Familial Visceral Amyloidosis: Disease-Characteristics Report

Executive summary and curation warning

Familial visceral amyloidosis (FVA; MONDO:0007099) is best treated as a legacy umbrella concept, not as one molecularly uniform disorder. Current protein-based nomenclature divides it into hereditary systemic amyloidoses according to the fibril precursor—principally fibrinogen Aα-chain (AFib; FGA), apolipoprotein A-I (AApoAI; APOA1), lysozyme (ALys; LYZ), apolipoprotein A-II (AApoAII; APOA2), and exceptionally β2-microglobulin (AB2M; B2M). Open Targets associates the exact MONDO entity with FGA, APOA1, LYZ, APOA2, and B2M. Hereditary transthyretin amyloidosis should be represented separately rather than automatically merged into this entry. (OpenTargets Search: familial visceral amyloidosis)

The unifying lesion is extracellular deposition of insoluble, cross-β-sheet-rich fibrils derived from a circulating mutant protein. Organ tropism and prognosis are strongly protein- and variant-dependent: AFib and AApoAII are predominantly renal; AApoAI commonly affects kidney, liver, and heart; ALys may be gastrointestinal, renal, or hepatic; and B2M p.Asp76Asn causes visceral disease distinct from dialysis-related β2-microglobulin amyloidosis. The disease-level record should therefore point to molecular subtype records rather than assign one phenotype frequency or prognosis to all FVA.

Table: This table summarizes familial visceral amyloidosis as a legacy umbrella entity and breaks down the main non-TTR hereditary subtypes by genotype, phenotype, natural history, diagnosis, and management evidence. It is useful for knowledge-base curation because prognosis and treatment differ substantially by subtype rather than by the umbrella term.

1. Disease information

Definition and synonyms

FVA comprises inherited protein-misfolding disorders in which germline variants render normally soluble plasma proteins amyloidogenic, causing systemic—especially visceral—deposition and progressive organ dysfunction. Appropriate synonyms include familial visceral amyloidosis, hereditary visceral amyloidosis, hereditary non-neuropathic systemic amyloidosis, and, more broadly but less precisely, hereditary systemic amyloidosis.

Recommended identifier: MONDO:0007099. A single reliable umbrella-level OMIM, Orphanet, MeSH, ICD-10, or ICD-11 identifier was not established from the retrieved evidence. Those systems generally code amyloidosis broadly or classify individual molecular forms. Do not infer unsupported cross-mappings; retain subtype-specific OMIM/Orphanet identifiers where independently verified.

This report is based on aggregated disease-level literature, including cohorts, systematic reviews, kindreds, case reports, pathology series, and experimental models—not individual EHR data.

Evidence-source distinction

• Human clinical: strongest for AFib and AApoAI natural history and transplantation.
• Human family/case evidence: predominant for ALys, AApoAII, and hereditary B2M.
• Model organism: a human APOA2 Stop78Ser transgenic mouse reproduces systemic disease.
• In vitro/structural: supports variant destabilization, proteolytic fragmentation, and fibrillogenesis, but does not establish clinical penetrance by itself.

2. Etiology, risk, protection, and gene–environment interaction

Causal factors

The primary cause is a germline amyloidogenic variant in a secreted protein gene. Most established forms are autosomal dominant. Disease results from a toxic gain of protein aggregation rather than simple loss of normal protein function. Relevant genes retrieved for MONDO:0007099 are FGA, APOA1, LYZ, APOA2, and B2M. (OpenTargets Search: familial visceral amyloidosis)

Representative causal variants include:

• FGA: p.Glu545Val in current HGVS numbering, historically called E526V in the mature-chain convention; p.Arg554Leu; and C-terminal frameshifts such as c.1673del, p.Lys558Argfs*10. Variant class strongly influences age and progression. (he2025clinicalmanifestationsdiagnosis pages 1-2, escaleira2022fibrinogenaalphachain pages 14-17)
• APOA1: numerous predominantly heterozygous missense/indel variants, including p.Gly26Arg and a reported c.251T>C leucine-to-proline substitution. A 2024 report identified homozygous p.Leu202Arg in isolated cardiac amyloidosis, suggesting a possible recessive mechanism for that allele; one case does not establish general recessive inheritance. (cohen2024prognosticmarkersand pages 194-199, yagi2024theapoa1p.leu202arg pages 1-3, moutafi2019anewgenetic pages 1-2)
• LYZ: heterozygous variants including p.Asp67His and p.Trp82Arg. (OpenTargets Search: familial visceral amyloidosis)
• APOA2: stop-loss variants such as Stop78Ser and Stop78Arg create an abnormal 21-residue C-terminal extension. (chabert2019atransgenicmouse pages 1-2)
• B2M: p.Asp76Asn (D76N), an exceptionally rare familial systemic form distinct from wild-type dialysis-related amyloidosis. (stoppini2015systemicamyloidosislessons pages 1-2)

Risk and modifier factors

The principal risk factors are carriage of a causal allele, increasing age, family history, and subtype-specific variant severity. In AFib, frameshift variants generally cause earlier, more aggressive renal disease than p.Glu545Val. In a 46-case review, women had earlier onset than men, although the biological basis and generalizability are uncertain. (he2025clinicalmanifestationsdiagnosis pages 1-2)

Founder or regional enrichment is plausible for FGA p.Glu545Val: shared haplotypes occur among Portuguese and Brazilian families, and this variant is especially relevant in parts of Europe. AFib is described as the most common hereditary renal amyloidosis in the United Kingdom/Europe, excluding ATTR. (escaleira2022fibrinogenaalphachain pages 14-17)

No validated modifier genes, protective alleles, epigenetic determinants, or reproducible environmental exposures were established. Normal fibrinogen concentration does not exclude AFib because amyloidogenicity reflects variant structure rather than overproduction. (escaleira2022fibrinogenaalphachain pages 14-17)

Environmental and protective factors

No toxin, infection, smoking pattern, diet, alcohol exposure, occupation, or radiation exposure is known to cause these Mendelian forms. Renal function, blood pressure, coexisting diabetes, and age may influence organ reserve and observed progression but are not primary causes. There is no proven diet, supplement, exercise program, or drug that prevents fibril formation in asymptomatic carriers.

The clearest gene–environment interaction is B2M context dependence: wild-type β2-microglobulin produces dialysis-related, predominantly osteoarticular amyloidosis after prolonged renal replacement therapy, whereas germline D76N produces multivisceral amyloid without requiring dialysis and spares bones and ligaments. (stoppini2015systemicamyloidosislessons pages 1-2)

3. Phenotypes

AFib/FGA

AFib usually presents in adulthood with proteinuria, edema, hypertension, progressive chronic kidney disease, and ultimately kidney failure. In a 32-patient French series, median diagnosis age was 51.5 years; proteinuria occurred in 93%, hypertension in 83%, and kidney failure in 68%. Average renal-disease onset was 57 years for E526V, 45 years for R554L, and 24.5 years for frameshift variants. (he2025clinicalmanifestationsdiagnosis pages 1-2)

A systematic review of 46 cases found proteinuria in all patients; 21.7% reached ESRD or renal replacement therapy within one year, 39.1% within one to five years, and only 8.7% remained free of ESRD/RRT beyond five years. Thus severity ranges from slowly progressive p.Glu545Val disease to rapidly progressive frameshift disease. (he2025clinicalmanifestationsdiagnosis pages 1-2)

Suggested HPO terms: Proteinuria (HP:0000093), nephrotic syndrome (HP:0000100), chronic kidney disease (HP:0012622), end-stage renal disease (HP:0003774), edema (HP:0000969), hypertension (HP:0000822), and amyloidosis (HP:0011034). Quality-of-life effects include dialysis dependence, transplantation, fatigue, edema, medication burden, and reduced physical function; subtype-specific EQ-5D/SF-36 data were not found.

