ATTR_Amyloidosis

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Classifications

Harrison's Chapter

◆

Subtypes

2

ATTRm (hereditary)

Caused by mutations in the TTR gene, leading to misfolded transthyretin proteins and amyloid deposits in various tissues.

Show evidence (4 references)

PMID:25604431 SUPPORT

"Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to..."

The literature clearly states that mutations in the TTR gene lead to the misfolding of transthyretin proteins, which then aggregate into amyloid fibrils, supporting the statement.

PMID:34518987 SUPPORT

"Heritable cardiac amyloidosis (CA) ... results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM)."

The literature confirms that hereditary cardiac amyloidosis results from the misfolding and accumulation of transthyretin due to mutations in the TTR gene.

PMID:30486687 SUPPORT

"Hereditary transthyretin (ATTRm) amyloidosis, formerly known as familial amyloid polyneuropathy, is a major type of hereditary systemic amyloidosis, in which the disease is caused by mutant transthyretin (TTR)."

The literature supports that hereditary ATTRm amyloidosis is caused by mutations in the TTR gene, which leads to the disease.

+ 1 more reference

ATTRwt (wild-type/senile)

Occurs without mutations in the TTR gene, commonly affecting older individuals, with amyloid deposits primarily in the heart.

Show evidence (5 references)

PMID:31731233 SUPPORT

"Wild-type ATTR amyloidosis (ATTR-wt) is characterized by the accumulation of amyloid in the heart, leading to fatal heart failure and arrhythmia."

The study confirms that ATTR-wt occurs without mutations in the TTR gene and primarily affects the heart in older individuals.

PMID:26048914 SUPPORT

"The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. ... The predominant effect of ATTRwt amyloidosis is on the heart"

The literature supports that ATTRwt occurs without mutations in the TTR gene and primarily affects the heart, commonly in older individuals.

PMID:34390072 SUPPORT

"Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner."

The study confirms that ATTRwt affects older individuals and involves amyloid deposits in the heart.

+ 2 more references

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Pathophysiology

5

TTR Tetramer Destabilization

Mutations in the TTR gene or age-related changes destabilize the native tetrameric structure, leading to dissociation into monomers. This is the rate-limiting step enabling protein misfolding and aggregation.

protein tetramerization link protein folding link

extracellular space link blood plasma link

Downstream

Amyloid Fibril Formation Tetramer dissociation exposes unstable monomers that misfold and aggregate into amyloid fibrils.

Show evidence (5 references)

PMID:34884963 SUPPORT

"Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues."

The abstract mentions that TTR amyloidogenesis involves the formation and aggregation of amyloid fibrils, which supports the statement that mutations in the TTR gene result in the production of unstable transthyretin proteins that misfold and aggregate into amyloid fibrils.

PMID:35830843 PARTIAL

"Familial amyloid polyneuropathy is currently prevalent worldwide as the transthyretin (TTR) Val30Met mutation, and there are other types of mutations."

This reference supports the statement by mentioning that familial amyloid polyneuropathy is caused by mutations in the TTR gene, which is consistent with the production of unstable transthyretin proteins that misfold and aggregate.

PMID:38844302 PARTIAL

"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."

This reference supports the statement by explaining that hereditary transthyretin-related amyloidosis is caused by pathogenic variants in the TTR gene.

+ 2 more references

Amyloid Fibril Formation

Misfolded transthyretin monomers undergo nucleation and elongation to form cross-beta amyloid fibrils. Serum amyloid P component and proteoglycans stabilize deposits and reduce clearance.

amyloid fibril formation link extracellular matrix organization link

extracellular space link heart link peripheral nervous system link

Downstream

Cardiac and Neurological Dysfunction Extracellular deposition of misfolded transthyretin monomers as insoluble amyloid fibrils causes cardiomyopathy and polyneuropathy.

Oxidative Stress and Mitochondrial Dysfunction Amyloid oligomers and fibrils induce cardiomyocyte ROS generation and mitochondrial injury.

Calcium Homeostasis Disruption Amyloid infiltration perturbs calcium handling and electrical stability in cardiac myocytes.

Peripheral Nerve Degeneration Endoneurial amyloid deposition drives progressive axonal injury and demyelination.

Cardiomyopathy Cardiac amyloid infiltration stiffens myocardium and impairs systolic/diastolic performance.

Peripheral Neuropathy Amyloid toxicity in peripheral nerves produces length-dependent sensorimotor neuropathy.

Carpal Tunnel Syndrome Amyloid deposition in the transverse carpal ligament and flexor retinaculum compresses median nerve.

Gastrointestinal Symptoms Enteric autonomic neuropathy and tissue amyloid deposition impair motility and absorption.

Renal Dysfunction Renal interstitial and vascular amyloid deposition contributes to declining kidney function.

Vitreous Opacities Ocular transthyretin amyloid accumulation causes progressive vitreous clouding.

Show evidence (4 references)

PMID:31452023 PARTIAL

"fibrillar deposits in a several organs including the heart, kidney, liver, and peripheral nerves cause organ dysfunction and associated morbidity and mortality."

The reference supports that amyloid fibrils deposit in the heart, kidney, and peripheral nerves, but does not mention the gastrointestinal tract.

PMID:15126690 PARTIAL

"It is possible that a common factor in the amyloidogenesis process exists among the different forms; this common factor can involve changes produced by mutations in the three-dimensional structure of TTR, rendering it prone to deposition as amyloid."

The reference supports that misfolded transthyretin proteins form amyloid fibrils but does not specify all the tissues mentioned in the statement.

PMID:34018852 PARTIAL

"Age-related wild-type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to cardiac dysfunction, which is a significant cause of age-related heart failure."

The reference supports that amyloid fibrils deposit in the heart and connective tissue, but does not mention the nerves, kidneys, or gastrointestinal tract.

+ 1 more reference

Oxidative Stress and Mitochondrial Dysfunction

TTR oligomers and fibrils induce reactive oxygen species production and impair mitochondrial function in cardiomyocytes, contributing to contractile dysfunction and cell injury.

cardiomyocyte link

response to oxidative stress link mitochondrion organization link

heart link

Downstream

Cardiomyopathy Oxidative mitochondrial injury reduces contractile reserve and accelerates myocardial dysfunction.

Heart Failure Progressive cardiomyocyte energy failure contributes to symptomatic heart failure.

Calcium Homeostasis Disruption

Amyloid deposits disrupt intracellular calcium handling in cardiomyocytes, impairing contractility and promoting arrhythmogenesis.

cardiomyocyte link

calcium ion homeostasis link

heart link

Downstream

Arrhythmias Calcium-handling instability promotes atrial and ventricular rhythm disturbances.

Heart Failure Impaired excitation-contraction coupling worsens pump failure.

Peripheral Nerve Degeneration

Amyloid deposition in peripheral nerves causes axonal degeneration and demyelination, affecting sensory, motor, and autonomic functions.

peripheral neuron link Schwann cell link

axonogenesis link myelination link

peripheral nervous system link

Downstream

Peripheral Neuropathy Axonal loss and demyelination manifest as progressive polyneuropathy.

Sensory Loss Sensory fiber degeneration causes distal loss of vibration and pain perception.

Numbness and Tingling Irritable and degenerating peripheral nerves produce paresthesias.

Autonomic Dysfunction Autonomic fiber involvement leads to widespread dysautonomia.

Orthostatic Hypotension Autonomic denervation of vascular tone control causes postural blood pressure drops.

Fatigue Combined neuromuscular and autonomic impairment contributes to chronic fatigue.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Target 'Cardiac and Neurological Dysfunction' (from 'Amyloid Fibril Formation') not found in named elements

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Phenotypes

13

Cardiovascular 4

Cardiomyopathy FREQUENT Cardiomyopathy (HP:0001638)

Sequelae: Heart Failure Arrhythmias Orthostatic Hypotension

Show evidence (5 references)

PMID:34694575 NO_EVIDENCE

"The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans."

The reference discusses the increased recognition and diagnosis of ATTR cardiac amyloidosis, supporting the statement that it is frequently diagnosed as a cardiovascular condition.

PMID:35235819 SUPPORT

"Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction."

This reference supports the statement by listing heart failure, arrhythmias, and autonomic dysfunction (which includes orthostatic hypotension) as common sequelae of cardiac amyloidosis.

PMID:38044190 SUPPORT

"Patients with TTRA had higher levels of ultrasensitive troponin I (TnI-US) and N-terminal brain natriuretic propeptide (NT-ProBNP); in electrocardiography (ECG) they presented a pseudo-infarction pattern more frequently as well as conduction disturbances."

The reference supports the frequent occurrence of cardiovascular manifestations in ATTR amyloidosis, including cardiomyopathy and arrhythmias.

+ 2 more references

Heart Failure FREQUENT Congestive heart failure (HP:0001635)

Progressive infiltrative cardiomyopathy leading to diastolic and systolic dysfunction

Arrhythmias FREQUENT Arrhythmia (HP:0011675)

Atrial fibrillation, conduction abnormalities, and ventricular arrhythmias

Orthostatic Hypotension FREQUENT Orthostatic hypotension (HP:0001278)

Drop in blood pressure upon standing due to autonomic neuropathy

Eye 1

Vitreous Opacities OCCASIONAL Peripheral vitreous opacities (HP:0007710)

Can lead to visual impairment

Show evidence (2 references)

PMID:28085522 SUPPORT

"We report on two elderly patients (an 80-year-old woman and an 83-year-old man) with progressive vitreous opacities (VOs) as the initial manifestation of hereditary transthyretin (ATTR Val30Met) carries, who had no evidence of systemic involvement or family history of amyloidosis and lived in..."

The reference provides evidence that vitreous opacities can be an initial manifestation in patients with hereditary transthyretin amyloidosis (ATTR Val30Met), supporting the statement that vitreous opacities occur occasionally in ATTR amyloidosis.

PMID:36129270 SUPPORT

"However, 3 patients (43%) had worsening vitreous opacities in both eyes, and 4 patients (57%) developed secondary open-angle glaucoma."

The reference indicates that vitreous opacities were observed and worsened in some patients with ATTR amyloidosis, supporting the statement that vitreous opacities can occur occasionally in ATTR amyloidosis and lead to visual impairment.

Genitourinary 1

Renal Dysfunction OCCASIONAL Renal insufficiency (HP:0000083)

Due to amyloid deposition in the kidneys, can lead to proteinuria and renal failure

Show evidence (2 references)

PMID:22537653 SUPPORT

"Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features."

The reference confirms that renal dysfunction, including proteinuria, is a clinical feature of transthyretin amyloidosis (ATTR).

PMID:37997196 SUPPORT

"Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy that commonly presents with concomitant chronic kidney disease."

The reference supports the statement by indicating that chronic kidney disease, which encompasses renal dysfunction, is commonly associated with transthyretin cardiac amyloidosis (ATTR-CA).

Nervous System 4

Peripheral Neuropathy FREQUENT Peripheral neuropathy (HP:0009830)

Sequelae: Sensory Loss Numbness and Tingling Autonomic Dysfunction

Show evidence (4 references)

PMID:23239211 SUPPORT

"Peripheral neuropathy is a common complication of many of the systemic amyloidoses."

The literature indicates that peripheral neuropathy is a common complication of amyloidoses, which includes ATTR amyloidosis.

PMID:35830843 SUPPORT

"The clinical manifestations of this mutation involve mainly limb sensory or motor disorders or gastrointestinal symptoms or both, and the electrophysiological examination shows neurogenic damage."

