemic amyloid in gastrointestinal, cardiovascular, renal, and other tissues. They reproduce fibril composition and much of the human systemic deposition pattern but fail to deposit amyloid in peripheral and autonomic nervous tissues, limiting their fidelity for the defining human neuropathy.
Species
Mus musculus
Genotype
Human mutant TTR Met30 transgene
Genes
TTR hgnc:12405 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TTR (hgnc:12405). hgnc:12405 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:8086125 SUPPORT Model Organism
"In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys and extended to various other organs and tissues with advancing age."
The study documents age-progressive systemic deposition in the transgenic model.
PMID:8086125 SUPPORT Model Organism
"The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues."
The negative model result establishes a major translational limitation for amyloid neuropathy.
{ }

Source YAML

click to show 
name: Amyloidosis
creation_date: "2026-05-13T10:00:00Z"
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.
notes: >-
  This is an umbrella entry for the shared amyloidogenesis mechanism and the
  major systemic clinical forms. Dedicated entries provide deeper subtype
  curation for systemic AL amyloidosis and hereditary ATTR amyloidosis; this
  record does not project a treatment, frequency, inheritance pattern, or organ
  phenotype from one precursor-defined subtype onto all amyloidoses.
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
references:
- reference: PMID:33100054
  title: "Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee."
- reference: PMID:33787019
  title: "[Clinical Practice Guidelines for diagnosis of amyloidosis: Part 1/3 Year 2020]."
- reference: PMID:32861330
  title: "Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples."
- reference: PMID:34192431
  title: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
- reference: PMID:30145929
  title: Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
- reference: PMID:39213194
  title: Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
- reference: PMID:34215024
  title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
- reference: PMID:8086125
  title: Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I.
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.
  subtype_term:
    preferred_term: AL amyloidosis
    term:
      id: MONDO:0019438
      label: AL amyloidosis
  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: OTHER
    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).
  subtype_term:
    preferred_term: wild type ATTR amyloidosis
    term:
      id: MONDO:0018018
      label: wild type ATTR amyloidosis
  evidence:
  - reference: PMID:26048914
    reference_title: "The transthyretin amyloidoses: advances in therapy."
    supports: SUPPORT
    evidence_source: OTHER
    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.
  subtype_term:
    preferred_term: AA amyloidosis
    term:
      id: MONDO:0019439
      label: AA amyloidosis
  evidence:
  - reference: PMID:18514052
    reference_title: "[Amyloidosis AA]."
    supports: SUPPORT
    evidence_source: OTHER
    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: >-
    Amyloid deposition confined to one anatomic site rather than distributed
    systemically. Localized amyloid is etiologically heterogeneous, so this
    umbrella entry does not assume that every localized deposit is light-chain
    derived or produced by a local plasma-cell clone.
  evidence:
  - reference: PMID:33100054
    reference_title: "Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins."
    explanation: >-
      The ISA nomenclature update establishes that localized amyloid forms exist
      and gives AEFEMP1 portal-vein amyloid as one example; it does not imply a
      single precursor or clonal mechanism for all localized amyloidoses.
inheritance:
- name: Autosomal dominant inheritance of ATTRv amyloidosis
  description: >-
    Pathogenic TTR variants cause hereditary ATTR amyloidosis with autosomal
    dominant transmission and variable penetrance and age at onset.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: OTHER
    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: The review explicitly identifies the inherited ATTRv mechanism and autosomal dominant transmission.
pathophysiology:
- name: Clonal Immunoglobulin Light-Chain Precursor Excess
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  description: >-
    In AL amyloidosis, a clonal CD38-positive plasma-cell population produces
    an amyloidogenic immunoglobulin light chain. This is an acquired clonal
    precursor-supply mechanism and is not the mechanism of ATTR or AA disease.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  downstream:
  - target: Protein Misfolding and Beta-Sheet Oligomerization
    causal_link_type: DIRECT
    description: Amyloidogenic light chains misfold and self-associate into aggregation-prone species.
    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: The trial report's background directly identifies misfolded protein accumulation in AL, but does not independently establish the self-association step.
  evidence:
  - reference: PMID:34192431
    reference_title: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells."
    explanation: ANDROMEDA directly identifies the clonal plasma-cell source and light-chain precursor.