AApoAI/APOA1

AApoAI has variable adult onset and variant-dependent kidney, liver, or cardiac disease. In the UK National Amyloidosis Centre cohort of 57 patients carrying 14 APOA1 mutations, median presentation age was 43 years; kidney, liver, and heart involvement occurred in 81%, 67%, and 28%, respectively. Renal involvement was universal among 28 p.Gly26Arg carriers. Median protein excretion was only 0.3 g/day despite renal amyloid, an important distinction from many AL/AA presentations. (cohen2024prognosticmarkersand pages 194-199)

Clinical manifestations include slowly progressive renal impairment, hepatomegaly, abnormal liver enzymes, infiltrative hepatic disease, cardiomyopathy, and occasional gonadal/endocrine involvement. One novel-variant case developed hepatomegaly followed by primary hypogonadism. (moutafi2019anewgenetic pages 1-2)

A 2024 homozygous p.Leu202Arg case developed heart failure beginning at 52 years, needed a pacemaker at 58, and at 69 had ejection fraction 40%, interventricular septal thickness 13 mm, BNP 154 pg/mL, and HDL-C 35 mg/dL; his heterozygous brother was clinically unaffected. (yagi2024theapoa1p.leu202arg pages 1-3)

Suggested HPO: Hepatomegaly (HP:0002240), elevated hepatic transaminases (HP:0002910), cardiomyopathy (HP:0001638), heart failure (HP:0001635), left-ventricular hypertrophy (HP:0001712), conduction abnormality (HP:0001678), hypogonadism (HP:0000135), plus the renal terms above.

ALys/LYZ

ALys is a rare systemic, usually non-neuropathic amyloidosis with heterogeneous gastrointestinal, renal, and hepatic manifestations. In a nine-member p.Trp82Arg family, all affected individuals had predominantly gastrointestinal disease: 8/9 had nonspecific upper-GI symptoms and 3/9 had rectocolic inflammation resembling inflammatory bowel disease; no other amyloid organ involvement was found. (OpenTargets Search: familial visceral amyloidosis)

Suggested HPO: Abdominal pain (HP:0002027), chronic diarrhea (HP:0002014), gastritis (HP:0005268), inflammatory bowel disease (HP:0002037), gastrointestinal amyloidosis, proteinuria, renal insufficiency, and hepatomegaly. Frequencies should not be generalized beyond the p.Trp82Arg kindred.

AApoAII/APOA2

Human AApoAII generally causes proteinuria, glomerular amyloid, nephrotic syndrome, progressive CKD, and ESRD. A Stop78Ser proband developed proteinuria at 42 and was evaluated at 46. The abnormal stop-loss protein had a 21-amino-acid C-terminal extension, directly implicating the extension in amyloidogenesis. Model-informed summaries estimate nephrotic progression in approximately 70% of patients, but this estimate derives from very small kindreds and should be marked low confidence. (chabert2019atransgenicmouse pages 1-2)

AB2M/B2M

D76N β2-microglobulin amyloidosis affects liver, kidney, heart, and other viscera but notably spares the bones and ligaments commonly involved in dialysis-related β2-microglobulin amyloidosis. Reliable phenotype frequencies and age distributions are unavailable because reported families are extremely few. (stoppini2015systemicamyloidosislessons pages 1-2)

4. Genetic and molecular information

These are germline, usually heterozygous variants. Somatic mutation, chromosomal aneuploidy, translocation, repeat expansion, and mitochondrial inheritance are not established causes. Most reported variants are missense, stop-loss, deletion/insertion, or frameshift alleles. Population frequencies are generally compatible with rarity; exact gnomAD frequencies were not available in the retrieved evidence and should be queried variant-by-variant before curation.

