Hereditary Transthyretin Amyloidosis

Mendelian MONDO:0007100 Pathograph 35 Show in embeddings browser Genetic Disease Protein Misfolding Disease

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant, adult-onset systemic protein-misfolding disease caused by pathogenic TTR variants. Variant transthyretin tetramers are prone to dissociation; released monomers misfold and assemble into extracellular amyloid fibrils. Progressive tissue accumulation most often produces sensorimotor and autonomic neuropathy, infiltrative cardiomyopathy, or a mixed phenotype, with additional gastrointestinal, ocular, and renal manifestations that vary by genotype and disease stage.

Ask OpenScientist

Ask a research question about Hereditary Transthyretin Amyloidosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
16
Phenotypes
2
Hypotheses
1
Gaps
35
Pathograph
1
Genes
11
Medical Actions
3
Datasets
22
References
2
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
ATTRv amyloidosis is inherited in an autosomal dominant manner. Penetrance, age at onset, and organ-predominant presentation vary among TTR variants and families.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20301373 SUPPORT Other
"ATTRv amyloidosis is inherited in an autosomal dominant manner."
GeneReviews directly states the inheritance pattern.
PMID:36941075 SUPPORT Human Clinical
"Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation."
The clinical series supports variable penetrance and presentation within autosomal dominant ATTRv.
◈

Mechanistic Hypotheses

2
Canonical Variant-TTR Amyloidogenesis Model
canonical_variant_ttr_amyloidogenesis CANONICAL
Evidence balance 2 support
A pathogenic TTR variant destabilizes the circulating transthyretin tetramer. Tetramer dissociation releases monomers that misfold, oligomerize, and assemble into extracellular amyloid fibrils; progressive tissue accumulation then produces organ-specific dysfunction.
Pathograph links
Amyloidogenic Variant TTR Precursor -> TTR Tetramer Destabilization, Misfolding, and Oligomerization DIRECT Variant TTR reduces tetramer stability and permits dissociation into aggregation-prone monomers.
TTR Tetramer Destabilization, Misfolding, and Oligomerization -> TTR Amyloid Fibril Formation and Extracellular Deposition DIRECT Misfolded TTR monomers assemble into insoluble amyloid fibrils.
TTR Amyloid Fibril Formation and Extracellular Deposition -> Progressive Multitissue TTR Amyloid Accumulation DIRECT Continued fibril deposition increases amyloid burden in susceptible tissues.
Progressive Multitissue TTR Amyloid Accumulation -> Peripheral and Autonomic Nerve Injury DIRECT Endoneurial and ganglionic amyloid deposition injures peripheral nerve structures.
Progressive Multitissue TTR Amyloid Accumulation -> Cardiac Amyloid Infiltration and Dysfunction DIRECT Myocardial TTR deposition produces infiltrative cardiac disease.
Progressive Multitissue TTR Amyloid Accumulation -> Ocular and Renal Involvement INDIRECT UNKNOWN INTERMEDIATES Variant-dependent ATTR can affect ocular and renal tissues; the organ-level injury intermediates are not resolved here.
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"
This directly states the canonical variant-to-tetramer-to-fibril sequence.
PMID:29962408 SUPPORT Other
"The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis."
The review independently supports TTR destabilization and its therapeutic tractability.
Val30Met Glutathione and Inflammatory Metabolomic Signature
val30met_glutathione_signature EMERGING
Evidence balance 1 support
A cross-sectional metabolomics study associates symptomatic TTR-Val30Met disease with impaired glutathione homeostasis and inflammatory activation. Directionality and generalizability beyond this genotype remain unresolved.
Pathograph links
Progressive Multitissue TTR Amyloid Accumulation -> Glutathione and Inflammatory Metabolomic Signature INDIRECT UNKNOWN INTERMEDIATES Symptomatic Val30Met disease is associated with a circulating redox and inflammatory signature; the direction and intermediates are unresolved.
Show evidence (1 reference)
PMID:42436580 SUPPORT Human Clinical
"These findings identify disrupted GSH homeostasis and inflammatory activation as metabolic features associated with symptomatic TTR-V30M amyloidosis in vivo, supporting a link between redox imbalance and disease manifestation."
The study reports an association with manifest Val30Met disease without establishing the causal direction.
?

Discussions and Knowledge Gaps

1
Which variant-specific and host factors determine penetrance, age at onset, and whether ATTRv presents predominantly as neuropathy, cardiomyopathy, or a mixed multisystem phenotype?
KNOWLEDGE GAP OPEN gap_attrv_genotype_penetrance_and_tissue_tropism
Attached to
genetic#TTR pathophysiology#Progressive Multitissue TTR Amyloid Accumulation
Pathogenic TTR variation establishes the disease mechanism, but clinical penetrance and organ tropism remain heterogeneous even among common variants. The record therefore avoids treating one genotype or organ pattern as universal.
Show evidence (2 references)
PMID:36941075 SUPPORT Human Clinical
"Important clinical differences exist between ATTRv genotypes."
The cohort directly demonstrates genotype-associated clinical differences.
PMID:38844302 SUPPORT Other
"The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
The review frames variable organ presentation as a central genotype-phenotype problem.
⚙

Pathophysiology

8
Amyloidogenic Variant TTR Precursor
A heterozygous pathogenic TTR variant produces an amyloidogenic transthyretin precursor. TTR is synthesized predominantly in the liver and circulates as a tetramer; disease-associated variant protein makes the native complex more prone to leave its folded state.
Canonical Variant-TTR Amyloidogenesis Model
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
TTR Tetramer Destabilization, Misfolding, and Oligomerization Variant TTR reduces tetramer stability and permits dissociation into aggregation-prone monomers. Canonical Variant-TTR Amyloidogenesis Model
Show evidence (1 reference)
PMID:38844302 SUPPORT Other
"It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene."
The review identifies pathogenic TTR variation as the hereditary disease trigger.
TTR Tetramer Destabilization, Misfolding, and Oligomerization
Destabilized TTR tetramers dissociate into monomers that adopt abnormal, aggregation-prone conformations and self-associate. This is the proximal proteostasis defect targeted by TTR kinetic stabilizers.
Canonical Variant-TTR Amyloidogenesis Model
protein homotetramerization GO:0051289 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein homotetramerization (GO:0051289). GO:0051289 is a biological process from the Gene Ontology. ↓ DECREASED 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
blood plasma UBERON:0001969 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood plasma (UBERON:0001969). UBERON:0001969 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
TTR Amyloid Fibril Formation and Extracellular Deposition Misfolded TTR monomers assemble into insoluble amyloid fibrils. Canonical Variant-TTR Amyloidogenesis Model
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 supplies the complete tetramer-dissociation and monomer-misfolding sequence.
TTR Amyloid Fibril Formation and Extracellular Deposition
Misfolded variant and wild-type TTR monomers nucleate and elongate into insoluble amyloid fibrils that deposit in extracellular tissue spaces.
Canonical Variant-TTR Amyloidogenesis Model
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
extracellular region GO:0005576 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in extracellular region (GO:0005576). GO:0005576 is an anatomical location from the Gene Ontology.
Downstream
Progressive Multitissue TTR Amyloid Accumulation Continued fibril deposition increases amyloid burden in susceptible tissues. Canonical Variant-TTR Amyloidogenesis Model
Show evidence (1 reference)
PMID:25604431 SUPPORT Other
"Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR)."
The review identifies extracellular TTR fibrils as the disease-defining deposit.
Progressive Multitissue TTR Amyloid Accumulation
Ongoing extracellular deposition produces tissue amyloid burden in the peripheral and autonomic nervous systems, myocardium, eyes, kidneys, and other variant-dependent sites.
Canonical Variant-TTR Amyloidogenesis Model Val30Met Glutathione and Inflammatory Metabolomic Signature
peripheral nervous system UBERON:0000010 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in peripheral nervous system (UBERON:0000010). UBERON:0000010 is an anatomical location from the Uberon multi-species anatomy ontology. heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology. eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology. kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Glutathione and Inflammatory Metabolomic Signature Symptomatic Val30Met disease is associated with a circulating redox and inflammatory signature; the direction and intermediates are unresolved. Val30Met Glutathione and Inflammatory Metabolomic Signature
Peripheral and Autonomic Nerve Injury Endoneurial and ganglionic amyloid deposition injures peripheral nerve structures. Canonical Variant-TTR Amyloidogenesis Model
Cardiac Amyloid Infiltration and Dysfunction Myocardial TTR deposition produces infiltrative cardiac disease. Canonical Variant-TTR Amyloidogenesis Model
Ocular and Renal Involvement Variant-dependent ATTR can affect ocular and renal tissues; the organ-level injury intermediates are not resolved here. Canonical Variant-TTR Amyloidogenesis Model
Constrictive median neuropathy Local ATTR amyloid deposition in carpal-tunnel tissues causes median-nerve compression.
Show evidence (2 references)
PMID:20301373 SUPPORT Other
"Amyloidosis can involve the heart, central nervous system (CNS), eyes, and kidneys."
GeneReviews documents the multisystem tissue distribution of hereditary ATTR.
PMID:38923548 SUPPORT Other
"Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia"
The neuropathy review localizes deposits in peripheral and autonomic neural structures.
Glutathione and Inflammatory Metabolomic Signature
Symptomatic TTR-Val30Met carriers show elevated plasma pyroglutamate, consistent with impaired glutathione homeostasis, together with an increased kynurenine-to-tryptophan ratio consistent with inflammatory activation. This is an emerging genotype-specific association, not an established universal ATTR mechanism.
glutathione metabolic process GO:0006749 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves glutathione metabolic process (GO:0006749). GO:0006749 is a biological process from the Gene Ontology. inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
blood plasma UBERON:0001969 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood plasma (UBERON:0001969). UBERON:0001969 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:42436580 SUPPORT Human Clinical
"Symptomatic individuals had significantly elevated plasma PGA levels compared with both asymptomatic carriers and age-matched healthy controls, consistent with impaired GSH homeostasis."
Supports the pyroglutamate/glutathione component of the signature.
PMID:42436580 SUPPORT Human Clinical
"In parallel, the kynurenine/tryptophan ratio was increased in symptomatic TTR-V30M carriers, supporting inflammatory activation in manifest disease."
Supports the inflammatory kynurenine/tryptophan component.
Peripheral and Autonomic Nerve Injury
Endoneurial, dorsal-root-ganglion, and sympathetic-ganglion amyloid is associated with Schwann-cell atrophy and blood-nerve barrier disruption, producing a length-dependent sensory-predominant neuropathy with generalized autonomic failure.
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.
peripheral nervous system UBERON:0000010 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in peripheral nervous system (UBERON:0000010). UBERON:0000010 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sensorimotor neuropathy Peripheral nerve injury manifests as progressive sensorimotor neuropathy.
Abnormal autonomic nervous system physiology Sympathetic and autonomic fiber injury produces generalized dysautonomia.
Orthostatic hypotension due to autonomic dysfunction Dysautonomia impairs vascular-tone responses to standing.
Urinary retention Autonomic neuropathy can impair bladder emptying.
Diarrhea Enteric autonomic dysfunction can produce diarrhea.
Constipation Enteric autonomic dysfunction can reduce intestinal motility.
Gastroparesis Autonomic neuropathy can delay gastric emptying.
Show evidence (1 reference)
PMID:38923548 SUPPORT Other
"Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure."
The neuropathy review directly supports the combined sensorimotor and autonomic clinical branch.
Cardiac Amyloid Infiltration and Dysfunction
Interstitial myocardial TTR amyloid produces an infiltrative cardiomyopathy with ventricular wall thickening and restrictive physiology; conduction system involvement contributes to arrhythmia and heart block.
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.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Left ventricular hypertrophy Cardiac infiltration produces an apparent hypertrophic phenotype.
Restrictive cardiomyopathy Interstitial amyloid reduces myocardial compliance and produces restrictive physiology.
Congestive heart failure Progressive cardiomyopathy can culminate in clinical heart failure.
Arrhythmia Cardiac amyloid disease predisposes to rhythm disturbances.
Heart block Conduction tissue involvement can produce atrioventricular block.
Show evidence (1 reference)
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."
The review supports extracellular TTR deposition as the cause of ATTR organ disease.
Ocular and Renal Involvement
ATTRv can involve the vitreous and aqueous outflow structures of the eye and can be accompanied by kidney disease. These manifestations are variant-dependent, and this record does not assume a single universal renal injury route.
eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology. kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vitreous floaters Vitreous involvement can be perceived as floaters.
Glaucoma Ocular ATTRv involvement is associated with glaucoma.
Nephropathy Kidney disease can occur in ATTRv, with variant-dependent mechanisms and severity.
Show evidence (1 reference)
PMID:20301373 SUPPORT Other
"Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop."
GeneReviews directly supports the ocular and renal clinical branch.
⬡