- name: TTR Tetramer Destabilization and Monomer Release
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  gene:
    preferred_term: TTR
    term:
      id: hgnc:12405
      label: TTR
  description: >-
    In ATTRv, pathogenic TTR variants destabilize the circulating tetramer; in
    ATTRwt, age-associated destabilization occurs without a pathogenic coding
    variant. Tetramer dissociation releases monomers that can misfold.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  downstream:
  - target: Protein Misfolding and Beta-Sheet Oligomerization
    causal_link_type: DIRECT
    description: Dissociated TTR monomers enter the misfolding and aggregation pathway.
    evidence:
    - reference: PMID:25604431
      reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
      supports: SUPPORT
      evidence_source: OTHER
      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: The review directly states the causal sequence from tetramer destabilization through monomer misfolding and aggregation.
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: OTHER
    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: The review directly supports the variant-TTR tetramer-dissociation sequence; the description separately bounds this evidence to ATTRv.
- name: Sustained Serum Amyloid A Precursor Production
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  gene:
    preferred_term: SAA1
    term:
      id: hgnc:10513
      label: SAA1
  description: >-
    In AA amyloidosis, persistent inflammation maintains the hepatic acute-phase
    response and chronically elevates serum amyloid A, supplying the precursor
    from which AA fibrils are formed.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Protein Misfolding and Beta-Sheet Oligomerization
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - serum amyloid A cleavage and conformational conversion
    description: Sustained SAA supply permits cleavage, misfolding, and aggregation into AA amyloid.
    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: The review directly supports the stated SAA cleavage, misfolding, and aggregation intermediates.
  evidence:
  - reference: PMID:18514052
    reference_title: "[Amyloidosis AA]."
    supports: SUPPORT
    evidence_source: OTHER
    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: The review directly identifies persistent acute-phase SAA production as the AA precursor mechanism.
- name: Protein Misfolding and Beta-Sheet Oligomerization
  biological_scale: MOLECULAR
  role: amplifier
  conforms_to: "amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization"
  description: >-
    Disease-specific precursors leave their native conformations and
    self-associate into beta-sheet-rich oligomeric and prefibrillar species.
    Soluble species can be proteotoxic, but the magnitude and organ specificity
    of that toxicity vary by precursor and are not assumed to be uniform.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  downstream:
  - target: Amyloid Fibril Formation and Extracellular Deposition
    causal_link_type: DIRECT
    description: Beta-sheet-rich oligomers nucleate and elongate into insoluble extracellular amyloid fibrils.
    evidence:
    - reference: PMID:25604431
      reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
      supports: SUPPORT
      evidence_source: OTHER
      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: The review directly supports progression from misfolding and aggregation to fibrils in ATTR; the generic oligomer-nucleation wording is a cross-precursor abstraction.
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: OTHER
    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: The trial report's background supports the AL misfolding paradigm but is not primary mechanistic evidence for every oligomerization step.
- name: Amyloid Fibril Formation and Extracellular Deposition
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"
  description: >-
    Misfolded precursors polymerize into cross-beta-sheet amyloid fibrils that
    accumulate extracellularly in precursor-specific target tissues. Progressive
    deposits disrupt tissue architecture; precursor-specific soluble species
    may add direct cellular toxicity. The downstream organ effects are therefore
    modeled separately and retain subtype-specific evidence.
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  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
  evidence:
  - reference: PMID:40649158
    reference_title: "Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options."
    supports: SUPPORT
    evidence_source: OTHER
    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: OTHER
      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: OTHER
      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: OTHER
      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: OTHER
      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: OTHER
      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.
  - target: Carpal Tunnel Syndrome
    causal_link_type: DIRECT
    description: >-
      Tenosynovial amyloid deposition can produce median-nerve compression and
      carpal tunnel syndrome in hereditary ATTR amyloidosis.
    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: "Sperry et al. found amyloid deposits on tenosynovial tissue biopsy in 10 out of 98 patients (median age 68 years) undergoing carpal tunnel surgery for idiopathic carpal tunnel syndrome, and two of them were diagnosed with ATTRv"
      explanation: >-
        The tissue-biopsy evidence connects tenosynovial amyloid with carpal
        tunnel syndrome, while the ATTRv diagnoses preserve the subtype scope.
  - target: Proteinuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glomerular amyloid deposition
    description: >-
      Glomerular amyloid deposition disrupts filtration and produces
      nephrotic-range proteinuria in AA amyloidosis.
    evidence:
    - reference: "PMID:38568326"
      reference_title: "AA Amyloidosis: A Contemporary View."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Typically, the involvement of glomeruli precipitates nephrotic-range proteinuria and an accelerated decline in estimated glomerular filtration rate (eGFR)"
      explanation: >-
        The review explicitly links glomerular involvement to nephrotic-range
        proteinuria and declining filtration in AA amyloidosis.