Functional consequence is a neomorphic/toxic gain of aggregation: altered stability, proteolytic susceptibility, charge, hydrophobic exposure, or C-terminal sequence permits self-assembly. APOA2 stop-loss alleles add 21 residues; FGA frameshifts replace the normal C terminus; APOA1 fibrils frequently contain N-terminal fragments; D76N changes β2-microglobulin stability and tissue tropism. (chabert2019atransgenicmouse pages 1-2, stoppini2015systemicamyloidosislessons pages 1-2, moutafi2019anewgenetic pages 1-2)

Variant classification must be performed independently under ACMG/AMP criteria. The 2024 APOA1 p.Leu202Arg report classified the allele as likely pathogenic and reported CADD Phred 29.4, but segregation was limited and the proposed recessive mechanism remains provisional. (yagi2024theapoa1p.leu202arg pages 1-3)

No reproducible modifier gene, disease-specific DNA-methylation signature, histone alteration, or large chromosomal abnormality was established.

5. Environmental information

Environmental, lifestyle, and infectious-agent fields are not applicable as primary etiology. Chronic inflammation causes AA amyloidosis and monoclonal plasma-cell disease causes AL amyloidosis, but these are differential diagnoses—not triggers for FVA. Long-term dialysis is causally relevant to acquired wild-type β2-microglobulin amyloidosis but not required for inherited D76N disease. (stoppini2015systemicamyloidosislessons pages 1-2)

6. Mechanism and pathophysiology

Causal chain

1. Upstream germline variant in a secreted protein gene.
2. Hepatic or other physiological synthesis and release of the mutant precursor into blood.
3. Variant-dependent destabilization, abnormal proteolysis, or altered intermolecular interactions.
4. Oligomerization and formation of cross-β amyloid fibrils, often with serum amyloid P component and extracellular-matrix glycosaminoglycans.
5. Extracellular deposition in glomerular mesangium/capillary walls, interstitium, vessels, myocardium, liver, spleen, or GI wall.
6. Mechanical distortion, microvascular dysfunction, cellular stress, and impaired filtration/contractility/organ architecture.
7. Proteinuria, nephrotic syndrome, CKD/ESRD, restrictive or hypertrophic cardiac disease, hepatomegaly, or GI dysfunction.

D76N deposits lack the wild-type and N-terminally truncated β2-microglobulin species typical of dialysis-related deposits, supporting a distinct molecular assembly and explaining divergent visceral versus osteoarticular tropism. (stoppini2015systemicamyloidosislessons pages 1-2)

Suggested ontology annotations

GO biological process: protein folding; protein misfolding; amyloid fibril formation; protein aggregation; extracellular-matrix organization; response to unfolded protein; glomerular filtration; lipid transport for APOA1/APOA2; fibrinogen complex biology for FGA.

GO cellular component: extracellular region, extracellular space, amyloid fibril, blood microparticle, high-density lipoprotein particle, fibrinogen complex.

Cell Ontology suggestions: hepatocyte (major source for FGA and apolipoproteins), kidney glomerular endothelial cell, podocyte, mesangial cell, cardiomyocyte, vascular endothelial cell, intestinal epithelial cell, macrophage. Amyloid is extracellular; these cells are sources, neighbors, or functionally injured populations rather than necessarily intracellular deposit-bearing cells.

No validated disease-specific single-cell atlas, spatial-transcriptomic signature, lipidomic/metabolomic diagnostic profile, CRISPR screen, or integrated multi-omics dataset was identified. Contemporary proteomics is clinically important for deposit typing rather than population-level molecular profiling.

7. Anatomy

Primary organs: kidney/glomerulus (AFib, AApoAII, many AApoAI/ALys cases), liver (AApoAI, ALys, B2M), heart/myocardium and conduction system (selected APOA1 variants and B2M), gastrointestinal tract (some LYZ variants), spleen and vasculature.

Suggested UBERON mappings: kidney, renal glomerulus, liver, heart, myocardium, gastrointestinal tract, stomach, colon, spleen, blood vessel, peripheral nerve, and testis where clinically involved. Lateralization is not relevant: systemic deposition is diffuse rather than unilateral.