Pathograph

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

Phenotypes

16
Cardiovascular 3
Left ventricular hypertrophy FREQUENT HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0001712 | Left ventricular hypertrophy | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Congestive heart failure FREQUENT HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0001635 | Congestive heart failure | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Arrhythmia FREQUENT HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0011675 | Arrhythmia | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Digestive 2
Diarrhea FREQUENT HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0002014 | Diarrhea | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Constipation FREQUENT HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0002019 | Constipation | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Eye 2
Vitreous floaters FREQUENT HP:0100832 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vitreous floaters (HP:0100832). HP:0100832 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0100832 | Vitreous floaters | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Glaucoma FREQUENT HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0000501 | Glaucoma | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Genitourinary 2
Urinary retention FREQUENT HP:0000016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary retention (HP:0000016). HP:0000016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0000016 | Urinary retention | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Nephropathy FREQUENT HP:0000112 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephropathy (HP:0000112). HP:0000112 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0000112 | Nephropathy | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Nervous System 1
Abnormal autonomic nervous system physiology FREQUENT HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0012332 | Abnormal autonomic nervous system physiology | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Other 6
Sensorimotor neuropathy FREQUENT HP:0007141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorimotor neuropathy (HP:0007141). HP:0007141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0007141 | Sensorimotor neuropathy | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Orthostatic hypotension due to autonomic dysfunction FREQUENT HP:0004926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orthostatic hypotension due to autonomic dysfunction (HP:0004926). HP:0004926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0004926 | Orthostatic hypotension due to autonomic dysfunction | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Gastroparesis FREQUENT HP:0002578 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroparesis (HP:0002578). HP:0002578 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0002578 | Gastroparesis | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Constrictive median neuropathy FREQUENT HP:0012185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constrictive median neuropathy (HP:0012185). HP:0012185 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0012185 | Constrictive median neuropathy | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Restrictive cardiomyopathy FREQUENT HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0001723 | Restrictive cardiomyopathy | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
Heart block FREQUENT HP:0012722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart block (HP:0012722). HP:0012722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"HP:0012722 | Heart block | Frequent (79-30%)"
Orphanet provides the hereditary ATTR frequency band.
🧬

Genetic Associations

1
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
Show evidence (2 references)
PMID:38844302 SUPPORT Other
"Hereditary transthyretin-related amyloidosis (hATTR) is the most common form of familial amyloidosis. It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene."
The review directly identifies pathogenic TTR variation as causative.
PMID:38844302 SUPPORT Other
"The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
The review supports variant-dependent expressivity.
💊

Medical Actions

11
Tafamidis
Category: Therapeutic 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.
Oral TTR kinetic stabilizer used for ATTR cardiomyopathy and, in some jurisdictions, hereditary ATTR polyneuropathy. Binding the thyroxine-binding channel stabilizes the tetramer and inhibits the dissociation step that precedes fibril formation.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization, Misfolding, and Oligomerization — Kinetic stabilization inhibits tetramer dissociation into amyloidogenic monomers.
Show evidence (3 references)
PMID:30145929 SUPPORT Human Clinical
"In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001)."
ATTR-ACT demonstrates clinical benefit in ATTR cardiomyopathy.
PMID:42265992 SUPPORT Other
"the use of tafamidis has been found to be associated with better outcomes and lower overall mortality at 30 months compared with placebo (HR 0.70 [0.51; 0.96])."
2026 clinical review synthesizes tafamidis mortality reduction in ATTR cardiac amyloidosis.
PMID:42423415 SUPPORT Other
"Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM)"
The 2026 ISA guideline supports tafamidis use across hereditary polyneuropathy and cardiomyopathy phenotypes, subject to local authorization.
Diflunisal
Category: Therapeutic 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: diflunisal CHEBI:39669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diflunisal (CHEBI:39669). CHEBI:39669 is a therapeutic agent from Chemical Entities of Biological Interest.
Diflunisal is a repurposed nonsteroidal anti-inflammatory drug used off-label as a TTR kinetic stabilizer. A randomized trial demonstrated slower polyneuropathy progression and preserved quality of life in hereditary ATTR with polyneuropathy. It is an older option rather than an equivalent substitute for currently authorized stabilizers or gene-silencing therapies, and NSAID-related gastrointestinal, cardiac, and renal risks require careful patient selection and monitoring.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization, Misfolding, and Oligomerization — Binding at the thyroxine-binding site kinetically stabilizes TTR tetramers and inhibits release of amyloidogenic monomers.
Show evidence (3 references)
PMID:24368466 SUPPORT Human Clinical
"Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro."
The randomized-trial report supplies the kinetic-stabilization rationale for repurposed diflunisal.
PMID:24368466 SUPPORT Human Clinical
"the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life."
The randomized trial demonstrates benefit for hereditary ATTR polyneuropathy while not establishing equivalence to newer therapies.
PMID:24368466 SUPPORT Human Clinical
"Drug-related adverse events led to study drug discontinuation in 4 patients from the diflunisal group (gastrointestinal bleed, congestive heart failure, glaucoma, nausea)"
Trial discontinuations support explicit safety and patient-selection caveats for repurposed NSAID therapy.
Acoramidis
Category: Therapeutic 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.
High-affinity oral TTR tetramer stabilizer used for ATTR cardiomyopathy.
Mechanism Target:
INHIBITS TTR Tetramer Destabilization, Misfolding, and Oligomerization — Acoramidis inhibits tetramer dissociation and thereby reduces formation of amyloidogenic monomers.
Show evidence (2 references)
PMID:38197816 SUPPORT Human Clinical
"Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo."
The pivotal trial describes the intended tetramer-stabilizing mechanism.
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 demonstrates clinical benefit in ATTR cardiomyopathy.
Vutrisiran
Category: Therapeutic 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.
Subcutaneous GalNAc-conjugated siRNA that reduces hepatic synthesis of both variant and wild-type TTR. It is used in hereditary ATTR polyneuropathy and ATTR cardiomyopathy, with eligibility varying by jurisdiction.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — RNA interference lowers hepatic TTR production and the circulating amyloid precursor pool.
Show evidence (3 references)
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 demonstrates benefit in ATTR cardiomyopathy.
PMID:42265992 SUPPORT Other
"Vutrisiran also lowers overall mortality and reduces recurrent cardiovascular events compared to placebo (HR 0.72 [0.56; 0.93])."
2026 clinical review reports vutrisiran mortality and cardiovascular event reduction in ATTR cardiomyopathy.
PMID:42423415 SUPPORT Other
"Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM)"
The 2026 ISA guideline supplies phenotype-specific hereditary ATTR treatment scope.
Patisiran
Category: Therapeutic 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.
Intravenous lipid-nanoparticle siRNA used for hereditary ATTR polyneuropathy. It inhibits hepatic TTR synthesis and is not represented here as an approved ATTR cardiomyopathy treatment.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — RNA interference lowers hepatic synthesis of transthyretin.
Show evidence (2 references)
PMID:29972753 SUPPORT Human Clinical
"Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin."
APOLLO directly supports the RNA-interference mechanism.
PMID:29972753 SUPPORT Human Clinical
"In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis."
APOLLO demonstrates clinical benefit in hereditary ATTR with polyneuropathy.
Inotersen
Category: Therapeutic 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.
Antisense oligonucleotide used for hereditary ATTR polyneuropathy. It lowers hepatic TTR synthesis; thrombocytopenia and glomerulonephritis require the monitoring specified by the product's clinical program.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — RNase-H-dependent TTR mRNA knockdown reduces the circulating precursor pool.
Show evidence (2 references)
PMID:29972757 SUPPORT Human Clinical
"Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis."
NEURO-TTR demonstrates neurologic and quality-of-life benefit.
PMID:29972757 SUPPORT Human Clinical
"Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring."
The pivotal trial supports the explicit monitoring caveat.
Eplontersen
Category: Therapeutic 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.
Monthly GalNAc-conjugated antisense oligonucleotide used for hereditary ATTR polyneuropathy. Hepatocyte targeting lowers serum TTR and slows neurologic impairment.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — Hepatocyte-directed antisense knockdown reduces TTR precursor production.
Show evidence (1 reference)
PMID:37768671 SUPPORT Human Clinical
"the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo."
NEURO-TTRansform supports TTR lowering and clinical benefit in ATTRv polyneuropathy.
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.
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. The first-in-human report included only six participants with hereditary ATTR polyneuropathy and established target engagement, not clinical efficacy; it remains an emerging therapy rather than established care.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — In vivo CRISPR-Cas9 knockout of hepatic TTR reduces the circulating precursor available for misfolding and deposition.
Show evidence (2 references)
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.
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."
Six-patient early-phase evidence demonstrates target engagement but does not establish clinical benefit or long-term safety.
Orthotopic liver transplantation
Category: Therapeutic Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
Historical disease-modifying option for carefully selected hereditary ATTR cases because the liver supplies most circulating variant TTR. It is not first-line therapy in the current drug era, does not reliably reverse established organ injury, and disease can progress after transplantation.
Mechanism Target:
INHIBITS Amyloidogenic Variant TTR Precursor — Replacing the liver markedly reduces production of circulating variant TTR.
Show evidence (2 references)
PMID:25482846 SUPPORT Other
"Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR."
The review supports the precursor-production rationale for transplantation.
PMID:25482846 SUPPORT Other
"After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses."
The review directly supports the non-curative caveat.
Multidisciplinary supportive care
Category: Therapeutic Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Manifestation-directed care includes neuropathic-pain treatment, mobility support, management of autonomic and gastrointestinal dysfunction, cardiac rhythm devices when indicated, ophthalmic procedures, and renal support.
Show evidence (2 references)
PMID:20301373 SUPPORT Other
"Pharmacologic treatments for neuropathic pain; surgical release for carpal tunnel syndrome; ankle-foot orthoses and physical therapy for motor neuropathy; standard treatments for autonomic dysfunction and CNS manifestations."
GeneReviews lists manifestation-directed neurologic and autonomic care.
PMID:20301373 SUPPORT Other
"In those with sick sinus syndrome or second- or third-degree atrioventricular block, a cardiac pacemaker may be indicated."
GeneReviews supports rhythm-device management for clinically important conduction disease.
SGLT2 Inhibitors
Category: Therapeutic 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: dapagliflozin CHEBI:85078 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dapagliflozin (CHEBI:85078). CHEBI:85078 is a therapeutic agent from Chemical Entities of Biological Interest.
Sodium-glucose cotransporter 2 inhibitors used to manage the cardiac complications and comorbidities of ATTR amyloidosis, selected according to left ventricular function and drug tolerability.
Mechanism Target:
MODULATES Cardiac Amyloid Infiltration and Dysfunction — Symptomatic management of the heart-failure consequences of amyloid infiltration. The cited review positions SGLT2 inhibitors as treatment for cardiac complications and comorbidities; it does not claim an effect on amyloid deposition itself.
Show evidence (1 reference)
PMID:42265992 SUPPORT Other
"Cardiac complications and comorbidities can be treated, depending on left ventricular function and drug tolerability, with SGLT2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, among other drugs."
2026 clinical review recommends SGLT2 inhibitors for managing cardiac complications in ATTR amyloidosis.
🔬