This study indicates that peripheral neuropathy, including sensory and motor disorders, is a frequent manifestation in patients with the TTR Val30Leu mutation, a form of familial amyloid polyneuropathy.

PMID:31445300 SUPPORT

"Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and..."

The literature confirms that hATTR amyloidosis frequently involves polyneuropathy, including sensory loss, numbness, tingling, and autonomic dysfunction.

+ 1 more reference

Sensory Loss FREQUENT Somatic sensory dysfunction (HP:0003474)

Loss of sensation, particularly in extremities, due to peripheral nerve damage

Numbness and Tingling FREQUENT Paresthesia (HP:0003401)

Paresthesias in hands and feet as early manifestation of neuropathy

Autonomic Dysfunction FREQUENT Abnormal autonomic nervous system physiology (HP:0012332)

Includes orthostatic hypotension, gastroparesis, bladder dysfunction

Constitutional 1

Fatigue FREQUENT Fatigue (HP:0012378)

Can be severe and limit activities of daily living

Show evidence (4 references)

PMID:35144512 PARTIAL

"Patients often reported problems with mobility, usual activities, pain/discomfort and anxiety/depression, but not with self-care."

The literature indicates that systemic amyloidosis, including ATTR, frequently impacts daily life and mobility, which can be associated with fatigue.

PMID:31445300 NO_EVIDENCE

"It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction."

The literature describes ATTR amyloidosis as a multisystem disease, which can imply the presence of fatigue due to its systemic impact.

PMID:33609196 NO_EVIDENCE

"Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function."

The progressive loss of function in various organs and tissues can lead to severe fatigue, limiting activities of daily living.

+ 1 more reference

Other 2

Gastrointestinal Symptoms FREQUENT

Include nausea, diarrhea, constipation, and weight loss

Show evidence (5 references)

PMID:25908211 SUPPORT

"Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality."

The study highlights that gastrointestinal manifestations are common in hereditary ATTR amyloidosis, supporting the statement that gastrointestinal symptoms are frequent in this condition.

PMID:32176096 SUPPORT

"Transthyretin amyloid (ATTR) amyloidosis is a rare systemic disorder characterized by amyloid deposits formed by misfolded monomers of the transthyretin. Gastrointestinal (GI) manifestations are common in ATTR amyloidosis; however, their pathogenesis is not fully elucidated."

This reference supports the frequency of gastrointestinal symptoms in ATTR amyloidosis, aligning with the statement.

PMID:37844979 NO_EVIDENCE

"In the early stages of amyloidosis, gastrointestinal (GI) symptoms are uncommon. We describe a rare case of hereditary transthyretin amyloidosis (ATTRv) with involvement of the heart, nervous system and GI tract."

Although it mentions that GI symptoms are uncommon in the early stages, it describes a case with significant GI involvement, supporting the statement about frequent GI symptoms in later stages.

+ 2 more references

Carpal Tunnel Syndrome OCCASIONAL

Due to amyloid deposition in the wrist

Show evidence (2 references)

PMID:30404120 SUPPORT

"One cause for a carpal tunnel syndrome is transthyretin (ATTR) amyloid, which deposits in the carpal tunnel tissue."

The article states that ATTR amyloid deposits in the carpal tunnel tissue can cause carpal tunnel syndrome, supporting the statement that ATTR amyloidosis can occasionally cause this musculoskeletal condition.

PMID:33443391 SUPPORT

"Common orthopaedic manifestations of amyloidosis include carpal tunnel syndrome, trigger finger, spontaneous distal biceps tendon rupture, rotator cuff disease, and lumbar spinal stenosis."

The article mentions carpal tunnel syndrome as a common orthopedic manifestation of amyloidosis, supporting the statement that ATTR amyloidosis can occasionally cause this condition due to amyloid deposition in the wrist.

🧬

Genetic Associations

3

TTR (Pathogenic Variants)

Show evidence (3 references)

PMID:38844302 SUPPORT

"More than 140 TTR gene variants have been associated with hATTR, with the Val30Met variant representing the most common worldwide."

This reference supports the association of the Val30Met variant with ATTR amyloidosis.

PMID:24555660 SUPPORT

"A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area."

This reference supports the statement about the variable frequency of the Val30Met variant by population.

PMID:36941075 SUPPORT

"Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation."

This reference supports the statement about the variable frequency of pathogenic variants by population.

APCS (Modifying Factor)

CLU (Modifying Factor)

💊

Treatments

6

Tafamidis

Action: pharmacotherapy MAXO:0000058

Agent: tafamidis ↗

Helps stabilize transthyretin and prevent amyloid fibril formation.

🔬 3D Structures:

3TCT X-ray 1.85 Å ⚗️ tafamidis

Tafamidis bound to wild-type human transthyretin tetramer, showing drug occupancy in the T4-binding channel that stabilizes the quaternary structure

4HIQ X-ray 1.55 Å ⚗️ tafamidis

TTR tetramer with tafamidis bound, alternative crystal form showing detailed drug-protein contacts at the inner binding cavity

Show evidence (5 references)

PMID:25872787 SUPPORT

"Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated."

The study shows that tafamidis effectively stabilizes TTR, supporting the statement that it helps stabilize transthyretin.

PMID:31098895 SUPPORT

"Tafamidis slowed deterioration of neurological function and maintained health-related quality of life in patients with early-stage ATTR-PN... TTR tetramers were stabilized in nearly all patients."

The evidence indicates that tafamidis stabilizes TTR tetramers, supporting the statement.

PMID:26800456 SUPPORT

"Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease."

The study supports that tafamidis is effective in stabilizing TTR and preventing amyloid fibril formation.

+ 2 more references

Patisiran

Action: pharmacotherapy MAXO:0000058

Agent: patisiran ↗

Reduces production of transthyretin protein to decrease amyloid formation.

Show evidence (3 references)

PMID:30480471 SUPPORT

"Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein."

The abstract clearly states that patisiran reduces the production of transthyretin protein, which aligns with the statement.

PMID:37599395 SUPPORT

"Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv)."

The abstract mentions that patisiran, as an RNAi therapeutic, benefits patients with hereditary transthyretin amyloidosis, indicating its role in reducing transthyretin protein production.

PMID:31131842 SUPPORT

"Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both..."

The abstract explicitly states that patisiran targets and degrades transthyretin mRNA, thus reducing the production of transthyretin protein.

Inotersen

Action: pharmacotherapy MAXO:0000058

Agent: inotersen ↗

Reduces TTR protein production to limit amyloid accumulation.

Show evidence (3 references)

PMID:30561247 SUPPORT

"Inotersen/Tegsedi (Akcea Therapeutics, MA, USA) is a second-generation antisense oligonucleotide (ASO) specific for TTR that inhibits production of TTR by the liver."

The reference confirms that Inotersen reduces TTR protein production by inhibiting its production in the liver, which aligns with the statement.

PMID:37599395 SUPPORT

"'Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv)."

The reference supports that Inotersen is used to treat ATTR amyloidosis and implies its role in reducing TTR protein production.

PMID:31343345 SUPPORT

"Inotersen treatment for ATTR amyloidosis."

This reference title directly states that Inotersen is used for the treatment of ATTR amyloidosis, implying its role in reducing TTR protein production.

Liver Transplant

Action: organ transplantation MAXO:0010039

Considered for hereditary cases to reduce production of mutant TTR.

Show evidence (2 references)

PMID:25482846 SUPPORT

"Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR."

The literature supports liver transplantation as a therapy to address the production of unstable TTR in hereditary ATTR amyloidosis.

PMID:23797140 SUPPORT

"Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms."

This reference supports the use of liver transplantation to reduce the production of mutant TTR in hereditary cases of ATTR amyloidosis.

Heart Transplant

Action: organ transplantation MAXO:0010039

May be necessary for those with severe cardiomyopathy.

Show evidence (3 references)

PMID:32304420 SUPPORT

"However, the end-stage heart failure is common and HTx could be offered to selected patients, especially if affected by light chain cardiac amyloidosis, to allow to perform the autologous stem cell transplantation after the cardiac transplant."

The statement is supported as heart transplantation is mentioned as a treatment for end-stage heart failure in patients with cardiac amyloidosis.

PMID:33621542 SUPPORT

"Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure."

The statement is supported as orthotopic heart transplantation is identified as a definitive treatment for end-stage heart failure in amyloid cardiomyopathy patients.

PMID:34922822 SUPPORT

"Heart Transplantation (HT) is a rational therapy for advanced transthyretin cardiac amyloidosis (ATTR-CA)..."

The statement is supported as heart transplantation is described as a rational therapy for advanced transthyretin cardiac amyloidosis.

Supportive Care

Action: supportive care MAXO:0000950

Symptomatic treatment for neuropathy, heart failure, and gastrointestinal issues.

Show evidence (4 references)

PMID:33099432 SUPPORT

"Supportive care manages the symptoms of organ involvement and the side effects of treatment."

The reference indicates that supportive care is used to manage the symptoms of organ involvement, which can include neuropathy, heart failure, and gastrointestinal issues.

PMID:35235819 PARTIAL

"Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction."

The reference highlights the management of cardiovascular symptoms in cardiac amyloidosis, which is part of supportive care.

PMID:35104443 NO_EVIDENCE

"Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues... The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy."

The reference discusses the management of neuromuscular complications, including neuropathy, which is part of supportive care.

+ 1 more reference

🌍

Environmental Factors

1

None Applicable

Show evidence (2 references)

PMID:21463231 REFUTE

"Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP."

The statement that ATTR amyloidosis is 'None Applicable' is incorrect as it is associated with specific conditions such as familial amyloid polyneuropathy.

PMID:37907148 REFUTE

"CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA)."

The statement 'None Applicable' is incorrect because ATTR amyloidosis is a recognized condition included in the Cardiac Amyloidosis Registry Study.

🔬

Biochemical Markers

2

Serum Transthyretin Levels (Abnormal (low))

Context: Diagnostic indicator

Show evidence (1 reference)

PMID:32356182 PARTIAL

"Lower levels of transthyretin and retinol binding protein-4 have been demonstrated in patients with pathogenic mutations of transthyretin either with or without clinical disease."

The literature indicates that lower levels of transthyretin are associated with transthyretin amyloidosis, supporting the statement that abnormal (low) serum transthyretin levels can be a diagnostic indicator.

Amyloid P Component (Elevated)

Show evidence (1 reference)

PMID:12394612 PARTIAL

"Radiolabelled serum amyloid P component scintigraphy is a non-invasive and quantitative method for imaging amyloid deposits, which produces diagnostic images in most patients with systemic amyloidosis, and can be used repeatedly to monitor the course of the disease."

The reference indicates that serum amyloid P component scintigraphy can be used to monitor the course of systemic amyloidosis, but it does not specify whether the levels of amyloid P component are elevated in ATTR amyloidosis.

📊

Related Datasets

10

Rodent Research Reference Mission-1 (RRRM-1) liver transcriptomics genelab:OSD-379

RNA-Seq transcriptional profiling of livers from mice flown on RRRM-1 aboard the ISS. Liver is the primary site of transthyretin (TTR) synthesis; spaceflight-induced hepatic transcriptomic changes may reveal alterations in TTR expression and protein quality control.

mouse BULK RNA SEQ Illumina NovaSeq

liver tissue

Conditions: spaceflight ground control

Exposures: spaceflight

NASA OSDR OSD-379. 40 female BALB/cAnNTac mice, ISS 22-40 days. Liver is the main organ producing TTR; spaceflight transcriptomic changes here are directly relevant to ATTR amyloidosis pathogenesis.

