Hereditary amyloidosis

Summary

Hereditary amyloidosis (MONDO:0018634) is a disease (an umbrella term covering 9 Mondo subtypes) caused by APOA4 (GenCC Strong), with 2 cohort genes and 8 clinical trials. Top therapeutic interventions include diflunisal, acoramidis, and patisiran.

At a glance

• Causal gene: APOA4 (GenCC Strong)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary amyloidosis
Mondo ID	MONDO:0018634
MeSH	D028226
Orphanet	444116
ICD-11	1152878652
NCIT	C84555
SNOMED CT	367601000119103
UMLS	C0740340
MedGen	148146
GARD	0006611
Is cancer (heuristic)	no

Also known as: amyloidosis hereditary · amyloidosis, Familial · familial amyloidosis · hereditary amyloidosis (disease)

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record · 8 cell lines.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hereditary amyloidosis

Related subtypes (92): thiopurine metabolic disease, hypercalcemia, infantile, hypermanganesemia with dystonia, abdominal obesity-metabolic syndrome, plasma protein metabolism disease, inherited lipid metabolism disorder, lysosomal storage disease, striatonigral degeneration, inborn metal metabolism disorder, inborn vitamin metabolic disorder, chondrocalcinosis 2, Ehlers-Danlos syndrome, spondylodysplastic type, fish eye disease, aromatase excess syndrome, spondyloepiphyseal dysplasia with congenital joint dislocations, hypertriglyceridemia 1, autosomal dominant myoglobinuria, diastrophic dysplasia, hemolytic anemia due to diphosphoglycerate mutase deficiency, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, inherited threoninemia, inborn glycerol kinase deficiency, achondrogenesis type IB, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, diabetes mellitus, noninsulin-dependent, 3, hypercholesterolemia, familial, 4, hypoalphalipoproteinemia, primary, 1, autosomal recessive proximal renal tubular acidosis, diabetes mellitus, noninsulin-dependent, 4, normophosphatemic familial tumoral calcinosis, apolipoprotein c-III deficiency, hypotonia-failure to thrive-microcephaly syndrome, chondrodysplasia with joint dislocations, gPAPP type, gluthathione peroxidase deficiency, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diabetes mellitus, noninsulin-dependent, 5, congenital disorder of glycosylation, monogenic diabetes, 2-hydroxyglutaric aciduria, familial hypoparathyroidism, familial intrahepatic cholestasis, inborn aminoacylase deficiency, disorder of lysosomal-related organelles, inborn disorder of porphyrin metabolism, disorder of metabolite absorption and transport, autosomal dominant proximal renal tubular acidosis, neurodegeneration with brain iron accumulation, ferro-cerebro-cutaneous syndrome, familial hypocalciuric hypercalcemia, hypophosphatasia, peroxisomal disease, inborn disorder of amino acid and other organic acid metabolism, inborn carbohydrate metabolic disorder, inborn disorder of energy metabolism, inborn disorder of biogenic amine metabolism and transport, inborn disorder of purine or pyrimidine metabolism, spondyloepimetaphyseal dysplasia, PAPSS2 type, hereditary lipodystrophy, hereditary recurrent myoglobinuria, DNA repair disease, 4-hydroxyphenylacetic aciduria, 5-nucleotidase syndrome, antigen-peptide-transporter 2 deficiency, APO A-i deficiency, cardiomyopathy hypogonadism metabolic anomalies, deficiency of coenzyme q cytochrome c reductase, defective apolipoprotein b-100, sulfide quinone oxidoreductase deficiency, congenital disorder of deglycosylation, hypoalphalipoproteinemia, primary, 2, uridine-cytidineuria, NAD(P)HX dehydratase deficiency, inborn disorder of aspartate family metabolism, weinstein kliman scully syndrome, glycoprotein metabolism disease, inherited thyroid metabolism disease, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, combined ApoA-I and ApoC-III deficiency, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 1, Waldenstrom macroglobulinemia, mucopolysaccharidosis or mucopolysaccharidosis-like disorder, disorder of peptide and amine metabolism, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, Lane Hamilton syndrome, SQSTM1-related multisystem proteinopathy, hypertriglyceridemia 2, autosomal dominant dopa-responsive dystonia