Biochemical Markers

2
Plasma pyroglutamate (Elevated in symptomatic TTR-Val30Met carriers)
Context: Candidate circulating marker of impaired glutathione homeostasis
Show evidence (1 reference)
PMID:42436580 SUPPORT Human Clinical
"Symptomatic individuals had significantly elevated plasma PGA levels compared with both asymptomatic carriers and age-matched healthy controls, consistent with impaired GSH homeostasis."
The cross-sectional cohort reports higher plasma pyroglutamate in symptomatic carriers than both comparator groups.
Plasma kynurenine-to-tryptophan ratio (Elevated in symptomatic TTR-Val30Met carriers)
Context: Candidate circulating marker of inflammatory activation
Show evidence (1 reference)
PMID:42436580 SUPPORT Human Clinical
"In parallel, the kynurenine/tryptophan ratio was increased in symptomatic TTR-V30M carriers, supporting inflammatory activation in manifest disease."
The study reports an elevated ratio in symptomatic carriers.
🔬

Diagnosis

4
Molecular confirmation of hereditary ATTR amyloidosis
Active ATTRv diagnosis requires compatible clinical manifestations plus imaging or histopathologic evidence of amyloidosis and identification of a heterozygous pathogenic TTR variant. A pathogenic variant alone indicates genetic risk, not necessarily clinically manifest amyloidosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301373 SUPPORT Other
"The diagnosis of ATTRv amyloidosis is established in a proband with characteristic clinical features, including imaging or histopathology findings of amyloidosis, and a heterozygous pathogenic variant in TTR identified by molecular genetic testing."
GeneReviews states the combined phenotypic, amyloid, and molecular requirements.
Monoclonal protein testing and bone-avid cardiac scintigraphy with SPECT
In suspected cardiac ATTR, serum free light chains plus serum and urine immunofixation assess for a monoclonal protein before interpreting technetium-PYP, DPD, or HMDP scintigraphy. Grade 2-3 myocardial uptake with no monoclonal protein supports a nonbiopsy ATTR-CM diagnosis; SPECT confirms myocardial rather than blood-pool uptake.
cardiac radionuclide scintigraphy NCIT:C62667 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27143678 SUPPORT Human Clinical
"Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy."
The multicenter study establishes the nonbiopsy pathway only when monoclonal gammopathy is absent.
PMID:33221204 SUPPORT Human Clinical
"the inclusion of monoclonal protein testing and SPECT imaging is crucial to rule out amyloid light chain amyloidosis and distinguish myocardial retention from blood pooling."
This supports both AL exclusion and tomographic confirmation of myocardial uptake.
Tissue biopsy with amyloid typing when nonbiopsy criteria are not met
Discordant imaging, a monoclonal protein, or other diagnostic uncertainty requires tissue demonstration of Congo-red-positive amyloid followed by typing, preferably by mass spectrometry, because Congo red alone does not distinguish ATTR from AL amyloid.
Show evidence (1 reference)
DOI:10.3389/frhem.2024.1378451 SUPPORT Other
"Histological diagnosis with Congo red staining is the gold standard, but typing the amyloid with immunohistochemistry or mass spectrometry of the Congo red positive tissue is necessary to establish if an AL or ATTR amyloidosis could be diagnosed."
The review directly states that Congo red must be followed by amyloid typing to distinguish AL from ATTR.
Neurologic phenotyping and denervation assessment
Neurologic examination, nerve-conduction studies, sudomotor testing, and intraepidermal nerve-fiber assessment characterize neuropathy and denervation. These tests support organ phenotyping but do not replace TTR genetic testing and amyloid identification.
Show evidence (1 reference)
PMID:38923548 SUPPORT Other
"Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation."
The neuropathy review supports these tools for physiologic characterization of denervation.
📈

Progression

1
Progressive multisystem disease
Age: Adult onset; age varies by genotype and population
Neuropathy is usually slowly progressive, while cardiac, ocular, renal, and central nervous system involvement varies by TTR variant and disease stage. A fixed onset range is not asserted because genotype and geography strongly affect presentation.
Show evidence (2 references)
PMID:20301373 SUPPORT Other
"Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy."
GeneReviews supports progressive neuropathy as a central natural-history feature.
PMID:38844302 SUPPORT Other
"The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
The review supports genotype-dependent organ presentation rather than one universal onset course.
📊

Prevalence

1
Worldwide
Point Prevalence 0.1–0.9 per 100,000 1–9 per 1,000,000
Orphanet reports a worldwide point-prevalence band of 1-9 per million. Endemic regions and individual pathogenic variants can have substantially different carrier and disease frequencies.
Show evidence (1 reference)
ORPHA:271861 SUPPORT Other
"1-9 / 1 000 000 | Worldwide | Point prevalence | PMID:29211930"
Orphanet supplies the hereditary ATTR worldwide prevalence band.
📊

Related Datasets

3
A Gene Expression-based Blood Diagnostic for Symptomatic Transthyretin Amyloidosis Revealing Male and Female-specific Signatures geo:GSE67784
Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g.
human MICROARRAY n=309
PMID:27570551
Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Circulating microRNAs profile in patients with transthyretin variant amyloidosis geo:GSE149665
Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. 10 symptomatic ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied.
human MICROARRAY n=40
PMID:32655365
Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms geo:GSE154683
The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other non-cardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator.
human METHYLATION n=96
PMID:33428857
Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Hereditary Transthyretin Amyloidosis
creation_date: '2025-12-04T16:57:31Z'
description: >-
  Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal
  dominant, adult-onset systemic protein-misfolding disease caused by pathogenic
  TTR variants. Variant transthyretin tetramers are prone to dissociation;
  released monomers misfold and assemble into extracellular amyloid fibrils.
  Progressive tissue accumulation most often produces sensorimotor and
  autonomic neuropathy, infiltrative cardiomyopathy, or a mixed phenotype, with
  additional gastrointestinal, ocular, and renal manifestations that vary by
  genotype and disease stage.
category: Mendelian
parents:
- Genetic Disease
- Protein Misfolding Disease
disease_term:
  preferred_term: familial amyloid neuropathy
  term:
    id: MONDO:0007100
    label: familial amyloid neuropathy
synonyms:
- ATTRv amyloidosis
- Familial amyloid polyneuropathy
- Familial transthyretin amyloidosis
- Hereditary ATTR amyloidosis
- Hereditary transthyretin-mediated amyloidosis
- hATTR
notes: >-
  This record is intentionally restricted to hereditary/variant ATTR because
  MONDO:0007100 denotes the familial genetic disease. Age-related wild-type
  ATTR (MONDO:0018018) is not a subtype of this record; the shared ATTRv/ATTRwt
  mechanism is represented in the broader Amyloidosis entry. This scope avoids
  projecting hereditary Orphanet frequencies, inheritance, genetic testing,
  and polyneuropathy treatment indications onto wild-type disease.
references:
- reference: PMID:20301373
  title: Hereditary Transthyretin Amyloidosis.
  tags:
  - GeneReviews
- reference: ORPHA:271861
  title: Hereditary ATTR amyloidosis
- reference: PMID:25604431
  title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
- reference: PMID:29962408
  title: Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds.
- reference: PMID:38923548
  title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
- reference: PMID:38844302
  title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
- reference: PMID:36941075
  title: Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis.
- reference: PMID:40649158
  title: "Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options."
- reference: PMID:27143678
  title: Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.
- reference: PMID:33221204
  title: "Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution."
- reference: DOI:10.3389/frhem.2024.1378451
  title: "AL amyloidosis: an overview on diagnosis, staging system, and treatment"
- reference: PMID:30145929
  title: Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
- reference: PMID:38197816
  title: Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.
- reference: PMID:24368466
  title: "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial."
- reference: PMID:34215024
  title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
- reference: PMID:39213194
  title: Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
- reference: PMID:29972753
  title: Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
- reference: PMID:29972757
  title: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
- reference: PMID:37768671
  title: Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.
- reference: PMID:25482846
  title: "Liver transplantation in transthyretin amyloidosis: issues and challenges."
- reference: PMID:30404120
  title: "[Carpal tunnel syndrome and ATTR-amyloidosis]."
- reference: PMID:42423415
  title: Guidelines for the management of hereditary ATTR amyloidosis 2026.

inheritance:
- name: Autosomal dominant inheritance
  description: >-
    ATTRv amyloidosis is inherited in an autosomal dominant manner. Penetrance,
    age at onset, and organ-predominant presentation vary among TTR variants and
    families.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ATTRv amyloidosis is inherited in an autosomal dominant manner."
    explanation: GeneReviews directly states the inheritance pattern.
  - reference: PMID:36941075
    reference_title: Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation."
    explanation: The clinical series supports variable penetrance and presentation within autosomal dominant ATTRv.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.1
  rate_high: 0.9
  notes: >-
    Orphanet reports a worldwide point-prevalence band of 1-9 per million.
    Endemic regions and individual pathogenic variants can have substantially
    different carrier and disease frequencies.
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Worldwide | Point prevalence | PMID:29211930"
    explanation: Orphanet supplies the hereditary ATTR worldwide prevalence band.

progression:
- phase: Progressive multisystem disease
  age_range: Adult onset; age varies by genotype and population
  notes: >-
    Neuropathy is usually slowly progressive, while cardiac, ocular, renal, and
    central nervous system involvement varies by TTR variant and disease stage.
    A fixed onset range is not asserted because genotype and geography strongly
    affect presentation.
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy."
    explanation: GeneReviews supports progressive neuropathy as a central natural-history feature.
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
    explanation: The review supports genotype-dependent organ presentation rather than one universal onset course.

mechanistic_hypotheses:
- hypothesis_group_id: canonical_variant_ttr_amyloidogenesis
  hypothesis_label: Canonical Variant-TTR Amyloidogenesis Model
  status: CANONICAL
  description: >-
    A pathogenic TTR variant destabilizes the circulating transthyretin
    tetramer. Tetramer dissociation releases monomers that misfold, oligomerize,
    and assemble into extracellular amyloid fibrils; progressive tissue
    accumulation then produces organ-specific dysfunction.
  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: This directly states the canonical variant-to-tetramer-to-fibril sequence.
  - reference: PMID:29962408
    reference_title: Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis."
    explanation: The review independently supports TTR destabilization and its therapeutic tractability.
- hypothesis_group_id: val30met_glutathione_signature
  hypothesis_label: Val30Met Glutathione and Inflammatory Metabolomic Signature
  status: EMERGING
  description: >-
    A cross-sectional metabolomics study associates symptomatic TTR-Val30Met
    disease with impaired glutathione homeostasis and inflammatory activation.
    Directionality and generalizability beyond this genotype remain unresolved.
  evidence:
  - reference: PMID:42436580
    reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings identify disrupted GSH homeostasis and inflammatory activation as metabolic features associated with symptomatic TTR-V30M amyloidosis in vivo, supporting a link between redox imbalance and disease manifestation."
    explanation: >-
      The study reports an association with manifest Val30Met disease without
      establishing the causal direction.

pathophysiology:
- name: Amyloidogenic Variant TTR Precursor
  description: >-
    A heterozygous pathogenic TTR variant produces an amyloidogenic
    transthyretin precursor. TTR is synthesized predominantly in the liver and
    circulates as a tetramer; disease-associated variant protein makes the
    native complex more prone to leave its folded state.
  role: trigger
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  gene:
    preferred_term: TTR
    term:
      id: hgnc:12405
      label: TTR
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene."
    explanation: The review identifies pathogenic TTR variation as the hereditary disease trigger.
  downstream:
  - target: TTR Tetramer Destabilization, Misfolding, and Oligomerization
    causal_link_type: DIRECT
    description: Variant TTR reduces tetramer stability and permits dissociation into aggregation-prone monomers.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    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"
      explanation: The source directly connects TTR mutation to tetramer dissociation.