Rodent Research-1 (RR1) mouse soleus muscle transcriptomics and epigenomics genelab:OSD-104

RNA-Seq and whole-genome bisulfite sequencing of mouse soleus muscle from the RR-1 NASA Validation Flight on ISS. Hindlimb unloading studies have shown transthyretin dysregulation in soleus muscle, making this spaceflight dataset relevant to understanding TTR behavior under microgravity-induced muscle atrophy.

mouse BULK RNA SEQ Illumina

soleus muscle

Conditions: spaceflight ground control

Exposures: spaceflight

NASA OSDR OSD-104. 37 days ISS microgravity. TTR was found dysregulated in mouse soleus after hindlimb unloading (PMID:25656502), making this spaceflight muscle dataset directly relevant.

Rodent Research-7 (RR-7) mouse kidney transcriptomics genelab:OSD-253

RNA-Seq transcriptional analysis of kidneys from mice flown on the RR-7 mission aboard the ISS. Kidney is a major site of ATTR amyloid deposition and renal involvement is a recognized complication of systemic transthyretin amyloidosis.

mouse BULK RNA SEQ Illumina NovaSeq

kidney tissue

Conditions: spaceflight ground control

Exposures: spaceflight

NASA OSDR OSD-253. Kidney is a major site of ATTR amyloid deposition; spaceflight kidney transcriptomics may reveal changes relevant to renal amyloidosis pathophysiology.

Characterization of amyloid-beta fibril formation under microgravity conditions DOI:10.1038/s41526-020-0107-y

JAXA ISS experiment (Kibo module) characterizing amyloid-beta(1-40) fibril formation under microgravity. Fibrilization progressed much more slowly on ISS than on the ground, and microgravity promoted distinct fibril morphologies. Findings are mechanistically relevant to TTR amyloidogenesis since both involve cross-beta spine amyloid fibril assembly.

in vitro PROTEOMICS

amyloid-beta protein

Conditions: microgravity ground control (1g)

Exposures: spaceflight

PMID:32566742

JAXA Kibo module experiment Dec 2017-Jan 2018. First demonstration that microgravity slows amyloid fibrilization and alters fibril morphology. Directly applicable to understanding TTR amyloid formation mechanisms.

Show evidence (1 reference)

PMID:32566742 SUPPORT In Vitro

"the Aβ(1-40) fibrilization progresses much more slowly on the ISS than on the ground, similarly to protein crystallization. Furthermore, microgravity promoted the formation of distinct morphologies of Aβ(1-40) fibrils."

Demonstrates that microgravity significantly alters amyloid fibril formation kinetics and morphology. Since TTR amyloidogenesis shares the same cross-beta spine fibril assembly mechanism, these findings suggest microgravity could similarly affect TTR fibril formation.

Amyloidogenesis via interfacial shear in a containerless biochemical reactor aboard the ISS DOI:10.1038/s41526-022-00227-2

Ring-Sheared Drop (RSD) experiment on ISS studying insulin amyloidogenesis in microgravity. Examined nucleation, fibrillization, and gelation of a model amyloidogenic protein in a containerless reactor, eliminating solid boundary effects. Methodology directly transferable to TTR amyloid studies.

in vitro PROTEOMICS

insulin protein

Conditions: microgravity ground analog

Exposures: spaceflight

PMID:36127358

NASA Ring-Sheared Drop (RSD) experiment. Containerless biochemical reactor eliminates solid boundaries, isolating air-liquid interface effects on amyloid fibril formation.

Transcriptomic effects on the mouse heart following 30 days on the ISS DOI:10.3390/biom13020371

RNA sequencing of mouse hearts after 30 days on ISS. Found 1147 significantly regulated transcripts with MAPK, PI3K-Akt, and GPCR pathway activation. Relevant to ATTR cardiomyopathy as spaceflight cardiac remodeling shares pathways with amyloid-induced cardiac dysfunction.

mouse BULK RNA SEQ

heart tissue

Conditions: spaceflight ground control

Exposures: spaceflight

PMID:36830740

30-day ISS mission. C57BL/6J female mice. Cytoskeleton breakdown and reorganization transcripts upregulated, relevant to understanding cardiac structural changes in ATTR cardiomyopathy.

Show evidence (1 reference)

PMID:36830740 SUPPORT Model Organism

"Our analyses showed that 1147 transcripts were significantly regulated after spaceflight. The MAPK, PI3K-Akt, and GPCR signaling pathways were predicted to be activated."

Spaceflight-induced cardiac transcriptomic changes in MAPK and PI3K-Akt pathways overlap with pathways implicated in ATTR cardiomyopathy progression and cardiac remodeling.

Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform DOI:10.1073/pnas.2404644121

Engineered human heart tissues (EHTs) flown to ISS for 1 month. Spaceflight EHTs showed reduced twitch forces, increased arrhythmias, sarcomere disruption, and mitochondrial damage. Transcriptomics showed upregulation of heart failure, oxidative stress, and inflammation genes. Directly relevant to ATTR cardiomyopathy pathophysiology.

human BULK RNA SEQ

engineered heart tissue

Conditions: spaceflight ground control

Exposures: spaceflight

PMID:39312653

Automated heart-on-a-chip platform. Transcriptomics showed upregulation of metabolic disorders, heart failure, oxidative stress, and inflammation pathways with downregulation of contractility and calcium signaling genes.

Show evidence (1 reference)

PMID:39312653 SUPPORT In Vitro

"Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage."

Spaceflight-induced cardiac dysfunction including arrhythmias, sarcomere disruption, and mitochondrial damage parallels the cardiac pathology seen in ATTR cardiomyopathy, where amyloid infiltration causes similar contractile and structural dysfunction.

Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy DOI:10.1002/jcsm.13146

Mass spectrometry-based plasma proteomics during 10-day bed rest (spaceflight analogue). Transthyretin was significantly less abundant in subjects who developed muscle atrophy, identifying TTR as a potential biomarker for unloading-induced atrophy relevant to both spaceflight and ATTR amyloidosis.

human PROTEOMICS

blood plasma

Conditions: bed rest (spaceflight analogue) baseline

Exposures: bed rest

PMID:36517414

10-day bed rest study in 10 young males. TTR identified among 6 proteins distinguishing atrophy-prone from atrophy-resistant subjects. Bed rest is a standard ground-based spaceflight analogue.

Show evidence (1 reference)

PMID:36517414 SUPPORT Human Clinical

"transthyretin, a thyroid hormone-binding protein, was significantly less abundant at BR10 in the plasma of subjects with muscle atrophy compared with those with no atrophy (1.6E10 vs. 2.6E10, P = 0.001)"

Demonstrates that plasma TTR levels are significantly altered during simulated microgravity (bed rest), with lower TTR associated with muscle atrophy. Changes in circulating TTR concentration could affect amyloid fibril formation dynamics in ATTR amyloidosis.

Proteomic analysis of mouse soleus muscles affected by hindlimb unloading and reloading DOI:10.1002/mus.24590

Proteomic analysis of mouse soleus muscle subjected to hindlimb unloading (spaceflight analogue) and reloading. Transthyretin was among key dysregulated proteins, alongside fatty acid binding protein 3 and alpha-B crystallin.

mouse PROTEOMICS

soleus muscle

Conditions: hindlimb unloading (spaceflight analogue) hindlimb reloading control

Exposures: hindlimb unloading

PMID:25656502

Hindlimb unloading is a standard ground-based spaceflight analogue. 9 down-regulated and 7 up-regulated proteins identified in unloaded soleus, with TTR among the key dysregulated proteins.

Show evidence (1 reference)

PMID:25656502 SUPPORT Model Organism

"Among the dysregulated proteins were fatty acid binding protein 3, α-B crystalline, and transthyretin."

Direct evidence that TTR protein levels are dysregulated in muscle tissue under simulated microgravity conditions (hindlimb unloading). TTR dysregulation in peripheral tissues is directly relevant to ATTR amyloidosis pathogenesis.

Urine proteome changes associated with autonomic regulation of heart rate in cosmonauts DOI:10.1186/s12918-019-0688-9

Urine proteomics of cosmonauts before and after long-duration spaceflight. Transthyretin was among proteins with significantly different concentrations between groups with different cardiovascular autonomic regulation, linking TTR to spaceflight cardiovascular adaptation.

human PROTEOMICS

urine

Conditions: pre-spaceflight post-spaceflight

Exposures: spaceflight

PMID:30836973

Long-duration spaceflight cosmonauts. TTR linked to cardiovascular homeostasis, atherogenesis, and vascular rigidity adaptation.

Show evidence (1 reference)

PMID:30836973 SUPPORT Human Clinical

"The proteins cadherin-13, mucin-1, alpha-1 of collagen subunit type VI (COL6A1), hemisentin-1, semenogelin-2, SH3 domain-binding protein, transthyretin and serine proteases inhibitors realize a homeostatic role in individuals with different initial type of the cardiovascular system regulation."

Direct measurement of transthyretin changes in cosmonaut urine after long-duration spaceflight, linking TTR to cardiovascular homeostasis adaptation in microgravity. TTR concentration differences between cardiovascular regulation groups are relevant to understanding ATTR cardiomyopathy risk factors.

🧮

Computational Models

1

TTR Tetramer In Silico Docking Model for Kinetic Stabilizers MOLECULAR_DOCKING

Semi-quantitative in silico docking model for identifying potent and selective transthyretin amyloidogenesis inhibitors. Uses structure-activity relationship data and computational docking to TTR thyroxine-binding pockets to predict kinetic stabilizers that prevent tetramer dissociation. Validated by the clinical success of tafamidis, the first-in-class drug approved for TTR-FAP.

PMID:28625364 ↗

Findings

In silico docking model predicts potent TTR kinetic stabilizers validated by tafamidis clinical success

Show evidence (1 reference)

PMID:28625364 SUPPORT Computational

"The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated..."

Demonstrates that structure-based computational docking to the TTR tetramer successfully identified tafamidis-class kinetic stabilizers.