Subtypes (9): cerebral amyloid angiopathy, Finnish type amyloidosis, familial visceral amyloidosis, familial amyloid neuropathy, familial primary localized cutaneous amyloidosis, variant ABeta2M amyloidosis, ITM2B amyloidosis, pulmonary amyloidosis, APP-related brain and vascular amyloidosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13450	NM_000371.4(TTR):c.379A>G (p.Ile127Val)	TTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803482	NM_000371.4(TTR):c.277A>G (p.Ile93Val)	TTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APOA4	Strong	Autosomal dominant	hereditary amyloidosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTR	Orphanet:597939	Euthyroid dysprealbuminemic hyperthyroxinemia
TTR	Orphanet:85447	ATTRV30M amyloidosis
TTR	Orphanet:85451	ATTRV122I amyloidosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOA4	HGNC:602	ENSG00000110244	P06727	Apolipoprotein A-IV	gencc
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOA4	Apolipoprotein A-IV	May have a role in chylomicrons and VLDL secretion and catabolism.
TTR	Transthyretin	Thyroid hormone-binding protein.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOA4	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
TTR	Other/Unknown	no		Transthyretin/HIU_hydrolase, Transthyretin/HIU_hydrolase_d, Thyroxine_BS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
ileal mucosa	1
jejunal mucosa	1
choroid plexus epithelium	1
right lobe of liver	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOA4	122	tissue_specific	marker	jejunal mucosa, ileal mucosa, duodenum
TTR	185	broad	marker	choroid plexus epithelium, type B pancreatic cell, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTR	4,528
APOA4	1,268

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTR	P02766	462
APOA4	P06727	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Retinoid metabolism and transport	2	248.3×	3e-04	TTR, APOA4
Amyloid fiber formation	2	102.9×	9e-04	TTR, APOA4
Defective visual phototransduction due to STRA6 loss of function	1	1903.3×	0.003	TTR
Chylomicron assembly	1	571.0×	0.007	APOA4
Chylomicron remodeling	1	571.0×	0.007	APOA4
Plasma lipoprotein assembly	1	356.9×	0.009	APOA4
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.009	APOA4
The canonical retinoid cycle in rods (twilight vision)	1	259.6×	0.009	TTR
Plasma lipoprotein remodeling	1	237.9×	0.009	APOA4
Metabolism of fat-soluble vitamins	1	190.3×	0.010	APOA4
Visual phototransduction	1	129.8×	0.013	APOA4
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.014	APOA4
Non-integrin membrane-ECM interactions	1	77.2×	0.019	TTR
Metabolism of vitamins and cofactors	1	58.3×	0.023	APOA4
Sensory Perception	1	47.6×	0.026	APOA4
Transport of small molecules	1	12.6×	0.093	APOA4
Neutrophil degranulation	1	11.5×	0.095	TTR
Metabolism of proteins	1	6.2×	0.164	APOA4
Metabolism	1	5.8×	0.165	APOA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein-lipid complex assembly	1	8426.0×	0.002	APOA4
response to lipid hydroperoxide	1	4213.0×	0.002	APOA4
response to triglyceride	1	4213.0×	0.002	APOA4
negative regulation of plasma lipoprotein oxidation	1	4213.0×	0.002	APOA4
negative regulation of glomerular filtration	1	2106.5×	0.002	TTR
regulation of intestinal cholesterol absorption	1	2106.5×	0.002	APOA4
chylomicron remodeling	1	2106.5×	0.002	APOA4
chylomicron assembly	1	2106.5×	0.002	APOA4
acylglycerol homeostasis	1	1685.2×	0.002	APOA4
response to stilbenoid	1	1404.3×	0.002	APOA4
purine nucleobase metabolic process	1	1203.7×	0.002	TTR
regulation of cholesterol transport	1	1203.7×	0.002	APOA4
positive regulation of triglyceride catabolic process	1	1053.2×	0.002	APOA4
peripheral nervous system axon regeneration	1	1053.2×	0.002	APOA4
very-low-density lipoprotein particle remodeling	1	1053.2×	0.002	APOA4
phototransduction, visible light	1	648.1×	0.003	TTR
positive regulation of fatty acid biosynthetic process	1	648.1×	0.003	APOA4
phospholipid efflux	1	561.7×	0.003	APOA4
removal of superoxide radicals	1	526.6×	0.003	APOA4
lipoprotein metabolic process	1	468.1×	0.003	APOA4
reverse cholesterol transport	1	468.1×	0.003	APOA4
high-density lipoprotein particle remodeling	1	401.2×	0.004	APOA4
phosphatidylcholine metabolic process	1	401.2×	0.004	APOA4
innate immune response in mucosa	1	337.0×	0.004	APOA4
hydrogen peroxide catabolic process	1	337.0×	0.004	APOA4
cholesterol efflux	1	263.3×	0.005	APOA4
retinoid metabolic process	1	247.8×	0.005	TTR
leukocyte cell-cell adhesion	1	234.1×	0.005	APOA4
lipid homeostasis	1	168.5×	0.007	APOA4
lipid transport	1	131.7×	0.008	APOA4