- name: TTR Tetramer Destabilization, Misfolding, and Oligomerization
  description: >-
    Destabilized TTR tetramers dissociate into monomers that adopt abnormal,
    aggregation-prone conformations and self-associate. This is the proximal
    proteostasis defect targeted by TTR kinetic stabilizers.
  role: amplifier
  conforms_to: "amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization"
  biological_processes:
  - preferred_term: protein homotetramerization
    term:
      id: GO:0051289
      label: protein homotetramerization
    modifier: DECREASED
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  locations:
  - preferred_term: blood plasma
    term:
      id: UBERON:0001969
      label: blood plasma
  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 supplies the complete tetramer-dissociation and monomer-misfolding sequence.
  downstream:
  - target: TTR Amyloid Fibril Formation and Extracellular Deposition
    causal_link_type: DIRECT
    description: Misfolded TTR monomers assemble into insoluble amyloid fibrils.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    evidence:
    - reference: PMID:25604431
      reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "to then misfold and aggregate into amyloid fibrils"
      explanation: The source directly links monomer misfolding to amyloid fibril aggregation.

- name: TTR Amyloid Fibril Formation and Extracellular Deposition
  description: >-
    Misfolded variant and wild-type TTR monomers nucleate and elongate into
    insoluble amyloid fibrils that deposit in extracellular tissue spaces.
  role: central_effector
  conforms_to: "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  locations:
  - preferred_term: extracellular region
    term:
      id: GO:0005576
      label: extracellular region
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR)."
    explanation: The review identifies extracellular TTR fibrils as the disease-defining deposit.
  downstream:
  - target: Progressive Multitissue TTR Amyloid Accumulation
    causal_link_type: DIRECT
    description: Continued fibril deposition increases amyloid burden in susceptible tissues.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    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 links extracellular TTR fibril deposition to progressive multisystem disease.

- name: Progressive Multitissue TTR Amyloid Accumulation
  description: >-
    Ongoing extracellular deposition produces tissue amyloid burden in the
    peripheral and autonomic nervous systems, myocardium, eyes, kidneys, and
    other variant-dependent sites.
  role: tissue_accumulation
  conforms_to: "amyloidogenesis#Progressive Tissue Amyloid Accumulation"
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Amyloidosis can involve the heart, central nervous system (CNS), eyes, and kidneys."
    explanation: GeneReviews documents the multisystem tissue distribution of hereditary ATTR.
  - reference: PMID:38923548
    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"
    explanation: The neuropathy review localizes deposits in peripheral and autonomic neural structures.
  downstream:
  - target: Glutathione and Inflammatory Metabolomic Signature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Symptomatic Val30Met disease is associated with a circulating redox and
      inflammatory signature; the direction and intermediates are unresolved.
    hypothesis_groups:
    - val30met_glutathione_signature
    evidence:
    - reference: PMID:42436580
      reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings identify disrupted GSH homeostasis and inflammatory activation as metabolic features associated with symptomatic TTR-V30M amyloidosis in vivo, supporting a link between redox imbalance and disease manifestation."
      explanation: >-
        Supports association with symptomatic disease but not a direct causal
        arrow from amyloid burden.
  - target: Peripheral and Autonomic Nerve Injury
    causal_link_type: DIRECT
    description: Endoneurial and ganglionic amyloid deposition injures peripheral nerve structures.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    evidence:
    - reference: PMID:38923548
      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 and blood-nerve barrier disruption."
      explanation: The source links neural deposition to Schwann-cell atrophy and blood-nerve barrier injury.
  - target: Cardiac Amyloid Infiltration and Dysfunction
    causal_link_type: DIRECT
    description: Myocardial TTR deposition produces infiltrative cardiac disease.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    evidence:
    - 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: The review identifies cardiomyopathy as a major organ manifestation of deposited TTR amyloid.
  - target: Ocular and Renal Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Variant-dependent ATTR can affect ocular and renal tissues; the organ-level injury intermediates are not resolved here.
    hypothesis_groups:
    - canonical_variant_ttr_amyloidogenesis
    evidence:
    - reference: PMID:20301373
      reference_title: Hereditary Transthyretin Amyloidosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop."
      explanation: GeneReviews supports ocular and renal involvement while not requiring one universal tissue-injury mechanism.
  - target: Constrictive median neuropathy
    causal_link_type: DIRECT
    description: Local ATTR amyloid deposition in carpal-tunnel tissues causes median-nerve compression.
    evidence:
    - reference: PMID:30404120
      reference_title: "[Carpal tunnel syndrome and ATTR-amyloidosis]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One cause for a carpal tunnel syndrome is transthyretin (ATTR) amyloid, which deposits in the carpal tunnel tissue."
      explanation: The histopathology series directly links local carpal-tunnel ATTR deposition to compression neuropathy.

- name: Glutathione and Inflammatory Metabolomic Signature
  description: >-
    Symptomatic TTR-Val30Met carriers show elevated plasma pyroglutamate,
    consistent with impaired glutathione homeostasis, together with an increased
    kynurenine-to-tryptophan ratio consistent with inflammatory activation.
    This is an emerging genotype-specific association, not an established
    universal ATTR mechanism.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  locations:
  - preferred_term: blood plasma
    term:
      id: UBERON:0001969
      label: blood plasma
  evidence:
  - reference: PMID:42436580
    reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic individuals had significantly elevated plasma PGA levels compared with both asymptomatic carriers and age-matched healthy controls, consistent with impaired GSH homeostasis."
    explanation: >-
      Supports the pyroglutamate/glutathione component of the signature.
  - reference: PMID:42436580
    reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In parallel, the kynurenine/tryptophan ratio was increased in symptomatic TTR-V30M carriers, supporting inflammatory activation in manifest disease."
    explanation: >-
      Supports the inflammatory kynurenine/tryptophan component.

- name: Peripheral and Autonomic Nerve Injury
  description: >-
    Endoneurial, dorsal-root-ganglion, and sympathetic-ganglion amyloid is
    associated with Schwann-cell atrophy and blood-nerve barrier disruption,
    producing a length-dependent sensory-predominant neuropathy with generalized
    autonomic failure.
  role: organ_dysfunction
  conforms_to: "amyloidogenesis#Organ Dysfunction"
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure."
    explanation: The neuropathy review directly supports the combined sensorimotor and autonomic clinical branch.
  downstream:
  - target: Sensorimotor neuropathy
    causal_link_type: DIRECT
    description: Peripheral nerve injury manifests as progressive sensorimotor neuropathy.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007141 | Sensorimotor neuropathy | Frequent (79-30%)"
      explanation: Orphanet reports sensorimotor neuropathy as a frequent hereditary ATTR phenotype.
  - target: Abnormal autonomic nervous system physiology
    causal_link_type: DIRECT
    description: Sympathetic and autonomic fiber injury produces generalized dysautonomia.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012332 | Abnormal autonomic nervous system physiology | Frequent (79-30%)"
      explanation: Orphanet reports autonomic dysfunction as frequent.
  - target: Orthostatic hypotension due to autonomic dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired autonomic regulation of vascular tone
    description: Dysautonomia impairs vascular-tone responses to standing.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004926 | Orthostatic hypotension due to autonomic dysfunction | Frequent (79-30%)"
      explanation: Orphanet reports the specifically autonomic form of orthostatic hypotension as frequent.
  - target: Urinary retention
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - autonomic bladder dysfunction
    description: Autonomic neuropathy can impair bladder emptying.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000016 | Urinary retention | Frequent (79-30%)"
      explanation: Orphanet reports urinary retention as frequent.
  - target: Diarrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - gastrointestinal autonomic dysfunction
    description: Enteric autonomic dysfunction can produce diarrhea.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002014 | Diarrhea | Frequent (79-30%)"
      explanation: Orphanet reports diarrhea as frequent.
  - target: Constipation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - gastrointestinal autonomic dysfunction
    description: Enteric autonomic dysfunction can reduce intestinal motility.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
      explanation: Orphanet reports constipation as frequent.
  - target: Gastroparesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired autonomic control of gastric emptying
    description: Autonomic neuropathy can delay gastric emptying.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002578 | Gastroparesis | Frequent (79-30%)"
      explanation: Orphanet reports gastroparesis as frequent.
- name: Cardiac Amyloid Infiltration and Dysfunction
  description: >-
    Interstitial myocardial TTR amyloid produces an infiltrative cardiomyopathy
    with ventricular wall thickening and restrictive physiology; conduction
    system involvement contributes to arrhythmia and heart block.
  role: organ_dysfunction
  conforms_to: "amyloidogenesis#Organ Dysfunction"
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  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 TTR deposition as the cause of ATTR organ disease.
  downstream:
  - target: Left ventricular hypertrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - myocardial amyloid infiltration and increased wall thickness
    description: Cardiac infiltration produces an apparent hypertrophic phenotype.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001712 | Left ventricular hypertrophy | Frequent (79-30%)"
      explanation: Orphanet reports left ventricular hypertrophy as frequent.
  - target: Restrictive cardiomyopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - myocardial amyloid infiltration and stiffness
    description: Interstitial amyloid reduces myocardial compliance and produces restrictive physiology.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001723 | Restrictive cardiomyopathy | Frequent (79-30%)"
      explanation: Orphanet reports restrictive cardiomyopathy as frequent.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - infiltrative cardiomyopathy with impaired filling and output
    description: Progressive cardiomyopathy can culminate in clinical heart failure.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001635 | Congestive heart failure | Frequent (79-30%)"
      explanation: Orphanet reports congestive heart failure as frequent.
  - target: Arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - atrial and conduction-system involvement
    description: Cardiac amyloid disease predisposes to rhythm disturbances.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011675 | Arrhythmia | Frequent (79-30%)"
      explanation: Orphanet reports arrhythmia as frequent.
  - target: Heart block
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - conduction-system infiltration
    description: Conduction tissue involvement can produce atrioventricular block.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012722 | Heart block | Frequent (79-30%)"
      explanation: Orphanet reports heart block as frequent.

- name: Ocular and Renal Involvement
  description: >-
    ATTRv can involve the vitreous and aqueous outflow structures of the eye and
    can be accompanied by kidney disease. These manifestations are
    variant-dependent, and this record does not assume a single universal renal
    injury route.
  role: organ_dysfunction
  conforms_to: "amyloidogenesis#Organ Dysfunction"
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop."
    explanation: GeneReviews directly supports the ocular and renal clinical branch.
  downstream:
  - target: Vitreous floaters
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - vitreous TTR amyloid opacity
    description: Vitreous involvement can be perceived as floaters.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100832 | Vitreous floaters | Frequent (79-30%)"
      explanation: Orphanet reports vitreous floaters as frequent.
  - target: Glaucoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ocular ATTRv involvement is associated with glaucoma.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000501 | Glaucoma | Frequent (79-30%)"
      explanation: Orphanet reports glaucoma as frequent.
  - target: Nephropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Kidney disease can occur in ATTRv, with variant-dependent mechanisms and severity.
    evidence:
    - reference: ORPHA:271861
      reference_title: Hereditary ATTR amyloidosis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000112 | Nephropathy | Frequent (79-30%)"
      explanation: Orphanet reports nephropathy as frequent.

phenotypes:
- name: Sensorimotor neuropathy
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sensorimotor neuropathy
    term:
      id: HP:0007141
      label: Sensorimotor neuropathy
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007141 | Sensorimotor neuropathy | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Abnormal autonomic nervous system physiology
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012332 | Abnormal autonomic nervous system physiology | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Orthostatic hypotension due to autonomic dysfunction
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Orthostatic hypotension due to autonomic dysfunction
    term:
      id: HP:0004926
      label: Orthostatic hypotension due to autonomic dysfunction
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004926 | Orthostatic hypotension due to autonomic dysfunction | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Urinary retention
  category: Genitourinary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Urinary retention
    term:
      id: HP:0000016
      label: Urinary retention
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000016 | Urinary retention | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Diarrhea
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002014 | Diarrhea | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Constipation
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Gastroparesis
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroparesis
    term:
      id: HP:0002578
      label: Gastroparesis
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002578 | Gastroparesis | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Constrictive median neuropathy
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constrictive median neuropathy
    term:
      id: HP:0012185
      label: Constrictive median neuropathy
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012185 | Constrictive median neuropathy | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001712 | Left ventricular hypertrophy | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Restrictive cardiomyopathy
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001723 | Restrictive cardiomyopathy | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Congestive heart failure
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001635 | Congestive heart failure | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Arrhythmia
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011675 | Arrhythmia | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Heart block
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Heart block
    term:
      id: HP:0012722
      label: Heart block
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012722 | Heart block | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Vitreous floaters
  category: Ocular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vitreous floaters
    term:
      id: HP:0100832
      label: Vitreous floaters
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100832 | Vitreous floaters | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Glaucoma
  category: Ocular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000501 | Glaucoma | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.
- name: Nephropathy
  category: Genitourinary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephropathy
    term:
      id: HP:0000112
      label: Nephropathy
  evidence:
  - reference: ORPHA:271861
    reference_title: Hereditary ATTR amyloidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000112 | Nephropathy | Frequent (79-30%)"
    explanation: Orphanet provides the hereditary ATTR frequency band.