{ }

Source YAML

click to show

name: ATTR_Amyloidosis
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-06T00:00:00Z'
category: Genetic
parents:
- Amyloidosis
- Neuromuscular Disorder
- Cardiomyopathy
has_subtypes:
- name: ATTRm (hereditary)
  description: Caused by mutations in the TTR gene, leading to misfolded transthyretin proteins and amyloid deposits in various tissues.
  evidence:
  - reference: PMID:25604431
    reference_title: "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments."
    supports: SUPPORT
    snippet: Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis.
    explanation: The literature clearly states that mutations in the TTR gene lead to the misfolding of transthyretin proteins, which then aggregate into amyloid fibrils, supporting the statement.
  - reference: PMID:34518987
    reference_title: "The genetics of cardiac amyloidosis."
    supports: SUPPORT
    snippet: Heritable cardiac amyloidosis (CA) ... results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM).
    explanation: The literature confirms that hereditary cardiac amyloidosis results from the misfolding and accumulation of transthyretin due to mutations in the TTR gene.
  - reference: PMID:30486687
    reference_title: "Origin of sporadic late-onset hereditary ATTR Val30Met amyloidosis in Japan."
    supports: SUPPORT
    snippet: Hereditary transthyretin (ATTRm) amyloidosis, formerly known as familial amyloid polyneuropathy, is a major type of hereditary systemic amyloidosis, in which the disease is caused by mutant transthyretin (TTR).
    explanation: The literature supports that hereditary ATTRm amyloidosis is caused by mutations in the TTR gene, which leads to the disease.
  - reference: PMID:22094129
    reference_title: "Familial amyloid polyneuropathy."
    supports: SUPPORT
    snippet: Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR).
    explanation: The literature confirms that familial amyloid polyneuropathies, a form of hereditary ATTR amyloidosis, are caused by mutated TTR leading to amyloid deposits.
- name: ATTRwt (wild-type/senile)
  description: Occurs without mutations in the TTR gene, commonly affecting older individuals, with amyloid deposits primarily in the heart.
  evidence:
  - reference: PMID:31731233
    reference_title: "Wild-type ATTR amyloidosis may be associated with unexpected death among the elderly."
    supports: SUPPORT
    snippet: Wild-type ATTR amyloidosis (ATTR-wt) is characterized by the accumulation of amyloid in the heart, leading to fatal heart failure and arrhythmia.
    explanation: The study confirms that ATTR-wt occurs without mutations in the TTR gene and primarily affects the heart in older individuals.
  - reference: PMID:26048914
    reference_title: "The transthyretin amyloidoses: advances in therapy."
    supports: SUPPORT
    snippet: The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. ... The predominant effect of ATTRwt amyloidosis is on the heart
    explanation: The literature supports that ATTRwt occurs without mutations in the TTR gene and primarily affects the heart, commonly in older individuals.
  - reference: PMID:34390072
    reference_title: "Concurrent cardiac transthyretin and brain β amyloid accumulation among the older adults: The Hisayama study."
    supports: SUPPORT
    snippet: Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner.
    explanation: The study confirms that ATTRwt affects older individuals and involves amyloid deposits in the heart.
  - reference: PMID:32441155
    reference_title: "Cardiac sympathetic denervation in wild-type transthyretin amyloidosis."
    supports: SUPPORT
    snippet: Tissue accumulation of misfolded transthyretin (TTR) may occur because of TTR gene mutations (variant amyloid TTR amyloidosis, ATTRv), or as an age-related phenomenon (wild-type ATTR, ATTRwt).
    explanation: The literature supports that ATTRwt occurs without TTR gene mutations and is age-related, affecting the heart.
  - reference: PMID:28329248
    reference_title: "Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths."
    supports: SUPPORT
    snippet: Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages.
    explanation: The study supports that ATTRwt commonly affects older individuals and involves the heart.
prevalence:
- population: Global
  percentage: Rare
  evidence:
  - reference: PMID:35297258
    reference_title: "Hepatic amyloidosis: a prevalence study and clinical characterization of a rare and severe disease."
    supports: NO_EVIDENCE
    snippet: Amyloidosis is a systemic disease characterized by extracellular deposition of amyloid protein, most commonly in the heart and kidney. Hepatic amyloidosis is a rare form of presentation that ranges from mild hepatomegaly and altered liver biochemical tests to acute liver failure.
    explanation: The reference indicates that amyloidosis, including ATTR amyloidosis, is rare, supporting the statement that ATTR amyloidosis is rare globally.
  - reference: PMID:37907148
    reference_title: "The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology."
    supports: NO_EVIDENCE
    snippet: CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials.
    explanation: The reference discusses the CARS registry, which includes a diverse cohort of patients with cardiac amyloidosis, including ATTR amyloidosis, indicating that it is a condition under study due to its rarity and complexity.
progression:
- phase: Onset
  age_range: 30-70 (hereditary); 60-80 (wild-type)
  evidence:
  - reference: PMID:35717381
    reference_title: "Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update."
    supports: PARTIAL
    snippet: Symptomatic patients were predominantly male (71.4%) and had a mean ... age of symptom onset of 56.3 (17.8) years.
    explanation: The study provides data on the age of symptom onset for symptomatic patients with ATTR amyloidosis, indicating a mean age of onset within the provided range for hereditary cases. However, it does not specify the exact onset age range for wild-type cases.
  - reference: PMID:30199915
    reference_title: "[The Changing Appearance of Cardiac Amyloidosis]."
    supports: PARTIAL
    snippet: There is a significant increase in the number of patients with cardiac amyloidosis of the ATTR wild-type variety. These patients are often elderly males presenting with predominantly right sided heart failure.
    explanation: This reference suggests that ATTR wild-type amyloidosis commonly affects elderly males, but it does not provide a specific onset age range of 60-80 years.
  - reference: PMID:31731233
    reference_title: "Wild-type ATTR amyloidosis may be associated with unexpected death among the elderly."
    supports: PARTIAL
    snippet: The prevalence of ATTR-wt was 5.8% (32 of the 556), with the prevalence increasing as a function of age. We identified an ATTR-wt-specific morbidity rate of 12.3% for patients over 80 years of age, while the prevalence among individuals over 90 years of age was 34.9%.
    explanation: This study indicates that the prevalence of wild-type ATTR amyloidosis increases with age, particularly in those over 80 years. It supports the general notion that wild-type ATTR affects older individuals but does not provide a specific onset age range of 60-80 years.
  - reference: PMID:25586652
    reference_title: "Predictors of AA amyloidosis in familial Mediterranean fever."
    supports: NO_EVIDENCE
    snippet: The aim of the study was to evaluate the clinical and genetic predictors of AA amyloidosis in patients with familial Mediterranean fever (FMF).
    explanation: This study focuses on AA amyloidosis in familial Mediterranean fever and does not provide information on the age of onset for ATTR amyloidosis.
pathophysiology:
- name: TTR Tetramer Destabilization
  description: Mutations in the TTR gene or age-related changes destabilize the native tetrameric structure, leading to dissociation into monomers. This is the rate-limiting step enabling protein misfolding and aggregation.
  biological_processes:
  - preferred_term: protein tetramerization
    term:
      id: GO:0051289
      label: protein homotetramerization
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
  locations:
  - preferred_term: extracellular space
    term:
      id: GO:0005576
      label: extracellular region
  - preferred_term: blood plasma
    term:
      id: UBERON:0001969
      label: blood plasma
  evidence:
  - reference: PMID:34884963
    reference_title: "A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)."
    supports: SUPPORT
    snippet: Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues.
    explanation: The abstract mentions that TTR amyloidogenesis involves the formation and aggregation of amyloid fibrils, which supports the statement that mutations in the TTR gene result in the production of unstable transthyretin proteins that misfold and aggregate into amyloid fibrils.
  - reference: PMID:35830843
    reference_title: "A Study of Familial Amyloid Polyneuropathy Induced by the TTR Val30Leu Mutation in China."
    supports: PARTIAL
    snippet: Familial amyloid polyneuropathy is currently prevalent worldwide as the transthyretin (TTR) Val30Met mutation, and there are other types of mutations.
    explanation: This reference supports the statement by mentioning that familial amyloid polyneuropathy is caused by mutations in the TTR gene, which is consistent with the production of unstable transthyretin proteins that misfold and aggregate.
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: PARTIAL
    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: This reference supports the statement by explaining that hereditary transthyretin-related amyloidosis is caused by pathogenic variants in the TTR gene.
  - reference: PMID:22471982
    reference_title: "Transthyretin deposition in familial amyloidotic polyneuropathy."
    supports: PARTIAL
    snippet: hereditary transthyretin (TTR) amyloidosis which is a genetically transmitted disease that results from a mutation in the gene encoding the plasma TTR protein.
    explanation: The abstract confirms that hereditary transthyretin amyloidosis results from mutations in the TTR gene, which aligns with the statement.
  - reference: PMID:29962408
    reference_title: "Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds."
    supports: SUPPORT
    snippet: Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. 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: This reference explicitly states that hereditary transthyretin-related amyloidosis is caused by mutations in the TTR gene that destabilize the protein, supporting the statement.
  downstream:
  - target: Amyloid Fibril Formation
    description: Tetramer dissociation exposes unstable monomers that misfold and aggregate into amyloid fibrils.
- name: Amyloid Fibril Formation
  description: Misfolded transthyretin monomers undergo nucleation and elongation to form cross-beta amyloid fibrils. Serum amyloid P component and proteoglycans stabilize deposits and reduce clearance.
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: extracellular space
    term:
      id: GO:0005576
      label: extracellular region
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  downstream:
  - target: Cardiac and Neurological Dysfunction
    description: Extracellular deposition of misfolded transthyretin monomers as insoluble amyloid fibrils causes cardiomyopathy and polyneuropathy.
    evidence:
    - reference: PMID:40649158
      reference_title: "Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options."
      supports: SUPPORT
      snippet: Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes.
      explanation: This 2025 review explicitly states that misfolded TTR monomers cause both cardiomyopathy and polyneuropathy, establishing the causal link between amyloid deposition and organ dysfunction.
  - target: Oxidative Stress and Mitochondrial Dysfunction
    description: Amyloid oligomers and fibrils induce cardiomyocyte ROS generation and mitochondrial injury.
  - target: Calcium Homeostasis Disruption
    description: Amyloid infiltration perturbs calcium handling and electrical stability in cardiac myocytes.
  - target: Peripheral Nerve Degeneration
    description: Endoneurial amyloid deposition drives progressive axonal injury and demyelination.
  - target: Cardiomyopathy
    description: Cardiac amyloid infiltration stiffens myocardium and impairs systolic/diastolic performance.
  - target: Peripheral Neuropathy
    description: Amyloid toxicity in peripheral nerves produces length-dependent sensorimotor neuropathy.
  - target: Carpal Tunnel Syndrome
    description: Amyloid deposition in the transverse carpal ligament and flexor retinaculum compresses median nerve.
  - target: Gastrointestinal Symptoms
    description: Enteric autonomic neuropathy and tissue amyloid deposition impair motility and absorption.
  - target: Renal Dysfunction
    description: Renal interstitial and vascular amyloid deposition contributes to declining kidney function.
  - target: Vitreous Opacities
    description: Ocular transthyretin amyloid accumulation causes progressive vitreous clouding.
  evidence:
  - reference: PMID:31452023
    reference_title: "Diagnosis and treatment of heart failure in hereditary transthyretin amyloidosis."
    supports: PARTIAL
    snippet: fibrillar deposits in a several organs including the heart, kidney, liver, and peripheral nerves cause organ dysfunction and associated morbidity and mortality.
    explanation: The reference supports that amyloid fibrils deposit in the heart, kidney, and peripheral nerves, but does not mention the gastrointestinal tract.
  - reference: PMID:15126690
    reference_title: "Familial amyloidotic polyneuropathy: protein aggregation in the peripheral nervous system."
    supports: PARTIAL
    snippet: It is possible that a common factor in the amyloidogenesis process exists among the different forms; this common factor can involve changes produced by mutations in the three-dimensional structure of TTR, rendering it prone to deposition as amyloid.
    explanation: The reference supports that misfolded transthyretin proteins form amyloid fibrils but does not specify all the tissues mentioned in the statement.
  - reference: PMID:34018852
    reference_title: "Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression."
    supports: PARTIAL
    snippet: Age-related wild-type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to cardiac dysfunction, which is a significant cause of age-related heart failure.
    explanation: The reference supports that amyloid fibrils deposit in the heart and connective tissue, but does not mention the nerves, kidneys, or gastrointestinal tract.
  - reference: PMID:34361762
    reference_title: "The Ultrastructure of Tissue Damage by Amyloid Fibrils."
    supports: PARTIAL
    snippet: Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates.
    explanation: The reference supports that amyloid fibrils deposit in the nerves and heart but does not mention the kidneys or gastrointestinal tract.
- name: Oxidative Stress and Mitochondrial Dysfunction
  description: TTR oligomers and fibrils induce reactive oxygen species production and impair mitochondrial function in cardiomyocytes, contributing to contractile dysfunction and cell injury.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Cardiomyopathy
    description: Oxidative mitochondrial injury reduces contractile reserve and accelerates myocardial dysfunction.
  - target: Heart Failure
    description: Progressive cardiomyocyte energy failure contributes to symptomatic heart failure.
- name: Calcium Homeostasis Disruption
  description: Amyloid deposits disrupt intracellular calcium handling in cardiomyocytes, impairing contractility and promoting arrhythmogenesis.
  biological_processes:
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Arrhythmias
    description: Calcium-handling instability promotes atrial and ventricular rhythm disturbances.
  - target: Heart Failure
    description: Impaired excitation-contraction coupling worsens pump failure.
- name: Peripheral Nerve Degeneration
  description: Amyloid deposition in peripheral nerves causes axonal degeneration and demyelination, affecting sensory, motor, and autonomic functions.
  biological_processes:
  - preferred_term: axonogenesis
    term:
      id: GO:0007409
      label: axonogenesis
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
  cell_types:
  - preferred_term: peripheral neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  - 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
  downstream:
  - target: Peripheral Neuropathy
    description: Axonal loss and demyelination manifest as progressive polyneuropathy.
  - target: Sensory Loss
    description: Sensory fiber degeneration causes distal loss of vibration and pain perception.
  - target: Numbness and Tingling
    description: Irritable and degenerating peripheral nerves produce paresthesias.
  - target: Autonomic Dysfunction
    description: Autonomic fiber involvement leads to widespread dysautonomia.
  - target: Orthostatic Hypotension
    description: Autonomic denervation of vascular tone control causes postural blood pressure drops.
  - target: Fatigue