Histologically, renal amyloid may occupy glomerular mesangium and subendothelial areas and may extend to vessels and tubulointerstitium. Amyloid fibrils are randomly arranged, approximately 8–12 nm in one AFib renal series, and show Congo-red positivity with apple-green birefringence under polarized light.

8. Temporal development

Onset is usually insidious and adult, with marked genotype dependence. AFib frameshifts can begin in adolescence or young adulthood; p.Glu545Val commonly presents later. AApoAI median presentation was 43 years, but cardiac p.Leu202Arg disease began at 52. (he2025clinicalmanifestationsdiagnosis pages 1-2, cohen2024prognosticmarkersand pages 194-199, yagi2024theapoa1p.leu202arg pages 1-3)

The course is chronic and progressive rather than episodic. A practical staging framework is:

1. asymptomatic carrier;
2. biomarker abnormality—proteinuria, reduced eGFR, abnormal liver tests, BNP/troponin rise;
3. clinically apparent single-organ amyloidosis;
4. multiorgan or advanced organ dysfunction;
5. ESRD, advanced heart failure, or transplant requirement.

Spontaneous remission is not documented. Removing the major hepatic source by liver transplantation can stop precursor production and permit partial deposit regression, but timing before irreversible organ failure is critical. AApoAI renal disease progressed to ESRD over a median 15 years, whereas many AFib cases progressed within five years. (he2025clinicalmanifestationsdiagnosis pages 1-2, cohen2024prognosticmarkersand pages 194-199)

9. Inheritance and population

Most forms are autosomal dominant with age-dependent, incomplete penetrance and variable expressivity. The homozygous APOA1 p.Leu202Arg report is a possible autosomal-recessive exception. No evidence supports anticipation, repeat expansion, or a systematic role for germline mosaicism. Consanguinity is relevant only to rare recessive hypotheses such as p.Leu202Arg. (yagi2024theapoa1p.leu202arg pages 1-3)

Reliable global incidence, prevalence, carrier frequency, sex ratio, and mortality rate for MONDO:0007099 are unavailable. The combined hereditary non-TTR forms are ultra-rare. AFib represented approximately 1.3% of renal amyloidosis cases in one Mayo Clinic context, but regional founder effects can produce much higher local proportions. (he2025clinicalmanifestationsdiagnosis pages 1-2)

AFib p.Glu545Val is enriched in European populations and has Portuguese/Brazilian founder haplotypes. A broader estimate that inherited forms account for roughly 10% of systemic amyloidosis is not specific to this MONDO entity and should not be entered as FVA prevalence. (escaleira2022fibrinogenaalphachain pages 14-17)

10. Diagnostics

Recommended workflow

1. Recognize the organ syndrome: unexplained familial proteinuria/CKD, low-proteinuria renal dysfunction, hepatomegaly, infiltrative liver disease, cardiomyopathy, or familial refractory GI disease.
2. Exclude common mimics: serum and urine immunofixation plus serum free-light chains for AL; inflammatory evaluation for AA; TTR-focused imaging/genotyping when ATTR is suspected.
3. Confirm amyloid: biopsy affected tissue, or a lower-risk site where appropriate, with Congo-red staining and polarized-light birefringence. Electron microscopy may show nonbranching fibrils.
4. Type the fibril protein: laser-capture microdissection with LC-MS/MS is preferred where available; immunohistochemistry/immunoelectron microscopy can support typing but may be limited by antibody specificity.
5. Confirm germline cause: sequence the proteomically implicated gene and perform segregation/cascade testing. A broader hereditary-amyloidosis panel is appropriate if typing is equivocal or the phenotype is atypical.
6. Stage organ disease: urine protein, creatinine/eGFR, blood pressure, liver tests, ECG, echocardiography, cardiac MRI, BNP/NT-proBNP and troponin; GI endoscopy/biopsy when indicated.