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
  evidence:
  - reference: PMID:33787019
    reference_title: "[Clinical Practice Guidelines for diagnosis of amyloidosis: Part 1/3 Year 2020]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Confirmation in the tissue by biopsy and Congo red staining with the characteristic green birefringence under polarized light is recommended."
    explanation: >-
      The diagnostic guideline identifies tissue Congo-red positivity with
      characteristic birefringence as confirmatory evidence of 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: OTHER
    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: OTHER
    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: OTHER
    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: OTHER
    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
  subtype: AL
  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: OTHER
    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
    ATTRv 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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  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: OTHER
    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: OTHER
    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
  relationship_type: SUSCEPTIBILITY
  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
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Oral transthyretin tetramer stabilizer that binds the thyroxine-binding
    sites of TTR and prevents dissociation into amyloidogenic monomers. The
    pivotal ATTR-ACT trial established benefit in ATTR cardiomyopathy; regulatory
    indications for polyneuropathy vary by jurisdiction.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tafamidis
      term:
        id: CHEBI:78538
        label: tafamidis
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: Kinetic tetramer stabilization reduces release of aggregation-prone TTR monomers.
    evidence:
    - reference: PMID:25604431
      reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials"
      explanation: The review identifies tafamidis as a TTR tetramer stabilizer; the upstream node defines why stabilization inhibits monomer release.
  evidence:
  - reference: PMID:30145929
    reference_title: Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo."
    explanation: ATTR-ACT directly demonstrates clinical benefit in ATTR cardiomyopathy without extending the claim to other amyloid types.
- name: Patisiran
  therapeutic_modality: SIRNA
  oligonucleotide_details:
    oligonucleotide_mechanism: RNAI_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    conjugation: UNCONJUGATED
    delivery_platform: LIPID_NANOPARTICLE
  dosing_interval: once every 3 weeks
  dosing_interval_days: 21
  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
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: Hepatic TTR mRNA silencing lowers the circulating precursor pool upstream of tetramer dissociation.
    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: "Binding triggers activation of the Argonaute slicer protein, which degrades the mRNA, thereby inhibiting TTR synthesis"
      explanation: The review directly describes patisiran-mediated TTR mRNA degradation and synthesis inhibition in hepatocytes.
  evidence:
  - reference: PMID:29972753
    reference_title: Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis."
    explanation: The randomized APOLLO trial directly supports benefit in hereditary ATTR amyloidosis with polyneuropathy.
- 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
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: High-affinity tetramer stabilization reduces monomer dissociation.
    evidence:
    - reference: PMID:38197816
      reference_title: Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "(also called AG10) is a novel TTR stabilizer that is designed to mimic the action of the T119M variant."
      explanation: In context, the pivotal trial report directly identifies acoramidis (AG10) as a rationally designed TTR stabilizer; the snippet begins after a PDF line-break artifact in the drug name.
  evidence:
  - reference: PMID:38197816
    reference_title: Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo."
    explanation: ATTRibute-CM directly demonstrates clinical benefit in ATTR cardiomyopathy.
- name: Vutrisiran
  therapeutic_modality: SIRNA
  oligonucleotide_details:
    oligonucleotide_mechanism: RNAI_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    conjugation: GALNAC
    delivery_platform: CONJUGATE
  dosing_interval: once every 3 months
  dosing_interval_days: 90
  description: >-
    Subcutaneous GalNAc-conjugated small interfering RNA that silences hepatic
    TTR mRNA. It lowers variant and wild-type TTR and has randomized phase III
    outcome evidence in ATTR cardiomyopathy as well as an indication for
    hereditary ATTR polyneuropathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vutrisiran
      term:
        id: NCIT:C152919
        label: Vutrisiran
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: Hepatocyte-directed RNA interference lowers the circulating TTR precursor pool.
    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 achieved a dose-dependent TTR knockdown; a single 25 mg subcutaneous dose resulted in a maximum TTR reduction of 80%, which was sustained for 90 days"
      explanation: The review reports sustained, dose-dependent TTR lowering after vutrisiran.
  evidence:
  - reference: PMID:39213194
    reference_title: Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life."
    explanation: HELIOS-B directly demonstrates benefit in the ATTR-CM trial population.