    description: Combined neuromuscular and autonomic impairment contributes to chronic fatigue.
phenotypes:
- category: Neurologic
  name: Peripheral Neuropathy
  frequency: FREQUENT
  diagnostic: true
  sequelae:
  - target: Sensory Loss
  - target: Numbness and Tingling
  - target: Autonomic Dysfunction
  evidence:
  - reference: PMID:23239211
    reference_title: "Amyloid neuropathies."
    supports: SUPPORT
    snippet: Peripheral neuropathy is a common complication of many of the systemic amyloidoses.
    explanation: The literature indicates that peripheral neuropathy is a common complication of amyloidoses, which includes ATTR amyloidosis.
  - reference: PMID:35830843
    reference_title: "A Study of Familial Amyloid Polyneuropathy Induced by the TTR Val30Leu Mutation in China."
    supports: SUPPORT
    snippet: The clinical manifestations of this mutation involve mainly limb sensory or motor disorders or gastrointestinal symptoms or both, and the electrophysiological examination shows neurogenic damage.
    explanation: This study indicates that peripheral neuropathy, including sensory and motor disorders, is a frequent manifestation in patients with the TTR Val30Leu mutation, a form of familial amyloid polyneuropathy.
  - reference: PMID:31445300
    reference_title: "Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7."
    supports: SUPPORT
    snippet: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction.
    explanation: The literature confirms that hATTR amyloidosis frequently involves polyneuropathy, including sensory loss, numbness, tingling, and autonomic dysfunction.
  - reference: PMID:36504143
    reference_title: "Functional and structural markers of peripheral microvascular autonomic neuropathy."
    supports: NO_EVIDENCE
    snippet: Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN).
    explanation: This study suggests that autonomic dysfunction is a common complication in small-fiber neuropathy, which can be seen in conditions like amyloidosis.
  phenotype_term:
    preferred_term: Peripheral Neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
- category: Cardiovascular
  name: Cardiomyopathy
  frequency: FREQUENT
  diagnostic: true
  sequelae:
  - target: Heart Failure
  - target: Arrhythmias
  - target: Orthostatic Hypotension
  evidence:
  - reference: PMID:34694575
    reference_title: "Epidemiology and clinical manifestations of cardiac amyloidosis."
    supports: NO_EVIDENCE
    snippet: The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans.
    explanation: The reference discusses the increased recognition and diagnosis of ATTR cardiac amyloidosis, supporting the statement that it is frequently diagnosed as a cardiovascular condition.
  - reference: PMID:35235819
    reference_title: "Management of Cardiac Symptoms in Amyloidosis."
    supports: SUPPORT
    snippet: Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction.
    explanation: This reference supports the statement by listing heart failure, arrhythmias, and autonomic dysfunction (which includes orthostatic hypotension) as common sequelae of cardiac amyloidosis.
  - reference: PMID:38044190
    reference_title: "Clinical differences between transthyretin cardiac amyloidosis and hypertensive heart disease."
    supports: SUPPORT
    snippet: Patients with TTRA had higher levels of ultrasensitive troponin I (TnI-US) and N-terminal brain natriuretic propeptide (NT-ProBNP); in electrocardiography (ECG) they presented a pseudo-infarction pattern more frequently as well as conduction disturbances.
    explanation: The reference supports the frequent occurrence of cardiovascular manifestations in ATTR amyloidosis, including cardiomyopathy and arrhythmias.
  - reference: PMID:29770800
    reference_title: "Current and future circulating biomarkers for cardiac amyloidosis."
    supports: SUPPORT
    snippet: Cardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution.
    explanation: This reference supports the statement by describing the involvement of the myocardium (cardiomyopathy) and the frequent occurrence of cardiovascular symptoms in cardiac amyloidosis.
  - reference: PMID:38844297
    reference_title: "Pathophysiology of Cardiac Amyloidosis."
    supports: SUPPORT
    snippet: Cardiac amyloidosis (CA), usually caused by deposition of misfolded transthyretin or immunoglobulin light chains, is an increasingly recognized cause of heart failure burdened by a poor prognosis.
    explanation: This reference supports the statement by describing heart failure as a frequent sequela of ATTR amyloidosis.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
- category: Gastrointestinal
  name: Gastrointestinal Symptoms
  frequency: FREQUENT
  notes: Include nausea, diarrhea, constipation, and weight loss
  evidence:
  - reference: PMID:25908211
    reference_title: "Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis."
    supports: SUPPORT
    snippet: Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality.
    explanation: The study highlights that gastrointestinal manifestations are common in hereditary ATTR amyloidosis, supporting the statement that gastrointestinal symptoms are frequent in this condition.
  - reference: PMID:32176096
    reference_title: "Fecal calprotectin levels are elevated in transthyretin amyloidosis patients with gastrointestinal manifestations."
    supports: SUPPORT
    snippet: Transthyretin amyloid (ATTR) amyloidosis is a rare systemic disorder characterized by amyloid deposits formed by misfolded monomers of the transthyretin. Gastrointestinal (GI) manifestations are common in ATTR amyloidosis; however, their pathogenesis is not fully elucidated.
    explanation: This reference supports the frequency of gastrointestinal symptoms in ATTR amyloidosis, aligning with the statement.
  - reference: PMID:37844979
    reference_title: "Severe chronic diarrhoea caused by hereditary transthyretin amyloidosis."
    supports: NO_EVIDENCE
    snippet: In the early stages of amyloidosis, gastrointestinal (GI) symptoms are uncommon. We describe a rare case of hereditary transthyretin amyloidosis (ATTRv) with involvement of the heart, nervous system and GI tract.
    explanation: Although it mentions that GI symptoms are uncommon in the early stages, it describes a case with significant GI involvement, supporting the statement about frequent GI symptoms in later stages.
  - reference: PMID:8115892
    reference_title: "Gastrointestinal manifestations of amyloidosis."
    supports: PARTIAL
    snippet: Gastrointestinal symptoms included anorexia, macroglossia, intestinal pseudo-obstruction, and altered bowel habits.
    explanation: This reference mentions gastrointestinal symptoms but does not specifically focus on ATTR amyloidosis. It partially supports the statement by acknowledging the presence of GI symptoms in amyloidosis in general.
  - reference: PMID:6402969
    reference_title: "Disorders of gastrointestinal motility associated with diabetes mellitus."
    supports: NO_EVIDENCE
    snippet: Gastrointestinal symptoms such as vomiting, constipation, diarrhea, and fecal incontinence occur frequently in patients with diabetes mellitus.
    explanation: This reference is focused on diabetes mellitus and does not provide evidence related to ATTR amyloidosis.
- category: Ocular
  name: Vitreous Opacities
  frequency: OCCASIONAL
  notes: Can lead to visual impairment
  evidence:
  - reference: PMID:28085522
    reference_title: "Elderly onset vitreous opacities as the initial manifestation in hereditary transthyretin (ATTR Val30Met) carries."
    supports: SUPPORT
    snippet: We report on two elderly patients (an 80-year-old woman and an 83-year-old man) with progressive vitreous opacities (VOs) as the initial manifestation of hereditary transthyretin (ATTR Val30Met) carries, who had no evidence of systemic involvement or family history of amyloidosis and lived in non-endemic areas.
    explanation: The reference provides evidence that vitreous opacities can be an initial manifestation in patients with hereditary transthyretin amyloidosis (ATTR Val30Met), supporting the statement that vitreous opacities occur occasionally in ATTR amyloidosis.
  - reference: PMID:36129270
    reference_title: "CHOROIDAL AMYLOID DEPOSITION: A Multicenter Study of Amyloid Lesions Identified in Late Indocyanine Green Angiography."
    supports: SUPPORT
    snippet: However, 3 patients (43%) had worsening vitreous opacities in both eyes, and 4 patients (57%) developed secondary open-angle glaucoma.
    explanation: The reference indicates that vitreous opacities were observed and worsened in some patients with ATTR amyloidosis, supporting the statement that vitreous opacities can occur occasionally in ATTR amyloidosis and lead to visual impairment.
  phenotype_term:
    preferred_term: Vitreous Opacities
    term:
      id: HP:0007710
      label: Peripheral vitreous opacities
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Carpal Tunnel Syndrome
  notes: Due to amyloid deposition in the wrist
  evidence:
  - reference: PMID:30404120
    reference_title: "[Carpal tunnel syndrome and ATTR-amyloidosis]."
    supports: SUPPORT
    snippet: One cause for a carpal tunnel syndrome is transthyretin (ATTR) amyloid, which deposits in the carpal tunnel tissue.
    explanation: The article states that ATTR amyloid deposits in the carpal tunnel tissue can cause carpal tunnel syndrome, supporting the statement that ATTR amyloidosis can occasionally cause this musculoskeletal condition.
  - reference: PMID:33443391
    reference_title: "Orthopaedic Manifestations of Amyloidosis."
    supports: SUPPORT
    snippet: Common orthopaedic manifestations of amyloidosis include carpal tunnel syndrome, trigger finger, spontaneous distal biceps tendon rupture, rotator cuff disease, and lumbar spinal stenosis.
    explanation: The article mentions carpal tunnel syndrome as a common orthopedic manifestation of amyloidosis, supporting the statement that ATTR amyloidosis can occasionally cause this condition due to amyloid deposition in the wrist.
- category: Genitourinary
  frequency: OCCASIONAL
  name: Renal Dysfunction
  notes: Due to amyloid deposition in the kidneys, can lead to proteinuria and renal failure
  evidence:
  - reference: PMID:22537653
    reference_title: "Transthyretin amyloidosis and the kidney."
    supports: SUPPORT
    snippet: Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features.
    explanation: The reference confirms that renal dysfunction, including proteinuria, is a clinical feature of transthyretin amyloidosis (ATTR).
  - reference: PMID:37997196
    reference_title: "Albuminuria in transthyretin cardiac amyloidosis: Prevalence, progression and prognostic importance."
    supports: SUPPORT
    snippet: Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy that commonly presents with concomitant chronic kidney disease.
    explanation: The reference supports the statement by indicating that chronic kidney disease, which encompasses renal dysfunction, is commonly associated with transthyretin cardiac amyloidosis (ATTR-CA).
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
- category: Systemic
  frequency: FREQUENT
  name: Fatigue
  notes: Can be severe and limit activities of daily living
  evidence:
  - reference: PMID:35144512
    reference_title: "Amyloidosis from the patient perspective: the French daily impact of amyloidosis study."
    supports: PARTIAL
    snippet: Patients often reported problems with mobility, usual activities, pain/discomfort and anxiety/depression, but not with self-care.
    explanation: The literature indicates that systemic amyloidosis, including ATTR, frequently impacts daily life and mobility, which can be associated with fatigue.
  - reference: PMID:31445300
    reference_title: "Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7."
    supports: NO_EVIDENCE
    snippet: It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction.
    explanation: The literature describes ATTR amyloidosis as a multisystem disease, which can imply the presence of fatigue due to its systemic impact.
  - reference: PMID:33609196
    reference_title: "Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness."
    supports: NO_EVIDENCE
    snippet: Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function.
    explanation: The progressive loss of function in various organs and tissues can lead to severe fatigue, limiting activities of daily living.
  - reference: PMID:35128833
    reference_title: "Prevalence and determinants of iron deficiency in cardiac amyloidosis."
    supports: NO_EVIDENCE
    snippet: Amyloidosis is a severe and fatal systemic disease, characterized by an accumulation of amyloid fibrils in various tissues/organs, including nerves, kidneys, gastrointestinal tract, and heart.
    explanation: The systemic nature of ATTR amyloidosis affecting multiple organs can contribute to fatigue.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Neurologic
  name: Sensory Loss
  frequency: FREQUENT
  notes: Loss of sensation, particularly in extremities, due to peripheral nerve damage
  phenotype_term:
    preferred_term: Sensory loss
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
- category: Neurologic
  name: Numbness and Tingling
  frequency: FREQUENT
  notes: Paresthesias in hands and feet as early manifestation of neuropathy
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
- category: Neurologic
  name: Autonomic Dysfunction
  frequency: FREQUENT
  notes: Includes orthostatic hypotension, gastroparesis, bladder dysfunction
  phenotype_term:
    preferred_term: Autonomic dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
- category: Cardiovascular
  name: Heart Failure
  frequency: FREQUENT
  notes: Progressive infiltrative cardiomyopathy leading to diastolic and systolic dysfunction
  phenotype_term:
    preferred_term: Heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
- category: Cardiovascular
  name: Arrhythmias
  frequency: FREQUENT
  notes: Atrial fibrillation, conduction abnormalities, and ventricular arrhythmias
  phenotype_term:
    preferred_term: Cardiac arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
- category: Cardiovascular
  name: Orthostatic Hypotension
  frequency: FREQUENT
  notes: Drop in blood pressure upon standing due to autonomic neuropathy
  phenotype_term:
    preferred_term: Orthostatic hypotension
    term:
      id: HP:0001278
      label: Orthostatic hypotension
biochemical:
- name: Serum Transthyretin Levels
  presence: Abnormal (low)
  context: Diagnostic indicator
  evidence:
  - reference: PMID:32356182
    reference_title: "Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis."
    supports: PARTIAL
    snippet: Lower levels of transthyretin and retinol binding protein-4 have been demonstrated in patients with pathogenic mutations of transthyretin either with or without clinical disease.
    explanation: The literature indicates that lower levels of transthyretin are associated with transthyretin amyloidosis, supporting the statement that abnormal (low) serum transthyretin levels can be a diagnostic indicator.
- name: Amyloid P Component
  presence: Elevated
  notes: May be used to monitor disease progression
  evidence:
  - reference: PMID:12394612
    reference_title: "Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis."
    supports: PARTIAL
    snippet: Radiolabelled serum amyloid P component scintigraphy is a non-invasive and quantitative method for imaging amyloid deposits, which produces diagnostic images in most patients with systemic amyloidosis, and can be used repeatedly to monitor the course of the disease.
    explanation: The reference indicates that serum amyloid P component scintigraphy can be used to monitor the course of systemic amyloidosis, but it does not specify whether the levels of amyloid P component are elevated in ATTR amyloidosis.
genetic:
- name: TTR
  association: Pathogenic Variants
  notes: Primary amyloid precursor gene encoding transthyretin, a liver-derived homotetrameric transport protein for thyroxine and retinol. Tetramer instability leads to monomer misfolding and amyloid fibril formation.
  examples:
  - Val30Met
  - Thr60Ala
  frequency: Variable by population
  evidence:
  - reference: PMID:38844302
    reference_title: "Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update."
    supports: SUPPORT
    snippet: More than 140 TTR gene variants have been associated with hATTR, with the Val30Met variant representing the most common worldwide.
    explanation: This reference supports the association of the Val30Met variant with ATTR amyloidosis.
  - reference: PMID:24555660
    reference_title: "Frequency of the transthyretin Val30Met mutation in the northern Swedish population."
    supports: SUPPORT
    snippet: A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area.
    explanation: This reference supports the statement about the variable frequency of the Val30Met variant by population.
  - reference: PMID:36941075
    reference_title: "Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    snippet: Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation.
    explanation: This reference supports the statement about the variable frequency of pathogenic variants by population.
- name: APCS
  association: Modifying Factor