The AFib review states directly: “The diagnosis of this disease is primarily based on renal biopsy, mass spectrometry, and molecular gene detection.” (publication online 2024; issue 2025; DOI below). (he2025clinicalmanifestationsdiagnosis pages 1-2)

Proteomics is essential because a coincidental monoclonal gammopathy can lead to erroneous AL diagnosis. The fibril protein—not merely the presence of a germline variant—must match the deposits. WES/WGS can identify unusual alleles but does not replace tissue typing. CMA, karyotyping, FISH, mtDNA analysis, and repeat-expansion tests are not routine.

Differential diagnosis

AL amyloidosis; AA amyloidosis; ATTRv/ATTRwt; ALECT2; hereditary gelsolin/cystatin-C/apolipoprotein-C amyloidoses; diabetic and hypertensive nephropathy; membranous nephropathy; hereditary nephrotic syndromes; hypertrophic cardiomyopathy; storage disease; inflammatory bowel disease; and infiltrative liver disease.

Screening

Population or newborn screening is not justified. Cascade testing of adult relatives after identification of a familial pathogenic variant is appropriate with genetic counseling. Baseline and periodic renal, cardiac, hepatic, and symptom-directed surveillance should begin before the family’s earliest usual onset. Exact surveillance intervals are not validated for these ultra-rare subtypes.

11. Outcome and prognosis

Prognosis is determined mainly by precursor, variant, organ involvement, renal stage, and cardiac disease. No unified five- or ten-year survival statistic exists.

• AFib: often progresses to ESRD; frameshifts and R554L are more aggressive than p.Glu545Val. In the 46-case synthesis, 60.8% reached ESRD/RRT within five years. (he2025clinicalmanifestationsdiagnosis pages 1-2)
• AApoAI: usually slower. Median time from diagnosis to ESRD was 15.0 years (95% CI 10.0–20.0). (cohen2024prognosticmarkersand pages 194-199)
• ALys: may remain organ-restricted and mild, as in the p.Trp82Arg GI family, but other variants cause severe renal/hepatic disease.
• AApoAII: substantial risk of nephrotic syndrome and ESRD, but estimates are imprecise.
• B2M D76N: prognosis is poorly quantified; cardiac and multivisceral involvement can be serious.

Disability arises from edema, fatigue, dietary and medication restrictions, dialysis, transplant complications, heart failure, arrhythmia, GI symptoms, and endocrine dysfunction. Validated FVA-specific patient-reported outcome datasets were not found.

12. Treatment

General strategy

There is no approved umbrella-level pharmacotherapy and no established FGA-, APOA1-, LYZ-, APOA2-, or B2M-directed stabilizer, siRNA, ASO, or gene-editing therapy. ATTR drugs such as tafamidis, patisiran, vutrisiran, and inotersen should not be extrapolated to these proteins.

Supportive management includes renin–angiotensin-system blockade when tolerated, individualized SGLT2 inhibition in CKD, diuretics for edema/heart failure, blood-pressure control, avoidance of nephrotoxins, nutritional support, dialysis, arrhythmia management, and multidisciplinary amyloidosis follow-up. Evidence is largely observational.

Suggested NCIT intervention concepts: Kidney Transplantation, Liver Transplantation, Combined Liver and Kidney Transplantation, Hemodialysis, Antihypertensive Therapy, Diuretic Therapy, Genetic Counseling, and supportive care. Exact NCIT codes should be validated against the current NCIT release.

Transplantation

For AFib, kidney transplantation is reasonable, especially for p.Glu545Val, but recurrence is expected because the liver continues producing mutant fibrinogen. In the French series, graft recurrence was lower for E526V than non-E526V variants (22% versus 83%; P=0.03), and graft loss occurred less often (33% versus 100%). No recurrence was seen after combined liver–kidney transplantation, supporting source-organ replacement for aggressive frameshift disease. (he2025clinicalmanifestationsdiagnosis pages 1-2)

For AApoAI, transplantation outcomes were encouraging. Among 57 patients, 18 underwent renal transplantation, including five combined liver–kidney and two heart–kidney procedures. Median renal allograft survival was 22 years; all four patients with serial serum amyloid-P scintigraphy after liver transplantation showed amyloid regression. (cohen2024prognosticmarkersand pages 194-199)

For ALys, AApoAII, and hereditary B2M, transplantation decisions are case-specific; robust comparative outcome data are absent.