biochemical:
- name: Plasma pyroglutamate
  presence: Elevated in symptomatic TTR-Val30Met carriers
  context: Candidate circulating marker of impaired glutathione homeostasis
  biomarker_term:
    preferred_term: pyroglutamate
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
  evidence:
  - reference: PMID:42436580
    reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic individuals had significantly elevated plasma PGA levels compared with both asymptomatic carriers and age-matched healthy controls, consistent with impaired GSH homeostasis."
    explanation: >-
      The cross-sectional cohort reports higher plasma pyroglutamate in
      symptomatic carriers than both comparator groups.
- name: Plasma kynurenine-to-tryptophan ratio
  presence: Elevated in symptomatic TTR-Val30Met carriers
  context: Candidate circulating marker of inflammatory activation
  evidence:
  - reference: PMID:42436580
    reference_title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In parallel, the kynurenine/tryptophan ratio was increased in symptomatic TTR-V30M carriers, supporting inflammatory activation in manifest disease."
    explanation: >-
      The study reports an elevated ratio in symptomatic carriers.

genetic:
- name: TTR
  association: Pathogenic variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TTR
    term:
      id: hgnc:12405
      label: TTR
  notes: >-
    Pathogenic heterozygous TTR variants cause ATTRv through a toxic
    gain-of-function protein-misfolding mechanism. Penetrance and the balance of
    cardiac, neurologic, and mixed disease vary by variant.
  evidence:
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary transthyretin-related amyloidosis (hATTR) is the most common form of familial amyloidosis. It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene."
    explanation: The review directly identifies pathogenic TTR variation as causative.
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
    explanation: The review supports variant-dependent expressivity.

diagnosis:
- name: Molecular confirmation of hereditary ATTR amyloidosis
  description: >-
    Active ATTRv diagnosis requires compatible clinical manifestations plus
    imaging or histopathologic evidence of amyloidosis and identification of a
    heterozygous pathogenic TTR variant. A pathogenic variant alone indicates
    genetic risk, not necessarily clinically manifest amyloidosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of ATTRv amyloidosis is established in a proband with characteristic clinical features, including imaging or histopathology findings of amyloidosis, and a heterozygous pathogenic variant in TTR identified by molecular genetic testing."
    explanation: GeneReviews states the combined phenotypic, amyloid, and molecular requirements.

- name: Monoclonal protein testing and bone-avid cardiac scintigraphy with SPECT
  description: >-
    In suspected cardiac ATTR, serum free light chains plus serum and urine
    immunofixation assess for a monoclonal protein before interpreting
    technetium-PYP, DPD, or HMDP scintigraphy. Grade 2-3 myocardial uptake with
    no monoclonal protein supports a nonbiopsy ATTR-CM diagnosis; SPECT confirms
    myocardial rather than blood-pool uptake.
  diagnosis_term:
    preferred_term: cardiac radionuclide scintigraphy
    term:
      id: NCIT:C62667
      label: Radionuclide Imaging
  evidence:
  - reference: PMID:27143678
    reference_title: Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy."
    explanation: The multicenter study establishes the nonbiopsy pathway only when monoclonal gammopathy is absent.
  - reference: PMID:33221204
    reference_title: "Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the inclusion of monoclonal protein testing and SPECT imaging is crucial to rule out amyloid light chain amyloidosis and distinguish myocardial retention from blood pooling."
    explanation: This supports both AL exclusion and tomographic confirmation of myocardial uptake.

- name: Tissue biopsy with amyloid typing when nonbiopsy criteria are not met
  description: >-
    Discordant imaging, a monoclonal protein, or other diagnostic uncertainty
    requires tissue demonstration of Congo-red-positive amyloid followed by
    typing, preferably by mass spectrometry, because Congo red alone does not
    distinguish ATTR from AL amyloid.
  evidence:
  - reference: DOI:10.3389/frhem.2024.1378451
    reference_title: "AL amyloidosis: an overview on diagnosis, staging system, and treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histological diagnosis with Congo red staining is the gold standard, but typing the amyloid with immunohistochemistry or mass spectrometry of the Congo red positive tissue is necessary to establish if an AL or ATTR amyloidosis could be diagnosed."
    explanation: The review directly states that Congo red must be followed by amyloid typing to distinguish AL from ATTR.

- name: Neurologic phenotyping and denervation assessment
  description: >-
    Neurologic examination, nerve-conduction studies, sudomotor testing, and
    intraepidermal nerve-fiber assessment characterize neuropathy and
    denervation. These tests support organ phenotyping but do not replace TTR
    genetic testing and amyloid identification.
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation."
    explanation: The neuropathy review supports these tools for physiologic characterization of denervation.

treatments:
- name: Tafamidis
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Oral TTR kinetic stabilizer used for ATTR cardiomyopathy and, in some
    jurisdictions, hereditary ATTR polyneuropathy. Binding the thyroxine-binding
    channel stabilizes the tetramer and inhibits the dissociation step that
    precedes fibril formation.
  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, Misfolding, and Oligomerization
    treatment_effect: INHIBITS
    description: Kinetic stabilization inhibits tetramer dissociation into amyloidogenic monomers.
  evidence:
  - reference: PMID:30145929
    reference_title: Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001)."
    explanation: ATTR-ACT demonstrates clinical benefit in ATTR cardiomyopathy.
  - reference: PMID:42265992
    reference_title: "Cardiac Amyloidosis: Pathogenesis, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the use of tafamidis has been found to be associated with better outcomes and lower overall mortality at 30 months compared with placebo (HR 0.70 [0.51; 0.96])."
    explanation: 2026 clinical review synthesizes tafamidis mortality reduction in ATTR cardiac amyloidosis.
  - reference: PMID:42423415
    reference_title: Guidelines for the management of hereditary ATTR amyloidosis 2026.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM)"
    explanation: The 2026 ISA guideline supports tafamidis use across hereditary polyneuropathy and cardiomyopathy phenotypes, subject to local authorization.

- name: Diflunisal
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Diflunisal is a repurposed nonsteroidal anti-inflammatory drug used
    off-label as a TTR kinetic stabilizer. A randomized trial demonstrated
    slower polyneuropathy progression and preserved quality of life in
    hereditary ATTR with polyneuropathy. It is an older option rather than an
    equivalent substitute for currently authorized stabilizers or gene-silencing
    therapies, and NSAID-related gastrointestinal, cardiac, and renal risks
    require careful patient selection and monitoring.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diflunisal
      term:
        id: CHEBI:39669
        label: diflunisal
  target_mechanisms:
  - target: TTR Tetramer Destabilization, Misfolding, and Oligomerization
    treatment_effect: INHIBITS
    description: Binding at the thyroxine-binding site kinetically stabilizes TTR tetramers and inhibits release of amyloidogenic monomers.
  evidence:
  - reference: PMID:24368466
    reference_title: "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro."
    explanation: The randomized-trial report supplies the kinetic-stabilization rationale for repurposed diflunisal.
  - reference: PMID:24368466
    reference_title: "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life."
    explanation: The randomized trial demonstrates benefit for hereditary ATTR polyneuropathy while not establishing equivalence to newer therapies.
  - reference: PMID:24368466
    reference_title: "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Drug-related adverse events led to study drug discontinuation in 4 patients from the diflunisal group (gastrointestinal bleed, congestive heart failure, glaucoma, nausea)"
    explanation: Trial discontinuations support explicit safety and patient-selection caveats for repurposed NSAID therapy.

- name: Acoramidis
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    High-affinity oral TTR tetramer stabilizer used for ATTR cardiomyopathy.
  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, Misfolding, and Oligomerization
    treatment_effect: INHIBITS
    description: Acoramidis inhibits tetramer dissociation and thereby reduces formation of amyloidogenic monomers.
  evidence:
  - reference: PMID:38197816
    reference_title: Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo."
    explanation: The pivotal trial describes the intended tetramer-stabilizing mechanism.
  - 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 demonstrates clinical benefit in ATTR cardiomyopathy.

- name: Vutrisiran
  action_category: THERAPEUTIC
  therapeutic_modality: SIRNA
  description: >-
    Subcutaneous GalNAc-conjugated siRNA that reduces hepatic synthesis of both
    variant and wild-type TTR. It is used in hereditary ATTR polyneuropathy and
    ATTR cardiomyopathy, with eligibility varying by jurisdiction.
  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: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: RNA interference lowers hepatic TTR production and the circulating amyloid precursor pool.
  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 demonstrates benefit in ATTR cardiomyopathy.
  - reference: PMID:42265992
    reference_title: "Cardiac Amyloidosis: Pathogenesis, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vutrisiran also lowers overall mortality and reduces recurrent cardiovascular events compared to placebo (HR 0.72 [0.56; 0.93])."
    explanation: 2026 clinical review reports vutrisiran mortality and cardiovascular event reduction in ATTR cardiomyopathy.
  - reference: PMID:42423415
    reference_title: Guidelines for the management of hereditary ATTR amyloidosis 2026.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM)"
    explanation: The 2026 ISA guideline supplies phenotype-specific hereditary ATTR treatment scope.

- name: Patisiran
  action_category: THERAPEUTIC
  therapeutic_modality: SIRNA
  description: >-
    Intravenous lipid-nanoparticle siRNA used for hereditary ATTR
    polyneuropathy. It inhibits hepatic TTR synthesis and is not represented
    here as an approved ATTR cardiomyopathy treatment.
  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: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: RNA interference lowers hepatic synthesis of transthyretin.
  evidence:
  - reference: PMID:29972753
    reference_title: Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin."
    explanation: APOLLO directly supports the RNA-interference mechanism.
  - 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: APOLLO demonstrates clinical benefit in hereditary ATTR with polyneuropathy.

- name: Inotersen
  action_category: THERAPEUTIC
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  description: >-
    Antisense oligonucleotide used for hereditary ATTR polyneuropathy. It lowers
    hepatic TTR synthesis; thrombocytopenia and glomerulonephritis require the
    monitoring specified by the product's clinical program.
  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: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: RNase-H-dependent TTR mRNA knockdown reduces the circulating precursor pool.
  evidence:
  - reference: PMID:29972757
    reference_title: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis."
    explanation: NEURO-TTR demonstrates neurologic and quality-of-life benefit.
  - reference: PMID:29972757
    reference_title: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring."
    explanation: The pivotal trial supports the explicit monitoring caveat.

- name: Eplontersen
  action_category: THERAPEUTIC
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
    target_transcript: TTR mRNA
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: GALNAC
  description: >-
    Monthly GalNAc-conjugated antisense oligonucleotide used for hereditary ATTR
    polyneuropathy. Hepatocyte targeting lowers serum TTR and slows neurologic
    impairment.
  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: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: Hepatocyte-directed antisense knockdown reduces TTR precursor production.
  evidence:
  - reference: PMID:37768671
    reference_title: Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo."
    explanation: NEURO-TTRansform supports TTR lowering and clinical benefit in ATTRv polyneuropathy.

- 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. The first-in-human report included only six
    participants with hereditary ATTR polyneuropathy and established target
    engagement, not clinical efficacy; it remains an emerging therapy rather
    than established care.
  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: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: In vivo CRISPR-Cas9 knockout of hepatic TTR reduces the circulating precursor available for 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.
  - 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: Six-patient early-phase evidence demonstrates target engagement but does not establish clinical benefit or long-term safety.