- name: NTLA-2001 in vivo TTR gene editing
  action_category: THERAPEUTIC
  therapeutic_modality: GENE_EDITING
  description: >-
    NTLA-2001 (nexiguran ziclumeran) is an investigational, single-infusion
    lipid-nanoparticle CRISPR-Cas9 therapy designed to disrupt TTR in hepatocytes
    and durably lower circulating TTR. First-in-human evidence establishes
    target engagement in a very small cohort, not clinical efficacy.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
    therapeutic_agent:
    - preferred_term: NTLA-2001
      term:
        id: NCIT:C204942
        label: Lipid Nanoparticle Encapsulating mRNA Encoding Cas9 Protein and TTR-targeting Single Guide RNA NTLA-2001
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: In vivo CRISPR-Cas9 knockout of hepatic TTR reduces the circulating precursor available for tetramer formation, misfolding, and deposition.
    evidence:
    - reference: PMID:34215024
      reference_title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum."
      explanation: The first-in-human report directly defines the therapeutic platform and TTR-lowering mechanism.
  evidence:
  - reference: PMID:34215024
    reference_title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR."
    explanation: The six-patient early-phase study demonstrates target engagement but not clinical benefit or long-term safety.
- name: Inotersen
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
    delivery_platform: UNFORMULATED
  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
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: RNase H1-mediated TTR mRNA degradation lowers the circulating precursor pool.
    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: "Inotersen is a 2´-O-methoxyethyl-modified ASO that binds to the 3´ untranslated portion of the complementary mRNA, promoting ribonuclease H1-mediated mRNA degradation."
      explanation: The review directly describes inotersen's TTR-directed RNase H1 degradation mechanism.
  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
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: GALNAC
    delivery_platform: CONJUGATE
  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
  target_mechanisms:
  - target: TTR Tetramer Destabilization and Monomer Release
    treatment_effect: INHIBITS
    description: GalNAc-directed hepatocyte delivery of the ASO lowers TTR expression upstream of tetramer release.
    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: "eplontersen induced a 28-fold more potent TTR knockdown than inotersen"
      explanation: The review reports potent TTR knockdown by eplontersen in a transgenic model.
  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
  target_mechanisms:
  - target: Clonal Immunoglobulin Light-Chain Precursor Excess
    treatment_effect: INHIBITS
    description: CD38-directed plasma-cell depletion suppresses production of amyloidogenic light chains.
    evidence:
    - reference: PMID:34192431
      reference_title: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease."
      explanation: The trial report identifies both the CD38-positive clonal plasma-cell source and daratumumab's CD38 target; precursor suppression is the resulting therapeutic inference.
  evidence:
  - reference: PMID:34192431
    reference_title: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%)"
    explanation: ANDROMEDA directly supports the response advantage of daratumumab-CyBorD in newly diagnosed systemic AL amyloidosis.
- 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
  target_mechanisms:
  - target: Sustained Serum Amyloid A Precursor Production
    treatment_effect: INHIBITS
    description: IL-6 receptor blockade suppresses the inflammatory acute-phase drive and lowers SAA precursor concentrations.
    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: The AA review directly reports reduction of the SAA precursor with 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: Tissue Confirmation With Congo Red
  description: >-
    When tissue confirmation is required, biopsy demonstrates amyloid by Congo
    red staining with characteristic green birefringence under polarized light.
    A positive stain establishes amyloid deposition but does not identify the
    precursor protein.
  diagnosis_term:
    preferred_term: Histopathologic examination
    term:
      id: NCIT:C18190
      label: Histopathologic Examination
  evidence:
  - reference: PMID:33787019
    reference_title: "[Clinical Practice Guidelines for diagnosis of amyloidosis: Part 1/3 Year 2020]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Confirmation in the tissue by biopsy and Congo red staining with the characteristic green birefringence under polarized light is recommended."
    explanation: The guideline directly supports tissue confirmation and the defining optical finding.
- name: Proteomic Amyloid Typing
  description: >-
    Amyloid deposits should be biochemically typed because therapies are
    precursor-specific. Mass-spectrometry proteomics can identify established
    and uncommon amyloid types in a single assay and avoids inferring AL solely
    from an incidental monoclonal gammopathy.
  diagnosis_term:
    preferred_term: Mass spectrometry-based amyloid typing
  evidence:
  - reference: PMID:32861330
    reference_title: "Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice."
    explanation: The 16,175-specimen clinical series supports proteomic typing across amyloid types.