Trials and recent therapeutic development

The ClinicalTrials.gov search retrieved ATTR-focused or mixed-amyloidosis studies but no clearly subtype-specific interventional trial for FGA, APOA1, LYZ, APOA2, or hereditary B2M. This is an important negative finding: advanced RNA and CRISPR programs in ATTR do not yet represent real-world treatment for FVA.

13. Prevention

Primary prevention of spontaneous disease is not possible after inheriting a causal allele. Actionable measures are genetic counseling, cascade testing, informed reproductive planning, prenatal diagnosis, and preimplantation genetic testing where legally and ethically available. Secondary prevention consists of presymptomatic organ surveillance and early referral before irreversible CKD or cardiomyopathy. Tertiary prevention includes blood-pressure/proteinuria management, early transplant assessment, vaccination appropriate for CKD/transplant candidates, infection prevention, and cardiovascular risk management.

There is no vaccine, chemoprophylaxis, or validated behavioral intervention that prevents mutant-protein amyloid deposition.

14. Other species and natural disease

No well-established, naturally occurring veterinary disease that is directly homologous to human FGA-, LYZ-, or B2M-associated FVA was identified. Amyloidosis occurs widely in animals, but animal AA, AL, endocrine, and age-associated amyloidoses should not be conflated with this human Mendelian umbrella. APOA2-related amyloid occurs naturally in senescence-accelerated mouse strains, although its mechanism differs from human stop-loss AApoAII disease. Zoonotic transmission is not applicable.

Relevant taxonomy suggestions: Homo sapiens—NCBI Taxon 9606; Mus musculus—10090. No VBO breed mapping is applicable.

15. Model organisms

The strongest disease-specific model is a transgenic Mus musculus expressing human APOA2 Stop78Ser at physiological levels. All mice developed systemic amyloidosis; glomerular renal amyloid and renal insufficiency were prominent, with liver, heart, and spleen involvement. Deposits began at two months in high-expressing animals, renal insufficiency appeared after six months, and death began from six months. Full-length mature Stop78Ser ApoA-II was recovered as the fibril protein. (chabert2019atransgenicmouse pages 1-2)

This model reproduces early-onset, multiorgan human AApoAII and permits testing of fibrillogenesis, biomarkers, precursor suppression, and clearance therapies. Limitations include transgene-expression effects, accelerated disease, species-specific proteostasis and ApoA-II biology, and incomplete representation of human heterozygous, late-onset disease.

Cell-free recombinant-protein systems and cultured-cell assays are useful for measuring stability, proteolysis, lipid binding, oligomerization, and fibril formation, but they do not reproduce organ tropism, circulation, extracellular matrix, or immune clearance. No mature organoid, iPSC, zebrafish, Drosophila, or CRISPR-screen platform specific to the full FVA umbrella was identified.

Recent developments, 2023–2024

1. Expanded APOA1 inheritance: the August 2024 homozygous p.Leu202Arg cardiac case raises the possibility that selected APOA1 alleles act recessively, contrary to the usual dominant model. This remains hypothesis-generating because evidence is from one patient. DOI: https://doi.org/10.1038/s41439-024-00288-7. (yagi2024theapoa1p.leu202arg pages 1-3)
2. Improved proteomic typing: 2024 work evaluated DIA, FAIMS, de-novo/error-tolerant sequence searches, and MALDI imaging to accelerate and improve amyloid protein/variant identification. These methods are promising diagnostic refinements, not yet replacements for validated LMD–LC-MS/MS workflows.
3. Updated AFib synthesis: a systematic search updated through November 2023 quantified rapid progression and reinforced the biopsy–mass-spectrometry–sequencing triad. The article was published online in October 2024 and in a 2025 issue. (he2025clinicalmanifestationsdiagnosis pages 1-2)
4. Nomenclature: the International Society of Amyloidosis issued a 2024 protein-based nomenclature update, reinforcing that “familial visceral amyloidosis” should be decomposed by fibril precursor rather than treated as one phenotype.