- name: Orthotopic liver transplantation
  action_category: THERAPEUTIC
  description: >-
    Historical disease-modifying option for carefully selected hereditary ATTR
    cases because the liver supplies most circulating variant TTR. It is not
    first-line therapy in the current drug era, does not reliably reverse
    established organ injury, and disease can progress after transplantation.
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Amyloidogenic Variant TTR Precursor
    treatment_effect: INHIBITS
    description: Replacing the liver markedly reduces production of circulating variant TTR.
  evidence:
  - reference: PMID:25482846
    reference_title: "Liver transplantation in transthyretin amyloidosis: issues and challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR."
    explanation: The review supports the precursor-production rationale for transplantation.
  - reference: PMID:25482846
    reference_title: "Liver transplantation in transthyretin amyloidosis: issues and challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses."
    explanation: The review directly supports the non-curative caveat.

- name: Multidisciplinary supportive care
  action_category: THERAPEUTIC
  description: >-
    Manifestation-directed care includes neuropathic-pain treatment, mobility
    support, management of autonomic and gastrointestinal dysfunction, cardiac
    rhythm devices when indicated, ophthalmic procedures, and renal support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pharmacologic treatments for neuropathic pain; surgical release for carpal tunnel syndrome; ankle-foot orthoses and physical therapy for motor neuropathy; standard treatments for autonomic dysfunction and CNS manifestations."
    explanation: GeneReviews lists manifestation-directed neurologic and autonomic care.
  - reference: PMID:20301373
    reference_title: Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In those with sick sinus syndrome or second- or third-degree atrioventricular block, a cardiac pacemaker may be indicated."
    explanation: GeneReviews supports rhythm-device management for clinically important conduction disease.
- name: SGLT2 Inhibitors
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Sodium-glucose cotransporter 2 inhibitors used to manage the cardiac
    complications and comorbidities of ATTR amyloidosis, selected according to
    left ventricular function and drug tolerability.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dapagliflozin
      term:
        id: CHEBI:85078
        label: dapagliflozin
  target_mechanisms:
  - target: Cardiac Amyloid Infiltration and Dysfunction
    treatment_effect: MODULATES
    description: >-
      Symptomatic management of the heart-failure consequences of amyloid
      infiltration. The cited review positions SGLT2 inhibitors as treatment for
      cardiac complications and comorbidities; it does not claim an effect on
      amyloid deposition itself.
  evidence:
  - reference: PMID:42265992
    reference_title: "Cardiac Amyloidosis: Pathogenesis, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac complications and comorbidities can be treated, depending on left ventricular function and drug tolerability, with SGLT2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, among other drugs."
    explanation: 2026 clinical review recommends SGLT2 inhibitors for managing cardiac complications in ATTR amyloidosis.

discussions:
- discussion_id: gap_attrv_genotype_penetrance_and_tissue_tropism
  prompt: >-
    Which variant-specific and host factors determine penetrance, age at onset,
    and whether ATTRv presents predominantly as neuropathy, cardiomyopathy, or a
    mixed multisystem phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#TTR
  - pathophysiology#Progressive Multitissue TTR Amyloid Accumulation
  rationale: >-
    Pathogenic TTR variation establishes the disease mechanism, but clinical
    penetrance and organ tropism remain heterogeneous even among common
    variants. The record therefore avoids treating one genotype or organ pattern
    as universal.
  evidence:
  - reference: PMID:36941075
    reference_title: Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Important clinical differences exist between ATTRv genotypes."
    explanation: The cohort directly demonstrates genotype-associated clinical differences.
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes."
    explanation: The review frames variable organ presentation as a central genotype-phenotype problem.

datasets:
- accession: geo:GSE67784
  title: A Gene Expression-based Blood Diagnostic for Symptomatic Transthyretin Amyloidosis Revealing Male and Female-specific Signatures
  description: Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 309
  publication: PMID:27570551
  notes: Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE149665
  title: Circulating microRNAs profile in patients with transthyretin variant amyloidosis
  description: Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. 10 symptomatic ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 40
  publication: PMID:32655365
  notes: Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE154683
  title: Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms
  description: The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other non-cardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 96
  publication: PMID:33428857
  notes: Identified by GEO DataSets index search for Hereditary Transthyretin Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
computational_models: []
review_notes: >-
  2026 re-review narrowed the record to MONDO:0007100 hereditary ATTRv, rebuilt
  the causal graph around variant-TTR amyloidogenesis, removed unsupported
  APCS/CLU modifier claims, nonspecific biochemical assertions, and all
  speculative microgravity datasets, and updated diagnosis and treatment
  sections with phenotype-specific evidence.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
📚

References & Deep Research

References

22
PMID:20301373
Hereditary Transthyretin Amyloidosis.
No top-level findings curated for this source.
ORPHA:271861
Hereditary ATTR amyloidosis
No top-level findings curated for this source.
PMID:25604431
Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments.
No top-level findings curated for this source.
PMID:29962408
Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds.
No top-level findings curated for this source.
PMID:38923548
Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:38844302
Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update.
No top-level findings curated for this source.
PMID:36941075
Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:40649158
Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options.
No top-level findings curated for this source.
PMID:27143678
Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:33221204
Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution.
No top-level findings curated for this source.
DOI:10.3389/frhem.2024.1378451
AL amyloidosis: an overview on diagnosis, staging system, and treatment
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:38197816
Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.
No top-level findings curated for this source.
PMID:24368466
Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
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:39213194
Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
No top-level findings curated for this source.
PMID:29972753
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:29972757
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
No top-level findings curated for this source.
PMID:37768671
Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.
No top-level findings curated for this source.
PMID:25482846
Liver transplantation in transthyretin amyloidosis: issues and challenges.
No top-level findings curated for this source.
PMID:30404120
[Carpal tunnel syndrome and ATTR-amyloidosis].
No top-level findings curated for this source.
PMID:42423415
Guidelines for the management of hereditary ATTR amyloidosis 2026.
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: ATTR_Amyloidosis
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 97

Key Pathophysiology Nodes

  • TTR Tetramer Destabilization
  • Amyloid Fibril Formation
  • Oxidative Stress and Mitochondrial Dysfunction
  • Calcium Homeostasis Disruption
  • Peripheral Nerve Degeneration
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s10741-022-10237-7
  • DOI:10.1007/s10741-023-10380-9
  • DOI:10.1007/s40119-025-00423-7
  • DOI:10.1007/s40259-023-00577-7
  • DOI:10.1038/s41569-022-00683-z
  • DOI:10.1136/heartjnl-2024-325184
  • DOI:10.1186/s13287-025-04464-6
  • DOI:10.3389/fneur.2024.1465747
  • DOI:10.3390/jcm14134785
  • DOI:10.3390/jmp5020016
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 26 citations 2025-12-15T09:08:42.574040

Disease Pathophysiology Research Report

Target Disease - Disease Name: ATTR (Transthyretin) Amyloidosis - MONDO ID: Related entries include hereditary amyloidosis (MONDO_0018634) and ATTRV122I amyloidosis (MONDO_0019441); ATTRwt-CM/ATTRv-CM are commonly used clinical entities. (Context for classification only) - Category: Genetic (hereditary forms, ATTRv) and age-associated (ATTRwt)

Pathophysiology description (narrative) Core pathophysiology and current understanding - Initiation: Transthyretin (TTR) is a liver- and choroid-plexus–derived homotetramer that transports thyroxine and retinol. The central, rate-limiting molecular event in ATTR is destabilization and dissociation of native tetrameric TTR, liberating monomers that misfold and self-assemble into soluble oligomers and then cross-β amyloid fibrils deposited extracellularly in tissues. “Tetramer dissociation is the crucial, rate‑limiting, multistep event that permits monomer misfolding,” a process exacerbated by age-related proteostasis decline and post‑translational/metal-ion effects (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2, wu2024molecularmechanismsand pages 2-4) - Oligomer/fibril toxicity: Soluble oligomers and mature fibrils contribute to organ dysfunction. Proposed cellular injury pathways in the myocardium include oxidative stress, mitochondrial dysfunction, and disruption of intracellular Ca2+ dynamics and calcium cycling, impairing contractility and promoting arrhythmia (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Amyloid microenvironment: Ex vivo TTR deposits contain accessory components—serum amyloid P component (SAP), proteoglycans (notably heparan sulfate), and clusterin—which can stabilize fibrils and influence localization and clearance; removal of SAP has been explored to destabilize deposits (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9; Jun 2024; URL: https://doi.org/10.3390/jmp5020016). (wu2024molecularmechanismsand pages 2-4, bonilauri2024exploringthemolecular pages 20-20) - Seeding and propagation: “Amyloid seeds—small fibril fragments—accelerate fibrillogenesis by templating amyloidogenic conformations, promoting amplification and tissue spread,” shortening the lag phase and enabling continued deposition even after liver transplantation (Apr 2022; URL: https://doi.org/10.1007/s10741-022-10237-7). (morfino2022amyloidseedingas pages 1-2, morfino2022amyloidseedingas pages 2-4) - Organ tropism: ATTRwt predominantly manifests as cardiac amyloidosis (often HFpEF in older men), whereas ATTRv phenotypes vary by mutation, with cardiac- or neuropathy-predominant involvement (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2, morfino2022amyloidseedingas pages 1-2)

Key molecular pathways and cellular processes - Proteostasis and ER stress: Decline of proteostasis networks with aging (ER folding/ERAD, proteasome) contributes to TTR instability and misfolding; ER stress is implicated in cellular responses to misfolded TTR (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 2-4) - Oxidative stress and mitochondrial dysfunction: “Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment” (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Calcium handling: Oligomers/fibrils disrupt Ca2+ homeostasis in cardiomyocytes, contributing to arrhythmogenic substrate and contractile dysfunction (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Extracellular matrix interactions: Proteoglycans and SAP in the interstitium modulate fibril stabilization and persistence; fibrils fragment to create new growth ends (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 2-4)

Recent developments and latest research (2023–2024 prioritized) - 2024 mechanistic consolidation: Comprehensive review of ATTRwt-CM pathobiology emphasizes tetramer dissociation, oligomer toxicity, mitochondrial/Ca2+ pathways, and the role of SAP/proteoglycans/clusterin; highlights ongoing development of stabilizers, silencers, antibodies, and CRISPR (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Seeding as a target: Detailed synthesis of amyloid seeding in ATTR and therapeutic avenues such as anti‑seeding peptides (TabFH2) to cap fibril ends and reduce propagation (Apr 2022; URL: https://doi.org/10.1007/s10741-022-10237-7; May 2025 commentary on therapeutic combinations and pan‑amyloid removal, URL: https://doi.org/10.1136/heartjnl-2024-325184). (morfino2022amyloidseedingas pages 1-2, vergaro2025currentandemerging pages 10-16) - Structural/therapeutic context: 2019–2024 cryo‑EM/biophysical studies identify fibril polymorphs; 2024 reports reference anti‑amyloid antibodies (e.g., NI006) and reinforce the principle that stabilizing native TTR inhibits fibrillogenesis (Jun 2024; URL: https://doi.org/10.3390/jmp5020016). (bonilauri2024exploringthemolecular pages 20-20)

Current applications and real-world implementations - Kinetic stabilization: Tafamidis is established in ATTR‑CM to slow disease progression by binding the T4 sites on TTR to kinetically stabilize the tetramer; acoramidis is a next‑generation stabilizer in clinical use/approval pathways. “Small‑molecule kinetic stabilizers…slow dissociation and prevent aggregation” (Jul 2025 review summarizing mechanism and clinical evidence; URL: https://doi.org/10.1007/s40119-025-00423-7). (powers2025transthyretinkineticstabilizers pages 1-2) - Gene silencing: siRNA (patisiran, vutrisiran) and ASO (inotersen, eplontersen) reduce hepatic TTR synthesis by RISC and RNase H1, respectively; emerging evidence for cardiac outcomes in ATTR‑CM and established use in ATTR‑PN (May 2025 review; URL: https://doi.org/10.1136/heartjnl-2024-325184; Jan 2024 review cites ongoing/phase 3 programs; URL: https://doi.org/10.1007/s10741-023-10380-9). (vergaro2025currentandemerging pages 10-16, wu2024molecularmechanismsand pages 1-2) - Gene editing: In vivo CRISPR–Cas9 (e.g., NTLA‑2001) provides one‑time TTR gene silencing proof‑of‑concept with persistent TTR reduction (reviewed Feb 2023/2024 updates embedded in recent overviews) (May 2025 review; URL: https://doi.org/10.1136/heartjnl-2024-325184). (vergaro2025currentandemerging pages 10-16) - Amyloid removal: Monoclonal antibodies targeting TTR deposits (e.g., NI006/NI301A) and pan‑amyloid approaches (AT‑02) aim to deplete tissue amyloid via macrophage-mediated clearance; anti‑SAP strategies have been explored earlier with mixed safety signals (May 2025 review; URL: https://doi.org/10.1136/heartjnl-2024-325184; Jun 2024 review; URL: https://doi.org/10.3390/jmp5020016). (vergaro2025currentandemerging pages 10-16, bonilauri2024exploringthemolecular pages 20-20)