Therapeutics

Drugs indicated for this disease

2 approved, 12 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Patisiran Sodium	Approved (phase 4)
Tafamidis	Approved (phase 4)
Anselamimab	Phase 3 (in late-stage trials)
Birtamimab	Phase 3 (in late-stage trials)
Bortezomib	Phase 3 (in late-stage trials)
Daratumumab	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Hyaluronidase	Phase 3 (in late-stage trials)
Ixazomib	Phase 3 (in late-stage trials)
Lenalidomide	Phase 3 (in late-stage trials)
Melphalan	Phase 3 (in late-stage trials)
Patisiran	Phase 3 (in late-stage trials)
Thalidomide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Amiodarone, Belantamab Mafodotin, Bendamustine, Dapagliflozin, Elotuzumab, Epigalocatechin Gallate, Isatuximab, Pomalidomide.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TTR	TRICLABENDAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TTR	29	4
APOA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRICLABENDAZOLE	4	TTR
AMLEXANOX	4	TTR
TOLCAPONE	4	TTR
DICLOFENAC	4	TTR
LEVOTHYROXINE	4	TTR
TAFAMIDIS	4	TTR
BENZIODARONE	4	TTR
BITHIONOL	4	TTR
BENZBROMARONE	4	TTR
ACORAMIDIS	4	TTR
GEMFIBROZIL	4	TTR
MECLOFENAMIC ACID	4	TTR
DASATINIB	4	TTR
DEXTROTHYROXINE	4	TTR
TRICLOSAN	4	TTR
DIFLUNISAL	4	TTR
CAFFEIC ACID	3	TTR
RESVERATROL	3	TTR
EPIGALOCATECHIN GALLATE	3	TTR
DIACEREIN	3	TTR
TOLFENAMIC ACID	2	TTR
LUTEOLIN	2	TTR
FLUFENAMIC ACID	2	TTR
XANTHOHUMOL	2	TTR
GENISTEIN	2	TTR
NIFLUMIC ACID	2	TTR
DAIDZEIN	2	TTR
PTEROSTILBENE	2	TTR
ACECLOFENAC	2	TTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TTR	423	Binding:391, Functional:32

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TTR	423

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

27 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TRICLABENDAZOLE	4	TTR
AMLEXANOX	4	TTR
TOLCAPONE	4	TTR
DICLOFENAC	4	TTR
LEVOTHYROXINE	4	TTR
TAFAMIDIS	4	TTR
BENZIODARONE	4	TTR
BITHIONOL	4	TTR
BENZBROMARONE	4	TTR
GEMFIBROZIL	4	TTR
MECLOFENAMIC ACID	4	TTR
DASATINIB	4	TTR
DEXTROTHYROXINE	4	TTR
TRICLOSAN	4	TTR
CAFFEIC ACID	3	TTR
RESVERATROL	3	TTR
EPIGALOCATECHIN GALLATE	3	TTR
DIACEREIN	3	TTR
TOLFENAMIC ACID	2	TTR
LUTEOLIN	2	TTR
FLUFENAMIC ACID	2	TTR
XANTHOHUMOL	2	TTR
GENISTEIN	2	TTR
NIFLUMIC ACID	2	TTR
DAIDZEIN	2	TTR
PTEROSTILBENE	2	TTR
ACECLOFENAC	2	TTR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TTR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APOA4

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
APOA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00294671	PHASE2/PHASE3	COMPLETED	The Effect of Diflunisal on Familial Amyloidosis
NCT03862807	PHASE3	COMPLETED	Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant
NCT05489549	Not specified	RECRUITING	Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers
NCT07213297	Not specified	RECRUITING	Comprehensive Program for Hereditary Transthyretin Amyloidosis
NCT04695340	Not specified	WITHDRAWN	Effect of Psyllium (Plantago Ovata) on Digestive Disorders in Familial Amyloidosis
NCT05940922	Not specified	UNKNOWN	RWE-based Treatment Patterns and Outcomes in CIDP

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DIFLUNISAL	4	3
ACORAMIDIS	4	1
PATISIRAN	3	1
NEXIGURAN	2	1
PLANTAGO SEED	2	1
ZICLUMERAN	2	1