- name: Monoclonal Protein Evaluation
  description: >-
    Serum free light chains plus serum and urine immunofixation evaluate a
    monoclonal plasma-cell process. This screen is essential before accepting a
    non-biopsy ATTR-CM diagnosis and does not by itself prove that a deposit is AL.
  diagnosis_term:
    preferred_term: Laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:33787019
    reference_title: "[Clinical Practice Guidelines for diagnosis of amyloidosis: Part 1/3 Year 2020]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Measurement of serum free light chains is recommended for evaluation of a monoclonal plasma cell proliferative disorder."
    explanation: The guideline supports serum free-light-chain testing for a monoclonal plasma-cell disorder.
- 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: OTHER
    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: OTHER
    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
  subtype: AL
  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.
differential_diagnoses:
- name: Hypertrophic cardiomyopathy
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  description: >-
    Sarcomeric hypertrophic cardiomyopathy can resemble cardiac amyloidosis by
    producing increased ventricular wall thickness and heart failure symptoms.
  distinguishing_features:
  - Dynamic outflow-tract obstruction or systolic anterior motion favors sarcomeric hypertrophic cardiomyopathy.
  - Amyloid evaluation integrates monoclonal-protein testing, bone scintigraphy, cardiac imaging, and tissue typing when needed.
  evidence:
  - reference: PMID:41463072
    reference_title: "Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases."
    explanation: The review places amyloidosis among the major nonsarcomeric hypertrophic phenocopies that require differentiation from sarcomeric HCM.
- name: Fabry disease
  disease_term:
    preferred_term: Fabry disease
    term:
      id: MONDO:0010526
      label: Fabry disease
  description: >-
    Fabry cardiomyopathy is a metabolic phenocopy that can also present with
    ventricular wall thickening; correct identification matters because the
    amyloidosis and Fabry treatment pathways are different.
  distinguishing_features:
  - Fabry disease is evaluated with alpha-galactosidase A activity, GLA testing, and characteristic extracardiac findings rather than amyloid typing.
  evidence:
  - reference: PMID:41463072
    reference_title: "Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases."
    explanation: The review places amyloidosis and Fabry disease among the major nonsarcomeric hypertrophic phenocopies.
clinical_trials:
- name: NCT03201965
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ANDROMEDA compared daratumumab plus cyclophosphamide, bortezomib, and
    dexamethasone with CyBorD alone in newly diagnosed systemic AL amyloidosis.
  target_phenotypes:
  - preferred_term: Amyloid deposition
    term:
      id: HP:0011034
      label: Amyloid deposition
  evidence:
  - reference: clinicaltrials:NCT03201965
    reference_title: "A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants."
    explanation: The registry summary identifies the population, intervention, comparator, and purpose.
- name: NCT01994889
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ATTR-ACT compared two daily tafamidis meglumine doses with placebo in
    hereditary or wild-type transthyretin amyloid cardiomyopathy.
  target_phenotypes:
  - preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT01994889
    reference_title: "A MULTICENTER, INTERNATIONAL, PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF DAILY ORAL DOSING OF TAFAMIDIS MEGLUMINE (PF-06291826) 20 MG OR 80 MG IN COMPARISON TO PLACEBO IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN CARDIOMYOPATHY (TTR-CM)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy."
    explanation: The registry summary directly states the intervention and ATTR-CM population.
- name: NCT04153149
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    HELIOS-B evaluates quarterly subcutaneous vutrisiran versus placebo in
    patients with ATTR amyloidosis with cardiomyopathy; the randomized outcomes
    have been published while registry follow-up remains active.
  target_phenotypes:
  - preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT04153149
    reference_title: "HELIOS-B: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study will evaluate the efficacy and safety of vutrisiran 25 mg administered subcutaneously (SC) once every 3 months (q3M) compared to placebo in participants with ATTR amyloidosis with cardiomyopathy."
    explanation: The registry summary directly states the intervention and ATTR-CM population.