  notes: Encodes serum amyloid P component (SAP), a plasma protein that binds and stabilizes amyloid fibrils in deposits, reducing proteolytic clearance.
- name: CLU
  association: Modifying Factor
  notes: Encodes clusterin, an extracellular chaperone present in TTR deposits that modulates fibril localization and clearance.
diagnosis:
- name: Genetic Testing for TTR Mutations
  presence: Positive in hereditary cases
  evidence:
  - reference: PMID:31520266
    reference_title: "Impact of Genetic Testing in Transthyretin (ATTR) Cardiac Amyloidosis."
    supports: SUPPORT
    snippet: Genetic screening allows for the early identification of asymptomatic TTR mutation carriers.
    explanation: The literature supports that genetic testing for TTR mutations is positive in hereditary cases of ATTR amyloidosis.
  - reference: PMID:34076545
    reference_title: "Characterization of population genetic structure of hereditary transthyretin amyloidosis in Bulgaria."
    supports: PARTIAL
    snippet: The hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant genetic disease characterized by amyloid formation in different tissues due to pathogenic variants in the TTR gene.
    explanation: This reference supports that hereditary cases of ATTR amyloidosis involve pathogenic variants in the TTR gene, which can be identified through genetic testing.
  - reference: PMID:37725003
    reference_title: "Genetic screening for hereditary transthyretin amyloidosis with polyneuropathy in western Sicily: Two years of experience in a neurological clinic."
    supports: PARTIAL
    snippet: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils.
    explanation: This reference supports that genetic testing for TTR mutations is relevant in hereditary cases of ATTR amyloidosis.
- name: Biopsy with Congo Red Staining
  presence: Positive for amyloid deposits
  evidence:
  - reference: PMID:16493520
    reference_title: "Histochemical differential diagnosis and polarization optical analysis of amyloid and amyloidosis."
    supports: SUPPORT
    snippet: Congo red staining according to Romhányi (1971) is a highly specific and sensitive method for early microscopic recognition of amyloidosis.
    explanation: The reference confirms that Congo red staining is a specific and sensitive method for detecting amyloid deposits, supporting the statement.
  - reference: PMID:34637570
    reference_title: "Autopsy case with concurrent transthyretin and immunoglobulin amyloidosis."
    supports: SUPPORT
    snippet: Congo red staining detected amyloid deposits in systemic organs, including the heart, lungs, liver, and kidneys.
    explanation: The reference notes the use of Congo red staining to detect amyloid deposits in various organs, supporting the statement.
  - reference: PMID:28598015
    reference_title: "Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy."
    supports: SUPPORT
    snippet: Congo red staining revealed brilliant red amyloid deposits confirmed by apple-green birefringence within dermal collagen, sweat glands, and arrector pili that engulfed axons.
    explanation: The reference describes the detection of amyloid deposits using Congo red staining, supporting the statement.
  - reference: PMID:33433320
    reference_title: "Diagnostic value of electron microscopy detection using abdominal fat pad biopsy in systemic amyloidosis."
    supports: SUPPORT
    snippet: Light microscopy revealed marked brick-red staining in 11 of 42 samples, 6 moderate and 11 slight staining in the septum of cells, medium and small sized vessel, and apple green double refraction under polarized light microscopy.
    explanation: The reference confirms that Congo red staining is used to detect amyloid deposits in biopsy samples, supporting the statement.
- name: Cardiac MRI
  notes: May show characteristic patterns of amyloid deposition
  evidence:
  - reference: PMID:37553542
    reference_title: "[Diagnostics of cardiac amyloidosis]."
    supports: SUPPORT
    snippet: Cardiac amyloidosis shows a particularly characteristic contrast enhancement in cardiac MRI, which mostly begins in the inner (subendocardial) layers of the basal left ventricular (LV) wall and frequently appears to be circular in the cross-sectional view of the left ventricle.
    explanation: The literature confirms that cardiac MRI can show characteristic patterns of amyloid deposition in ATTR amyloidosis.
  - reference: PMID:28728692
    reference_title: "Magnetic Resonance in Transthyretin Cardiac Amyloidosis."
    supports: SUPPORT
    snippet: Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis.
    explanation: The literature supports that cardiac MRI (CMR) can show characteristic patterns in ATTR amyloidosis.
- name: Nerve Conduction Studies
  notes: Useful for diagnosing peripheral neuropathy
  evidence:
  - reference: PMID:21463231
    reference_title: "Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis."
    supports: PARTIAL
    snippet: Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients.
    explanation: The reference indicates that nerve conduction studies can show abnormalities in ATTR amyloidosis, but it does not explicitly state that they are useful for diagnosing peripheral neuropathy specifically in ATTR amyloidosis.
  - reference: PMID:37658177
    reference_title: "Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group."
    supports: PARTIAL
    snippet: Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively.
    explanation: The reference mentions neuropathy endpoints but does not provide specific information on the utility of nerve conduction studies for diagnosing peripheral neuropathy in ATTR amyloidosis.
environmental:
- name: None Applicable
  evidence:
  - reference: PMID:21463231
    reference_title: "Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis."
    supports: REFUTE
    snippet: Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP.
    explanation: The statement that ATTR amyloidosis is 'None Applicable' is incorrect as it is associated with specific conditions such as familial amyloid polyneuropathy.
  - reference: PMID:37907148
    reference_title: "The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology."
    supports: REFUTE
    snippet: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA).
    explanation: The statement 'None Applicable' is incorrect because ATTR amyloidosis is a recognized condition included in the Cardiac Amyloidosis Registry Study.
treatments:
- name: Tafamidis
  role: TTR Stabilizer
  description: Helps stabilize transthyretin and prevent amyloid fibril formation.
  pdb_structures:
  - pdb_id: 3TCT
    description: Tafamidis bound to wild-type human transthyretin tetramer, showing drug occupancy in the T4-binding channel that stabilizes the quaternary structure
    resolution_angstrom: 1.85
    method: X-ray
    ligand: tafamidis
    target_protein: transthyretin
    publication: PMID:22409525
  - pdb_id: 4HIQ
    description: TTR tetramer with tafamidis bound, alternative crystal form showing detailed drug-protein contacts at the inner binding cavity
    resolution_angstrom: 1.55
    method: X-ray
    ligand: tafamidis
    target_protein: transthyretin
  evidence:
  - reference: PMID:25872787
    reference_title: "Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes."
    supports: SUPPORT
    snippet: Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated.
    explanation: The study shows that tafamidis effectively stabilizes TTR, supporting the statement that it helps stabilize transthyretin.
  - reference: PMID:31098895
    reference_title: "Tafamidis: A Review in Transthyretin Amyloidosis with Polyneuropathy."
    supports: SUPPORT
    snippet: Tafamidis slowed deterioration of neurological function and maintained health-related quality of life in patients with early-stage ATTR-PN... TTR tetramers were stabilized in nearly all patients.
    explanation: The evidence indicates that tafamidis stabilizes TTR tetramers, supporting the statement.
  - reference: PMID:26800456
    reference_title: "TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies."
    supports: SUPPORT
    snippet: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease.
    explanation: The study supports that tafamidis is effective in stabilizing TTR and preventing amyloid fibril formation.
  - reference: PMID:29962408
    reference_title: "Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds."
    supports: SUPPORT
    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 supports that stabilizing TTR is crucial, and tafamidis is one of the compounds that achieve this.
  - reference: PMID:34609369
    reference_title: "TRANSTHYRETIN AMYLOIDOSIS THERAPIES: GUIDING THE FUTURE."
    supports: SUPPORT
    snippet: Several TTR molecule stabilizers were developed successfully... Silencing the TTR gene using different strategies is flourishing.
    explanation: The article states that TTR stabilizers, including tafamidis, have been successfully developed, supporting the statement.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: tafamidis
      term:
        id: CHEBI:78538
        label: tafamidis
- name: Patisiran
  role: RNA Interference
  description: Reduces production of transthyretin protein to decrease amyloid formation.
  evidence:
  - reference: PMID:30480471
    reference_title: "Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis."
    supports: SUPPORT
    snippet: Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein.
    explanation: The abstract clearly states that patisiran reduces the production of transthyretin protein, which aligns with the statement.
  - reference: PMID:37599395
    reference_title: "Reduction in (99m)Tc-DPD myocardial uptake with therapy of ATTR cardiomyopathy."
    supports: SUPPORT
    snippet: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv).
    explanation: The abstract mentions that patisiran, as an RNAi therapeutic, benefits patients with hereditary transthyretin amyloidosis, indicating its role in reducing transthyretin protein production.
  - reference: PMID:31131842
    reference_title: "Patisiran for the treatment of patients with familial amyloid polyneuropathy."
    supports: SUPPORT
    snippet: Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both mutant and wild-type amyloid transthyretin (ATTR) protein production becomes suppressed.
    explanation: The abstract explicitly states that patisiran targets and degrades transthyretin mRNA, thus reducing the production of transthyretin protein.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: patisiran
      term:
        id: NCIT:C116792
        label: Patisiran
- name: Inotersen
  role: Antisense Oligonucleotide
  description: Reduces TTR protein production to limit amyloid accumulation.
  evidence:
  - reference: PMID:30561247
    reference_title: "Inotersen (transthyretin-specific antisense oligonucleotide) for treatment of transthyretin amyloidosis."
    supports: SUPPORT
    snippet: Inotersen/Tegsedi (Akcea Therapeutics, MA, USA) is a second-generation antisense oligonucleotide (ASO) specific for TTR that inhibits production of TTR by the liver.
    explanation: The reference confirms that Inotersen reduces TTR protein production by inhibiting its production in the liver, which aligns with the statement.
  - reference: PMID:37599395
    reference_title: "Reduction in (99m)Tc-DPD myocardial uptake with therapy of ATTR cardiomyopathy."
    supports: SUPPORT
    snippet: '''Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv).'
    explanation: The reference supports that Inotersen is used to treat ATTR amyloidosis and implies its role in reducing TTR protein production.
  - reference: PMID:31343345
    reference_title: "Inotersen treatment for ATTR amyloidosis."
    supports: SUPPORT
    snippet: Inotersen treatment for ATTR amyloidosis.
    explanation: This reference title directly states that Inotersen is used for the treatment of ATTR amyloidosis, implying its role in reducing TTR protein production.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: inotersen
      term:
        id: NCIT:C121667
        label: Inotersen
- name: Liver Transplant
  description: Considered for hereditary cases to reduce production of mutant TTR.
  evidence:
  - reference: PMID:25482846
    reference_title: "Liver transplantation in transthyretin amyloidosis: issues and challenges."
    supports: SUPPORT
    snippet: Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR.
    explanation: The literature supports liver transplantation as a therapy to address the production of unstable TTR in hereditary ATTR amyloidosis.
  - reference: PMID:23797140
    reference_title: "Familial amyloid polyneuropathy."
    supports: SUPPORT
    snippet: Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms.
    explanation: This reference supports the use of liver transplantation to reduce the production of mutant TTR in hereditary cases of ATTR amyloidosis.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
- name: Heart Transplant
  description: May be necessary for those with severe cardiomyopathy.
  evidence:
  - reference: PMID:32304420
    reference_title: "Heart transplantation in cardiac storage diseases: data on Fabry disease and cardiac amyloidosis."
    supports: SUPPORT
    snippet: However, the end-stage heart failure is common and HTx could be offered to selected patients, especially if affected by light chain cardiac amyloidosis, to allow to perform the autologous stem cell transplantation after the cardiac transplant.
    explanation: The statement is supported as heart transplantation is mentioned as a treatment for end-stage heart failure in patients with cardiac amyloidosis.
  - reference: PMID:33621542
    reference_title: "Cardiac transplantation outcomes in patients with amyloid cardiomyopathy."
    supports: SUPPORT
    snippet: Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure.
    explanation: The statement is supported as orthotopic heart transplantation is identified as a definitive treatment for end-stage heart failure in amyloid cardiomyopathy patients.
  - reference: PMID:34922822
    reference_title: "Surveillance for disease progression of transthyretin amyloidosis after heart transplantation in the era of novel disease modifying therapies."
    supports: SUPPORT
    snippet: Heart Transplantation (HT) is a rational therapy for advanced transthyretin cardiac amyloidosis (ATTR-CA)...
    explanation: The statement is supported as heart transplantation is described as a rational therapy for advanced transthyretin cardiac amyloidosis.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
- name: Supportive Care
  description: Symptomatic treatment for neuropathy, heart failure, and gastrointestinal issues.
  evidence:
  - reference: PMID:33099432
    reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
    supports: SUPPORT
    snippet: Supportive care manages the symptoms of organ involvement and the side effects of treatment.
    explanation: The reference indicates that supportive care is used to manage the symptoms of organ involvement, which can include neuropathy, heart failure, and gastrointestinal issues.
  - reference: PMID:35235819
    reference_title: "Management of Cardiac Symptoms in Amyloidosis."
    supports: PARTIAL
    snippet: Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction.
    explanation: The reference highlights the management of cardiovascular symptoms in cardiac amyloidosis, which is part of supportive care.
  - reference: PMID:35104443
    reference_title: "Neuromuscular Complications of Systemic Amyloidosis."
    supports: NO_EVIDENCE
    snippet: Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues... The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy.
    explanation: The reference discusses the management of neuromuscular complications, including neuropathy, which is part of supportive care.
  - reference: PMID:7588042
    reference_title: "[The gastrointestinal manifestations of amyloidosis]."
    supports: NO_EVIDENCE
    snippet: The gastrointestinal manifestations of amyloidosis.
    explanation: The reference discusses gastrointestinal issues related to amyloidosis, which are managed through supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
datasets:
# Spaceflight / Microgravity - Liver transcriptomics (TTR synthesis site)
- accession: "genelab:OSD-379"
  title: Rodent Research Reference Mission-1 (RRRM-1) liver transcriptomics
  description: >-
    RNA-Seq transcriptional profiling of livers from mice flown on RRRM-1
    aboard the ISS. Liver is the primary site of transthyretin (TTR)
    synthesis; spaceflight-induced hepatic transcriptomic changes may
    reveal alterations in TTR expression and protein quality control.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: liver tissue
    term:
      id: UBERON:0002107
      label: liver
    tissue_term:
      preferred_term: liver
      term:
        id: UBERON:0002107
        label: liver
  conditions:
  - spaceflight
  - ground control
  exposures:
  - preferred_term: spaceflight
  platform: Illumina NovaSeq
  notes: >-
    NASA OSDR OSD-379. 40 female BALB/cAnNTac mice, ISS 22-40 days.
    Liver is the main organ producing TTR; spaceflight transcriptomic
    changes here are directly relevant to ATTR amyloidosis pathogenesis.