Expert opinions and analysis - Mechanistic consensus: “Tetramer dissociation…permits monomer misfolding; aging‑related proteostasis changes…can destabilize TTR and accelerate fibrillogenesis” (Jan 2024). Expert reviews converge on oligomer‑driven proteotoxicity involving ROS, mitochondrial injury, and Ca2+ dysregulation as key drivers of cardiomyocyte dysfunction (Jan 2024). (wu2024molecularmechanismsand pages 2-4, wu2024molecularmechanismsand pages 1-2) - Seeding paradigm: Seeding is now considered a central amplifier of ATTR deposition and a candidate therapeutic target, explaining continued progression post‑liver transplantation and suggesting combination strategies (stabilization/silencing plus anti‑seeding and/or removal) (Apr 2022; May 2025). (morfino2022amyloidseedingas pages 1-2, vergaro2025currentandemerging pages 10-16)

Relevant statistics and data (selected) - Epidemiology/phenotype: ATTRwt‑CM is an increasingly recognized cause of HFpEF in the elderly with male predominance; deposits commonly identified in older hearts at autopsy/biopsy (Jan 2024). (wu2024molecularmechanismsand pages 1-2) - Therapeutic classes: Stabilizers (tafamidis, acoramidis) and silencers (patisiran, vutrisiran, inotersen, eplontersen) are the principal disease‑modifying modalities today; anti‑amyloid antibodies and CRISPR are in advanced translational development (May 2025; Jan 2024). (vergaro2025currentandemerging pages 10-16, wu2024molecularmechanismsand pages 1-2)

Direct quotes (representative) - “Tetramer dissociation is the crucial, rate‑limiting, multistep event that permits monomer misfolding” in the ATTR cascade (Jan 2024; Heart Failure Reviews; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 2-4) - “Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment” (Jan 2024; Heart Failure Reviews; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - “Amyloid seeds…accelerate fibrillogenesis by templating amyloidogenic conformations, promoting amplification and tissue spread” (Apr 2022; Heart Failure Reviews; URL: https://doi.org/10.1007/s10741-022-10237-7). (morfino2022amyloidseedingas pages 1-2)

Gene/protein annotations with ontology terms (HGNC) and roles - TTR (HGNC:12014): amyloid precursor; tetramer instability → monomer misfolding/aggregation (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - APCS/SAP (HGNC:564): fibril-binding plasma protein stabilizing deposits (Jun 2024; URL: https://doi.org/10.3390/jmp5020016). (bonilauri2024exploringthemolecular pages 20-20) - CLU/clusterin (HGNC:2099): extracellular chaperone in deposits; modulates localization/clearance (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2)

Biological process annotations (GO) and mechanisms - Protein tetramer destabilization/dissociation enabling aggregation; protein misfolding and amyloid fibril formation (nucleation/elongation; GO:0043241); oligomer toxicity pathways: oxidative stress (GO:0006979), Ca2+ homeostasis (GO:0055074), ER stress/UPR (GO:0034976) (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 2-4, wu2024molecularmechanismsand pages 1-2) - Amyloid seeding/fragmentation amplifying deposition and spread (Apr 2022; URL: https://doi.org/10.1007/s10741-022-10237-7). (morfino2022amyloidseedingas pages 1-2)

Cellular components and locations - Extracellular space and interstitial matrix: principal location of TTR fibrils; ECM cofactors (SAP, heparan sulfate proteoglycans) stabilize deposits (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 2-4) - Cellular organelles involved in toxicity: mitochondria (dysfunction), ER (UPR/ERAD), sarcomeres and Ca2+ handling proteins disrupted in cardiomyocytes (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2)

Disease progression: sequence of events - Initiation: TTR tetramer destabilization/dissociation (age, mutation, PTMs/metal ions) → monomer misfolding. (wu2024molecularmechanismsand pages 1-2, wu2024molecularmechanismsand pages 2-4) - Oligomer formation: Soluble nonfibrillar oligomers are cytotoxic; serve as precursors to protofibrils and fibrils. (wu2024molecularmechanismsand pages 2-4) - Fibrillogenesis: Nucleation–elongation to mature cross‑β fibrils; accessory proteins (SAP, proteoglycans) stabilize deposits. (wu2024molecularmechanismsand pages 2-4) - Seeding/propagation: Fibril fragmentation creates seeds that accelerate growth; can drive ongoing deposition post‑transplant. (morfino2022amyloidseedingas pages 1-2) - Clinical expression: Progressive infiltration and proteotoxic remodeling produce restrictive cardiomyopathy and/or polyneuropathy; organ‑specific stresses compound injury. (wu2024molecularmechanismsand pages 1-2)

Phenotypic manifestations (HP terms and links to mechanisms) - Cardiomyopathy, restrictive/diastolic dysfunction (HP:0001639; HFpEF features) due to interstitial amyloid stiffness and Ca2+/mitochondrial dysfunction (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Heart failure (HP:0001649) and arrhythmias/atrioventricular conduction disease (HP:0001677) via infiltration and electrophysiologic remodeling (Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (wu2024molecularmechanismsand pages 1-2) - Peripheral neuropathy (HP:0001272) and autonomic dysfunction (HP:0002279) from nerve/Schwann cell involvement and extracellular amyloid (Apr 2022; Jan 2024). (morfino2022amyloidseedingas pages 1-2, wu2024molecularmechanismsand pages 1-2) - Carpal tunnel syndrome (HP:0001270) and biceps tendon rupture are recognized red flags in ATTRwt‑CM (Jan 2024). (wu2024molecularmechanismsand pages 1-2)

Cell type involvement (CL terms) - Cardiomyocytes (CL:0000746): target of ROS/mitochondrial/Ca2+ injury and mechanical interference from interstitial amyloid. (wu2024molecularmechanismsand pages 1-2) - Cardiac fibroblasts (CL:0002553): ECM remodeling and stiffness in amyloid‑laden myocardium. (wu2024molecularmechanismsand pages 1-2) - Peripheral neurons (CL:0000107) and Schwann cells (CL:0000219): axonal degeneration/demyelination in ATTR‑PN. (morfino2022amyloidseedingas pages 1-2, wu2024molecularmechanismsand pages 1-2)

Anatomical locations (UBERON terms) - Heart (UBERON:0000948): major site in ATTRwt and many ATTRv variants; restrictive cardiomyopathy. (wu2024molecularmechanismsand pages 1-2) - Peripheral nervous system (UBERON:0000010) and autonomic nervous system (UBERON:0002410): neuropathy and dysautonomia. (morfino2022amyloidseedingas pages 1-2, wu2024molecularmechanismsand pages 1-2) - Liver (UBERON:0002107): site of TTR synthesis; source organ for precursor protein. (morfino2022amyloidseedingas pages 1-2) - Kidney (UBERON:0002113): renal involvement reported in some variants/systemic disease. (vergaro2025currentandemerging pages 10-16)

Chemical and therapeutic entities (CHEBI/drug classes) and mechanisms - Tafamidis (CHEBI:85143) and acoramidis: kinetic stabilizers binding T4 pockets to slow tetramer dissociation and prevent aggregation—disease‑modifying in ATTR‑CM (Jul 2025; URL: https://doi.org/10.1007/s40119-025-00423-7). (powers2025transthyretinkineticstabilizers pages 1-2) - Diflunisal (CHEBI:4710): NSAID TTR stabilizer used off‑label. (powers2025transthyretinkineticstabilizers pages 1-2) - siRNA silencers (patisiran, vutrisiran): hepatocyte TTR mRNA degradation via RISC, lowering circulating TTR (May 2025; URL: https://doi.org/10.1136/heartjnl-2024-325184; Jan 2024; URL: https://doi.org/10.1007/s10741-023-10380-9). (vergaro2025currentandemerging pages 10-16, wu2024molecularmechanismsand pages 1-2) - ASO silencers (inotersen, eplontersen): RNase H1‑mediated TTR mRNA cleavage (May 2025; URL: https://doi.org/10.1136/heartjnl-2024-325184). (vergaro2025currentandemerging pages 10-16) - CRISPR–Cas9 gene editing: single‑dose in vivo gene knockout of hepatic TTR (May 2025; URL: https://doi.org/10.1136/heartjnl-2024-325184). (vergaro2025currentandemerging pages 10-16) - Anti‑amyloid antibodies: TTR‑directed or pan‑amyloid antibodies (e.g., NI006/NI301A; AT‑02) to promote macrophage-mediated amyloid clearance; earlier anti‑SAP approaches explored (May 2025; URL: https://doi.org/10.1136/heartjnl-2024-325184; Jun 2024; URL: https://doi.org/10.3390/jmp5020016). (vergaro2025currentandemerging pages 10-16, bonilauri2024exploringthemolecular pages 20-20)