- name: NCT04601051
  phase: PHASE_I
  status: COMPLETED
  description: >-
    First-in-human single-dose NTLA-2001 in vivo CRISPR-Cas9 editing evaluated
    safety and pharmacodynamic TTR lowering in ATTRv polyneuropathy and ATTR
    cardiomyopathy; early evidence establishes target engagement, not clinical efficacy.
  target_phenotypes:
  - preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  - preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT04601051
    reference_title: "Phase 1 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001"
    explanation: The registry summary establishes the early-phase safety and pharmacodynamic scope.
animal_models:
- species: Mus musculus
  genotype: Human mutant TTR Met30 transgene
  description: >-
    Transgenic mice expressing human mutant TTR Met30 develop age-progressive
    systemic amyloid in gastrointestinal, cardiovascular, renal, and other
    tissues. They reproduce fibril composition and much of the human systemic
    deposition pattern but fail to deposit amyloid in peripheral and autonomic
    nervous tissues, limiting their fidelity for the defining human neuropathy.
  genes:
  - preferred_term: TTR
    term:
      id: hgnc:12405
      label: TTR
  evidence:
  - reference: PMID:8086125
    reference_title: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys and extended to various other organs and tissues with advancing age."
    explanation: The study documents age-progressive systemic deposition in the transgenic model.
  - reference: PMID:8086125
    reference_title: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues."
    explanation: The negative model result establishes a major translational limitation for amyloid neuropathy.
discussions:
- discussion_id: amyloidosis_precursor_specificity_and_umbrella_scope
  prompt: >-
    How should precursor-specific epidemiology, organ tropism, and treatment
    effects be compared without treating amyloidosis as one homogeneous disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Amyloid Fibril Formation and Extracellular Deposition
  rationale: >-
    Amyloid fibril formation is shared, but AL, ATTRv, ATTRwt, AA, hereditary
    non-TTR, and localized forms differ in precursor supply, affected populations,
    organ distribution, prognosis, and therapy. This umbrella record therefore
    retains subtype qualifiers and defers subtype-level detail to dedicated entries.
  evidence:
  - reference: PMID:33100054
    reference_title: "Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation"
    explanation: The ISA update demonstrates precursor and localization heterogeneity and continuing candidate discovery, supporting the need to avoid a homogeneous umbrella interpretation.
- discussion_id: attr_mouse_neuropathy_model_mismatch
  prompt: >-
    Which model systems reproduce human peripheral and autonomic nerve deposition
    closely enough to test neuropathy-directed clearance and repair strategies?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Amyloid Fibril Formation and Extracellular Deposition
  rationale: >-
    The classic human TTR Met30 transgenic mouse develops systemic deposits but
    lacks deposition in the peripheral and autonomic nervous systems, so it
    cannot alone establish treatment effects on the defining human neuropathy.
  evidence:
  - reference: PMID:8086125
    reference_title: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues."
    explanation: The model directly demonstrates the human-model mismatch.
datasets:
- accession: geo:GSE293872
  title: Gene expression and V(D)J profiles of B-lineage cells from bone marrow samples of healthy adults (HA) and patients with multiple myeloma (MM)  and light-chain amyloidosis (AL).
  data_type: SINGLE_CELL_RNA_SEQ
  description: We employed single-cell RNA sequencing combined with BCR sequencing (scRNA/BCR-seq) to identify transcriptional differences between clonal B cells and non-clonal B cells from MM and AL patients versus their healthy counterparts.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 38
  publication: PMID:41812162
  notes: Identified by GEO DataSets index search for Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001001418
  title: Exome Sequencing to Define the Landscape of Plasma Cells in Systemic Light chain Amyloidosis
  description: Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, but limited whole exome data are available. We report the findings of an exome sequencing study in AL to define a plasma cell signature and compare this to monoclonal gammopathy of undefined significance (MGUS) and myeloma (MM). Twenty-four samples from unselected newly diagnosed untreated AL patients were analysed. CD138+ cells were isolated from bone marrow cells using MACSorting (Miltenyi Biotech, Bisley, UK).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001002730
  title: Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)
  description: HCHWA-D is an early onset hereditary form of Cerebral Amyloid Angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the Amyloid Precursor Protein (APP). Post-mortem brain tissue (9 patients and 9 age-related controls; frontal and occipital cortex) was used for next generation sequencing of RNA (RNA-Seq with ribosomal RNA depletion).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004214
  title: Analysis of exonic somatic variants in light-chain amyloidosis (ALA) and ALA concomitant with multiple myeloma
  description: We aim to provide the very first insight into ALA+MM molecular profiles and compare the results with ALA and with MM. Our detailed study of ALA and ALA+MM represents an important step towards improved understanding of their genetic and transcriptomic background, which is a prerequisite for development of optimal treatment strategies in the future.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Amyloidosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
computational_models: []
review_notes: >-
  Publication-readiness review in 2026 retained this MONDO umbrella entry but
  explicitly bounded subtype claims, aligned the causal graph to the
  amyloidogenesis module, replaced review-only treatment claims with pivotal
  trial evidence where available, expanded diagnostic typing and differential
  diagnosis, and added clinical-trial and model-fidelity context. Dedicated AL
  and hereditary ATTR entries remain the home for subtype-level depth.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: AL amyloidosis is a clonal plasma-cell disorder.