# Spaceflight / Microgravity - Soleus muscle (TTR dysregulation site)
- accession: "genelab:OSD-104"
  title: Rodent Research-1 (RR1) mouse soleus muscle transcriptomics and epigenomics
  description: >-
    RNA-Seq and whole-genome bisulfite sequencing of mouse soleus muscle
    from the RR-1 NASA Validation Flight on ISS. Hindlimb unloading
    studies have shown transthyretin dysregulation in soleus muscle,
    making this spaceflight dataset relevant to understanding TTR
    behavior under microgravity-induced muscle atrophy.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: soleus muscle
    term:
      id: UBERON:0001389
      label: soleus muscle
    tissue_term:
      preferred_term: soleus muscle
      term:
        id: UBERON:0001389
        label: soleus muscle
  conditions:
  - spaceflight
  - ground control
  exposures:
  - preferred_term: spaceflight
  platform: Illumina
  notes: >-
    NASA OSDR OSD-104. 37 days ISS microgravity. TTR was found
    dysregulated in mouse soleus after hindlimb unloading (PMID:25656502),
    making this spaceflight muscle dataset directly relevant.

# Spaceflight / Microgravity - Kidney transcriptomics (amyloid deposition site)
- accession: "genelab:OSD-253"
  title: Rodent Research-7 (RR-7) mouse kidney transcriptomics
  description: >-
    RNA-Seq transcriptional analysis of kidneys from mice flown on
    the RR-7 mission aboard the ISS. Kidney is a major site of ATTR
    amyloid deposition and renal involvement is a recognized
    complication of systemic transthyretin amyloidosis.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: kidney tissue
    term:
      id: UBERON:0002113
      label: kidney
    tissue_term:
      preferred_term: kidney
      term:
        id: UBERON:0002113
        label: kidney
  conditions:
  - spaceflight
  - ground control
  exposures:
  - preferred_term: spaceflight
  platform: Illumina NovaSeq
  notes: >-
    NASA OSDR OSD-253. Kidney is a major site of ATTR amyloid
    deposition; spaceflight kidney transcriptomics may reveal changes
    relevant to renal amyloidosis pathophysiology.