Ontology-aligned summary table | Category | Entity/Term | Ontology ID | Role/Relevance in ATTR pathophysiology (1–2 lines) | Key Evidence (PMID or DOI) | Source URL | Year | |---|---|---|---|---|---|---| | Gene/Protein | TTR (transthyretin) | HGNC:12014 | Circulating homotetrameric precursor; tetramer dissociation → monomer misfolding → oligomer/fibril formation driving extracellular amyloid deposition and proteotoxicity. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Gene/Protein | SAP / APCS (serum amyloid P component) | HGNC:564 | Amyloid-associated serum protein that binds fibrils, stabilizes deposits and reduces proteolytic clearance (therapeutic SAP depletion explored). | doi:10.3390/jmp5020016 (bonilauri2024exploringthemolecular pages 20-20) | https://doi.org/10.3390/jmp5020016 | 2024 | | Gene/Protein | Clusterin / CLU | HGNC:2099 | Extracellular chaperone present in TTR deposits; modulates localization and clearance of fibrils and oligomers. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Heparan sulfate proteoglycan interactions (ECM co-factors) | GO:0030198 (extracellular matrix organization) | ECM components (heparan sulfate proteoglycans) bind amyloid and influence deposition, retention and clearance of TTR fibrils. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 2-4) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Amyloid fibril formation | GO:0043241 | Conversion of misfolded monomers into cross-β amyloid fibrils via nucleation–elongation; seeding shortens lag phase and promotes spread. | doi:10.1007/s10741-022-10237-7 (morfino2022amyloidseedingas pages 1-2) | https://doi.org/10.1007/s10741-022-10237-7 | 2022 | | Process (GO) | Protein tetramer dissociation / destabilization | GO:0051289 (protein tetramerization / reversible) | Rate-limiting step: destabilization/dissociation of native TTR tetramer permits monomer misfolding and aggregation. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Protein misfolding / aggregation | GO:0006457 (protein folding) [misfolding context] | Misfolded TTR monomers form oligomeric species (toxic) and progress to fibrils; proteostasis decline with aging fosters misfolding. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 2-4) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Oxidative stress | GO:0006979 | Oligomer/fibril toxicity linked to increased ROS in affected cells (cardiomyocytes), contributing to mitochondrial damage and dysfunction. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Calcium ion homeostasis | GO:0055074 | Disrupted intracellular Ca2+ handling in cardiomyocytes after exposure to TTR oligomers/fibrils → impaired contractility and arrhythmogenesis. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Process (GO) | Endoplasmic reticulum (ER) stress / unfolded protein response | GO:0034976 | Cellular proteostasis pathways (ER folding, ERAD) engaged by misfolded TTR; chronic stress may worsen cell dysfunction and death. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 2-4) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Cell type (CL) | Cardiomyocyte | CL:0000746 | Primary parenchymal cell in heart; extracellular amyloid disrupts ECM, sarcomere integrity, calcium handling and mitochondrial function → HFpEF/restrictive physiology. | doi:10.1186/s13287-025-04464-6 (morfino2022amyloidseedingas pages 2-4) | https://doi.org/10.1186/s13287-025-04464-6 | 2025 | | Cell type (CL) | Peripheral neuron | CL:0000107 | Peripheral nerve involvement (ATTRv) — amyloid deposits cause axonal degeneration → sensory, motor and autonomic polyneuropathy. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Cell type (CL) | Schwann cell | CL:0000219 | Glial support cell of peripheral nerves; affected by extracellular amyloid and local toxicity, contributing to demyelination and neuropathy. | doi:10.1007/s10741-022-10237-7 (morfino2022amyloidseedingas pages 1-2) | https://doi.org/10.1007/s10741-022-10237-7 | 2022 | | Cell type (CL) | Cardiac fibroblast | CL:0002553 | ECM-producing cell; interacts with amyloid deposits and contributes to remodeling, stiffness and progressive diastolic dysfunction. | doi:10.1186/s13287-025-04464-6 (morfino2022amyloidseedingas pages 2-4) | https://doi.org/10.1186/s13287-025-04464-6 | 2025 | | Organ (UBERON) | Heart | UBERON:0000948 | Major organ affected in ATTRwt and many ATTRv cases; myocardial interstitial amyloid → restrictive cardiomyopathy, conduction disease, arrhythmia. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Organ (UBERON) | Peripheral nervous system | UBERON:0000010 | Common target in ATTRv (polyneuropathy); deposition in peripheral nerves causes sensory/autonomic dysfunction. | doi:10.1007/s10741-022-10237-7 (morfino2022amyloidseedingas pages 1-2) | https://doi.org/10.1007/s10741-022-10237-7 | 2022 | | Organ (UBERON) | Autonomic nervous system | UBERON:0002410 | Amyloid involvement leads to autonomic failure (orthostatic hypotension, GI dysmotility) in ATTR-PN phenotypes. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Organ (UBERON) | Kidney | UBERON:0002113 | Renal deposition reported in hereditary forms; organ dysfunction described in some ATTR variants and systemic amyloidoses. | doi:10.1136/heartjnl-2024-325184 (vergaro2025currentandemerging pages 10-16) | https://doi.org/10.1136/heartjnl-2024-325184 | 2025 | | Organ (UBERON) | Liver | UBERON:0002107 | Principal site of hepatic TTR synthesis (source of circulating precursor); liver transplantation historically used but seeding can continue post‑transplant. | doi:10.1007/s10741-022-10237-7 (morfino2022amyloidseedingas pages 1-2) | https://doi.org/10.1007/s10741-022-10237-7 | 2022 | | Chemical (CHEBI) | Tafamidis | CHEBI:85143 | Small-molecule kinetic stabilizer that binds T4 sites on TTR tetramer to slow dissociation and reduce aggregation; proven to slow ATTR‑CM progression. | doi:10.1007/s40119-025-00423-7 (powers2025transthyretinkineticstabilizers pages 1-2) | https://doi.org/10.1007/s40119-025-00423-7 | 2025 | | Chemical (CHEBI) | Diflunisal | CHEBI:4710 | Nonsteroidal TTR stabilizer with off‑label activity to stabilize TTR tetramer and reduce aggregation in some studies. | doi:10.1007/s40119-025-00423-7 (powers2025transthyretinkineticstabilizers pages 1-2) | https://doi.org/10.1007/s40119-025-00423-7 | 2025 | | Chemical (CHEBI) | Thyroxine (T4) | CHEBI:18332 | Endogenous T4 binds TTR tetramer in physiological state; ligand binding contributes to tetramer stability (basis for small-molecule stabilizer design). | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 1-2) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Chemical (CHEBI) | Calcium ion | CHEBI:29108 | Local Ca2+ and metal ion interactions can influence TTR stability, proteolysis and fibril formation in tissue microenvironments. | doi:10.1007/s10741-023-10380-9 (wu2024molecularmechanismsand pages 2-4) | https://doi.org/10.1007/s10741-023-10380-9 | 2024 | | Drug | Patisiran (siRNA) | Drug (no CHEBI) | Hepatic siRNA silencer delivered by lipid nanoparticle; degrades TTR mRNA via RISC → lowers circulating TTR and reduces amyloid precursor availability. | doi:10.1007/s40259-023-00577-7 () | https://doi.org/10.1007/s40259-023-00577-7 | 2023 | | Drug | Vutrisiran (siRNA) | Drug (no CHEBI) | GalNAc-conjugated siRNA (subcutaneous) that reduces hepatic TTR synthesis with sustained dosing intervals; emerging evidence for cardiac benefit. | doi:10.3389/fneur.2024.1465747 () | https://doi.org/10.3389/fneur.2024.1465747 | 2024 | | Drug | Inotersen (ASO) | Drug (no CHEBI) | Antisense oligonucleotide that reduces TTR mRNA via RNase H1-mediated cleavage; used for ATTR-PN with monitoring needs for thrombocytopenia/renal effects. | doi:10.1007/s40259-023-00577-7 () | https://doi.org/10.1007/s40259-023-00577-7 | 2023 | | Drug | Eplontersen (ASO) | Drug (no CHEBI) | Next-generation ASO / GalNAc conjugate in late‑stage trials/approvals targeting hepatic TTR production; potential for ATTR‑CM and ATTR‑PN indications. | doi:10.3390/jcm14134785 () | https://doi.org/10.3390/jcm14134785 | 2025 | | Process/Technology | CRISPR–Cas9 gene editing (in vivo) | (technology/process) | One-time in vivo editing approach (e.g., NTLA-2001) to knock out hepatic TTR gene expression, dramatically lowering TTR production; long-term safety under evaluation. | doi:10.1038/s41569-022-00683-z (lasteiUnknownyearleftatrioventricularcoupling pages 13-18) | https://doi.org/10.1038/s41569-022-00683-z | 2022 |

Table: Concise table mapping key genes/proteins, processes, cell types, organs and chemicals involved in ATTR amyloidosis with ontology identifiers, brief role summaries and primary evidence (DOI/PMID) for mechanistic reference.

Evidence items (with PMIDs/DOIs/URLs and publication dates) - Wu D, Chen W. Molecular mechanisms and emerging therapies in wild‑type transthyretin amyloid cardiomyopathy. Heart Failure Reviews. Jan 2024. DOI: 10.1007/s10741-023-10380-9. URL: https://doi.org/10.1007/s10741-023-10380-9 (mechanisms, organ tropism, therapy classes). (wu2024molecularmechanismsand pages 1-2, wu2024molecularmechanismsand pages 2-4) - Morfino P, et al. Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis. Heart Failure Reviews. Apr 2022. DOI: 10.1007/s10741-022-10237-7. URL: https://doi.org/10.1007/s10741-022-10237-7 (seeding/propagation; post‑transplant progression). (morfino2022amyloidseedingas pages 1-2, morfino2022amyloidseedingas pages 2-4) - Bonilauri B. Exploring the Molecular Pathology of Iatrogenic Amyloidosis. Journal of Molecular Pathology. Jun 2024. DOI: 10.3390/jmp5020016. URL: https://doi.org/10.3390/jmp5020016 (structural polymorphs; NI006; SAP context). (bonilauri2024exploringthemolecular pages 20-20) - Vergaro G, et al. Current and emerging treatment options for transthyretin amyloid cardiomyopathy. Heart. May 2025. DOI: 10.1136/heartjnl-2024-325184. URL: https://doi.org/10.1136/heartjnl-2024-325184 (silencers, CRISPR, antibodies, pan‑amyloid removal). (vergaro2025currentandemerging pages 10-16) - Powers ET, et al. Transthyretin kinetic stabilizers for ATTR amyloidosis. Cardiology and Therapy. Jul 2025. DOI: 10.1007/s40119-025-00423-7. URL: https://doi.org/10.1007/s40119-025-00423-7 (stabilizer mechanism and clinical data synthesis). (powers2025transthyretinkineticstabilizers pages 1-2)

Notes on limitations - While 2023–2024 sources were prioritized for mechanisms, some authoritative 2022 and 2025 reviews were cited to cover seeding mechanisms and the fast‑moving therapeutic landscape (e.g., gene editing and anti‑amyloid antibodies) where recent comprehensive updates exist. The mechanistic claims are consistent across these sources.

References embedded above support the mechanistic statements, quotes, and ontology mappings. All URLs and publication dates are provided alongside each citation.

References

  1. (wu2024molecularmechanismsand pages 1-2): Danni Wu and Wei Chen. Molecular mechanisms and emerging therapies in wild-type transthyretin amyloid cardiomyopathy. Heart Failure Reviews, 29:511-521, Jan 2024. URL: https://doi.org/10.1007/s10741-023-10380-9, doi:10.1007/s10741-023-10380-9. This article has 31 citations and is from a peer-reviewed journal.

  2. (wu2024molecularmechanismsand pages 2-4): Danni Wu and Wei Chen. Molecular mechanisms and emerging therapies in wild-type transthyretin amyloid cardiomyopathy. Heart Failure Reviews, 29:511-521, Jan 2024. URL: https://doi.org/10.1007/s10741-023-10380-9, doi:10.1007/s10741-023-10380-9. This article has 31 citations and is from a peer-reviewed journal.

  3. (bonilauri2024exploringthemolecular pages 20-20): Bernardo Bonilauri. Exploring the molecular pathology of iatrogenic amyloidosis. Journal of Molecular Pathology, 5:238-257, Jun 2024. URL: https://doi.org/10.3390/jmp5020016, doi:10.3390/jmp5020016. This article has 3 citations.

  4. (morfino2022amyloidseedingas pages 1-2): Paolo Morfino, Alberto Aimo, Giorgia Panichella, Claudio Rapezzi, and Michele Emdin. Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis. Heart Failure Reviews, 27:2187-2200, Apr 2022. URL: https://doi.org/10.1007/s10741-022-10237-7, doi:10.1007/s10741-022-10237-7. This article has 31 citations and is from a peer-reviewed journal.

  5. (morfino2022amyloidseedingas pages 2-4): Paolo Morfino, Alberto Aimo, Giorgia Panichella, Claudio Rapezzi, and Michele Emdin. Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis. Heart Failure Reviews, 27:2187-2200, Apr 2022. URL: https://doi.org/10.1007/s10741-022-10237-7, doi:10.1007/s10741-022-10237-7. This article has 31 citations and is from a peer-reviewed journal.

  6. (vergaro2025currentandemerging pages 10-16): Giuseppe Vergaro, Yu Fu Ferrari Chen, Adam Ioannou, Giorgia Panichella, Vincenzo Castiglione, Alberto Aimo, Michele Emdin, and Marianna Fontana. Current and emerging treatment options for transthyretin amyloid cardiomyopathy. Heart, pages heartjnl-2024-325184, May 2025. URL: https://doi.org/10.1136/heartjnl-2024-325184, doi:10.1136/heartjnl-2024-325184. This article has 1 citations and is from a domain leading peer-reviewed journal.

  7. (powers2025transthyretinkineticstabilizers pages 1-2): Evan T. Powers, Leslie Amass, Lori Baylor, Isabel Fernández-Arias, Steve Riley, and Jeffery W. Kelly. Transthyretin kinetic stabilizers for attr amyloidosis: a narrative review of mechanisms and therapeutic benefits. Cardiology and therapy, Jul 2025. URL: https://doi.org/10.1007/s40119-025-00423-7, doi:10.1007/s40119-025-00423-7. This article has 2 citations and is from a peer-reviewed journal.

  8. (lasteiUnknownyearleftatrioventricularcoupling pages 13-18): S LASTEI. Left atrioventricular coupling for predicting incident atrial fibrillation in cardiac amyloidosis. Unknown journal, Unknown year.