    evidence:
    - reference: PMID:34192431
      reference_title: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells."
      explanation: The clonal plasma-cell origin supports hematology classification for AL amyloidosis.
  - classification_value: CARDIOVASCULAR
    notes: Cardiac amyloidosis is a major systemic presentation.
    evidence:
    - reference: PMID:34518987
      reference_title: "The genetics of cardiac amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM)."
      explanation: Myocardial involvement and cardiomyopathy support cardiovascular classification.
  - classification_value: KIDNEY_URINARY_TRACT
    notes: Renal amyloid is central in AL and AA disease.
    evidence:
    - reference: PMID:18514052
      reference_title: "[Amyloidosis AA]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Nephropathy is the main clinical manifestation of amyloidosis."
      explanation: The AA review supports kidney and urinary-tract classification.
  - classification_value: NEUROLOGIC
    notes: ATTRv and AL can cause peripheral and autonomic neuropathy.
    evidence:
    - reference: PMID:22094129
      reference_title: "Familial amyloid polyneuropathy."
      supports: SUPPORT
      evidence_source: OTHER
      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: Peripheral and autonomic neuropathy support neurologic classification.
  mechanistic_category:
  - classification_value: proteotoxic disease
    evidence:
    - 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."
      explanation: Evidence for toxicity from soluble misfolded species supports the proteotoxic-disease classification.
📚

References & Deep Research

References

8
PMID:33100054
Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.
No top-level findings curated for this source.
PMID:33787019
[Clinical Practice Guidelines for diagnosis of amyloidosis: Part 1/3 Year 2020].
No top-level findings curated for this source.
PMID:32861330
Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples.
No top-level findings curated for this source.
PMID:34192431
Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
No top-level findings curated for this source.
PMID:30145929
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
No top-level findings curated for this source.
PMID:39213194
Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
No top-level findings curated for this source.
PMID:34215024
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:8086125
Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Augment: Amyloidosis (Falcon deep research) · 2026-07-06T02:04:14Z · View source

Integrated Falcon deep-research leads after NEC preflight PASS (report is genuinely systemic AL/ATTR/AA amyloidosis). Added 13 new evidence items, each a cache-verified exact substring quote. Pathophysiology: Louros 2023 DOI:10.1038/s41580-023-00647-2 soluble-oligomer membrane-permeabilization toxicity IN_VITRO plus macrophage CL:0000235; Chompoopong 2024 DOI:10.1002/ana.26965 endoneurial fibril deposition and Schwann-cell atrophy. Phenotypes: Carpal Tunnel Syndrome HP:0012185 from Poli 2023 DOI:10.3389/fneur.2023.1242815 two-thirds ATTRv; Proteinuria HP:0000093 from Mirioglu 2024 DOI:10.1007/s11926-024-01147-8 over 90 percent. Genetic: SAA1 hgnc:10513 AA precursor Mirioglu; UK-Biobank Val142Ile ancestry skew added to TTR entry Aung 2024 DOI:10.1001/jamacardio.2024.2190. Treatments: Acoramidis NCIT:C170791; Vutrisiran NCIT:C152919 SIRNA; Inotersen NCIT:C121667 and Eplontersen NCIT:C175062 ANTISENSE_OLIGONUCLEOTIDE with aso_details RNASE_H_KNOCKDOWN TTR hgnc:12405 2-prime-MOE inotersen UNCONJUGATED eplontersen GALNAC; Daratumumab NCIT:C74007 AL ANDROMEDA; Tocilizumab NCIT:C84217 AA. Prevalence: structured ATTR US 6.1/million and AL 10/million/yr records. All refs fetched via just fetch-reference DOI; validate-schema, validate-terms, validate-references all pass. Two snippets trimmed to avoid PDF hyphenation artifacts before verification.

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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