# Spaceflight / Microgravity - ISS amyloid fibril formation
- accession: "DOI:10.1038/s41526-020-0107-y"
  title: Characterization of amyloid-beta fibril formation under microgravity conditions
  description: >-
    JAXA ISS experiment (Kibo module) characterizing amyloid-beta(1-40)
    fibril formation under microgravity. Fibrilization progressed much
    more slowly on ISS than on the ground, and microgravity promoted
    distinct fibril morphologies. Findings are mechanistically relevant
    to TTR amyloidogenesis since both involve cross-beta spine amyloid
    fibril assembly.
  organism:
    preferred_term: in vitro
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: amyloid-beta protein
  conditions:
  - microgravity
  - ground control (1g)
  exposures:
  - preferred_term: spaceflight
  publication: PMID:32566742
  evidence:
  - reference: PMID:32566742
    reference_title: "Characterization of amyloid β fibril formation under microgravity conditions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the Aβ(1-40) fibrilization progresses much more slowly on the ISS than on the ground, similarly to protein crystallization. Furthermore, microgravity promoted the formation of distinct morphologies of Aβ(1-40) fibrils."
    explanation: >-
      Demonstrates that microgravity significantly alters amyloid fibril
      formation kinetics and morphology. Since TTR amyloidogenesis shares
      the same cross-beta spine fibril assembly mechanism, these findings
      suggest microgravity could similarly affect TTR fibril formation.
  notes: >-
    JAXA Kibo module experiment Dec 2017-Jan 2018. First demonstration
    that microgravity slows amyloid fibrilization and alters fibril
    morphology. Directly applicable to understanding TTR amyloid
    formation mechanisms.

# Spaceflight / Microgravity - ISS Ring-Sheared Drop amyloidogenesis
- accession: "DOI:10.1038/s41526-022-00227-2"
  title: Amyloidogenesis via interfacial shear in a containerless biochemical reactor aboard the ISS
  description: >-
    Ring-Sheared Drop (RSD) experiment on ISS studying insulin
    amyloidogenesis in microgravity. Examined nucleation, fibrillization,
    and gelation of a model amyloidogenic protein in a containerless
    reactor, eliminating solid boundary effects. Methodology directly
    transferable to TTR amyloid studies.
  organism:
    preferred_term: in vitro
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: insulin protein
  conditions:
  - microgravity
  - ground analog
  exposures:
  - preferred_term: spaceflight
  publication: PMID:36127358
  evidence: []
  notes: >-
    NASA Ring-Sheared Drop (RSD) experiment. Containerless biochemical
    reactor eliminates solid boundaries, isolating air-liquid interface
    effects on amyloid fibril formation.

# Spaceflight / Microgravity - Cardiac remodeling transcriptomics
- accession: "DOI:10.3390/biom13020371"
  title: Transcriptomic effects on the mouse heart following 30 days on the ISS
  description: >-
    RNA sequencing of mouse hearts after 30 days on ISS. Found 1147
    significantly regulated transcripts with MAPK, PI3K-Akt, and GPCR
    pathway activation. Relevant to ATTR cardiomyopathy as spaceflight
    cardiac remodeling shares pathways with amyloid-induced cardiac
    dysfunction.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: heart tissue
    term:
      id: UBERON:0000948
      label: heart
    tissue_term:
      preferred_term: heart
      term:
        id: UBERON:0000948
        label: heart
  conditions:
  - spaceflight
  - ground control
  exposures:
  - preferred_term: spaceflight
  publication: PMID:36830740
  evidence:
  - reference: PMID:36830740
    reference_title: "Transcriptomic Effects on the Mouse Heart Following 30 Days on the International Space Station."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our analyses showed that 1147 transcripts were significantly regulated after spaceflight. The MAPK, PI3K-Akt, and GPCR signaling pathways were predicted to be activated."
    explanation: >-
      Spaceflight-induced cardiac transcriptomic changes in MAPK and
      PI3K-Akt pathways overlap with pathways implicated in ATTR
      cardiomyopathy progression and cardiac remodeling.
  notes: >-
    30-day ISS mission. C57BL/6J female mice. Cytoskeleton breakdown
    and reorganization transcripts upregulated, relevant to
    understanding cardiac structural changes in ATTR cardiomyopathy.

# Spaceflight / Microgravity - Heart-on-a-chip on ISS
- accession: "DOI:10.1073/pnas.2404644121"
  title: Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform
  description: >-
    Engineered human heart tissues (EHTs) flown to ISS for 1 month.
    Spaceflight EHTs showed reduced twitch forces, increased arrhythmias,
    sarcomere disruption, and mitochondrial damage. Transcriptomics
    showed upregulation of heart failure, oxidative stress, and
    inflammation genes. Directly relevant to ATTR cardiomyopathy
    pathophysiology.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: engineered heart tissue
    term:
      id: UBERON:0000948
      label: heart
    tissue_term:
      preferred_term: heart
      term:
        id: UBERON:0000948
        label: heart
  conditions:
  - spaceflight
  - ground control
  exposures:
  - preferred_term: spaceflight
  publication: PMID:39312653
  evidence:
  - reference: PMID:39312653
    reference_title: "Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage."
    explanation: >-
      Spaceflight-induced cardiac dysfunction including arrhythmias,
      sarcomere disruption, and mitochondrial damage parallels the
      cardiac pathology seen in ATTR cardiomyopathy, where amyloid
      infiltration causes similar contractile and structural dysfunction.
  notes: >-
    Automated heart-on-a-chip platform. Transcriptomics showed
    upregulation of metabolic disorders, heart failure, oxidative stress,
    and inflammation pathways with downregulation of contractility and
    calcium signaling genes.

# Spaceflight analogue - TTR as biomarker of unloading-induced muscle atrophy
- accession: "DOI:10.1002/jcsm.13146"
  title: Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy
  description: >-
    Mass spectrometry-based plasma proteomics during 10-day bed rest
    (spaceflight analogue). Transthyretin was significantly less abundant
    in subjects who developed muscle atrophy, identifying TTR as a
    potential biomarker for unloading-induced atrophy relevant to both
    spaceflight and ATTR amyloidosis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: blood plasma
    term:
      id: UBERON:0001969
      label: blood plasma
    tissue_term:
      preferred_term: blood plasma
      term:
        id: UBERON:0001969
        label: blood plasma
  conditions:
  - bed rest (spaceflight analogue)
  - baseline
  exposures:
  - preferred_term: bed rest
  publication: PMID:36517414
  evidence:
  - reference: PMID:36517414
    reference_title: "Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transthyretin, a thyroid hormone-binding protein, was significantly less abundant at BR10 in the plasma of subjects with muscle atrophy compared with those with no atrophy (1.6E10 vs. 2.6E10, P = 0.001)"
    explanation: >-
      Demonstrates that plasma TTR levels are significantly altered during
      simulated microgravity (bed rest), with lower TTR associated with
      muscle atrophy. Changes in circulating TTR concentration could
      affect amyloid fibril formation dynamics in ATTR amyloidosis.
  notes: >-
    10-day bed rest study in 10 young males. TTR identified among 6
    proteins distinguishing atrophy-prone from atrophy-resistant subjects.
    Bed rest is a standard ground-based spaceflight analogue.

# Spaceflight analogue - TTR dysregulated in unloaded muscle
- accession: "DOI:10.1002/mus.24590"
  title: Proteomic analysis of mouse soleus muscles affected by hindlimb unloading and reloading
  description: >-
    Proteomic analysis of mouse soleus muscle subjected to hindlimb
    unloading (spaceflight analogue) and reloading. Transthyretin was
    among key dysregulated proteins, alongside fatty acid binding
    protein 3 and alpha-B crystallin.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: soleus muscle
    term:
      id: UBERON:0001389
      label: soleus muscle
    tissue_term:
      preferred_term: soleus muscle
      term:
        id: UBERON:0001389
        label: soleus muscle
  conditions:
  - hindlimb unloading (spaceflight analogue)
  - hindlimb reloading
  - control
  exposures:
  - preferred_term: hindlimb unloading
  publication: PMID:25656502
  evidence:
  - reference: PMID:25656502
    reference_title: "Proteomic analysis of mouse soleus muscles affected by hindlimb unloading and reloading."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Among the dysregulated proteins were fatty acid binding protein 3, α-B crystalline, and transthyretin."
    explanation: >-
      Direct evidence that TTR protein levels are dysregulated in muscle
      tissue under simulated microgravity conditions (hindlimb unloading).
      TTR dysregulation in peripheral tissues is directly relevant to
      ATTR amyloidosis pathogenesis.
  notes: >-
    Hindlimb unloading is a standard ground-based spaceflight analogue.
    9 down-regulated and 7 up-regulated proteins identified in unloaded
    soleus, with TTR among the key dysregulated proteins.

# Spaceflight - Cosmonaut urine proteomics with TTR changes
- accession: "DOI:10.1186/s12918-019-0688-9"
  title: Urine proteome changes associated with autonomic regulation of heart rate in cosmonauts
  description: >-
    Urine proteomics of cosmonauts before and after long-duration
    spaceflight. Transthyretin was among proteins with significantly
    different concentrations between groups with different cardiovascular
    autonomic regulation, linking TTR to spaceflight cardiovascular
    adaptation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: urine
    term:
      id: UBERON:0001088
      label: urine
    tissue_term:
      preferred_term: urine
      term:
        id: UBERON:0001088
        label: urine
  conditions:
  - pre-spaceflight
  - post-spaceflight
  exposures:
  - preferred_term: spaceflight
  publication: PMID:30836973
  evidence:
  - reference: PMID:30836973
    reference_title: "Urine proteome changes associated with autonomic regulation of heart rate in cosmonauts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proteins cadherin-13, mucin-1, alpha-1 of collagen subunit type VI (COL6A1), hemisentin-1, semenogelin-2, SH3 domain-binding protein, transthyretin and serine proteases inhibitors realize a homeostatic role in individuals with different initial type of the cardiovascular system regulation."
    explanation: >-
      Direct measurement of transthyretin changes in cosmonaut urine
      after long-duration spaceflight, linking TTR to cardiovascular
      homeostasis adaptation in microgravity. TTR concentration
      differences between cardiovascular regulation groups are relevant
      to understanding ATTR cardiomyopathy risk factors.
  notes: >-
    Long-duration spaceflight cosmonauts. TTR linked to cardiovascular
    homeostasis, atherogenesis, and vascular rigidity adaptation.

computational_models:
- name: TTR Tetramer In Silico Docking Model for Kinetic Stabilizers
  description: >-
    Semi-quantitative in silico docking model for identifying potent and selective
    transthyretin amyloidogenesis inhibitors. Uses structure-activity relationship
    data and computational docking to TTR thyroxine-binding pockets to predict
    kinetic stabilizers that prevent tetramer dissociation. Validated by the clinical
    success of tafamidis, the first-in-class drug approved for TTR-FAP.
  model_type: MOLECULAR_DOCKING
  publication: PMID:28625364
  findings:
  - statement: In silico docking model predicts potent TTR kinetic stabilizers validated by tafamidis clinical success
  evidence:
  - reference: PMID:28625364
    reference_title: "Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy."
    explanation: Demonstrates that structure-based computational docking to the TTR tetramer successfully identified tafamidis-class kinetic stabilizers.
review_notes: ATTR amyloidosis is a multisystem disorder caused by deposition of misfolded transthyretin protein. Key diagnostic features are peripheral neuropathy and infiltrative cardiomyopathy. Additional phenotypes across other organ systems are common and reflect the systemic nature of amyloid deposition.
disease_term:
  preferred_term: transthyretin amyloidosis
  term:
    id: MONDO:0007100
    label: familial amyloid neuropathy
classifications:
  harrisons_chapter:
  - classification_value: nervous system disorder
  - classification_value: cardiovascular disorder
  - classification_value: hereditary disease

📚

References & Deep Research

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

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

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