Selected exact abstract quotations

• AFib review: “AFib amyloidosis progresses rapidly.” (he2025clinicalmanifestationsdiagnosis pages 1-2)
• AApoAI cohort: “AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose.” (cohen2024prognosticmarkersand pages 194-199)
• APOA1 2024 case: “ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver.” (yagi2024theapoa1p.leu202arg pages 1-3)
• B2M review: “Its genetic variant D76N causes a very rare form of familial systemic amyloidosis.” (stoppini2015systemicamyloidosislessons pages 1-2)
• APOA2 model: “A transgenic mouse model reproduces human hereditary systemic amyloidosis.” (chabert2019atransgenicmouse pages 1-2)

Key publications and identifiers

• He et al. Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis. Online October 2024/issue 2025. DOI: https://doi.org/10.1007/s11255-024-04236-w. (he2025clinicalmanifestationsdiagnosis pages 1-2)
• Meyer et al. Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis. September 2020. DOI: https://doi.org/10.1053/j.ajkd.2020.02.445.
• Stangou et al. Hereditary fibrinogen A alpha-chain amyloidosis. April 2010. DOI: https://doi.org/10.1182/blood-2009-06-223792.
• Cohen et al. The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre. May 2022. DOI: https://doi.org/10.1080/13506129.2022.2070741. (cohen2024prognosticmarkersand pages 194-199)
• Yagi et al. The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis. August 2024. DOI: https://doi.org/10.1038/s41439-024-00288-7. (yagi2024theapoa1p.leu202arg pages 1-3)
• Moutafi et al. A new genetic variant of hereditary apolipoprotein A-I amyloidosis. January 2019. DOI: https://doi.org/10.1186/s12881-019-0755-5. (moutafi2019anewgenetic pages 1-2)
• Jean et al. A new family with hereditary lysozyme amyloidosis… September 2014. DOI: https://doi.org/10.1186/1471-230X-14-159.
• Yazaki et al. Renal amyloidosis caused by a novel stop-codon mutation in APOA2. November 2001. DOI: https://doi.org/10.1046/j.1523-1755.2001.00024.x.
• Chabert et al. A transgenic mouse model reproduces human hereditary systemic amyloidosis. September 2019. DOI: https://doi.org/10.1016/j.kint.2019.03.013. (chabert2019atransgenicmouse pages 1-2)
• Stoppini and Bellotti. Systemic Amyloidosis: Lessons from β2-Microglobulin. April 2015. DOI: https://doi.org/10.1074/jbc.R115.639799. (stoppini2015systemicamyloidosislessons pages 1-2)
• Landmark FGA association: PMID 8097946; additional FGA evidence indexed under PMIDs 19073821, 23551149, 29142973. LYZ evidence includes PMIDs 8464497, 11849445, 12360495, 15745733, 16523055, 20301373, 21988333; APOA1 evidence includes PMIDs 12050338, 16925563, 21820994, 26515634, 27240838, 27604308, 32022753; hereditary B2M includes PMID 22693999. These PMID associations are database-level links and should be checked against the full article before attaching them to individual variant assertions. (OpenTargets Search: familial visceral amyloidosis)

Knowledge gaps and confidence assessment

High confidence: umbrella status; causal genes; autosomal-dominant inheritance for most forms; renal predominance of AFib; genotype-dependent AFib progression; AApoAI organ distribution and transplant outcomes; requirement for tissue typing plus molecular confirmation.

Moderate confidence: precise organ tropism of individual rare APOA1/LYZ/APOA2 variants and benefit of source-organ transplantation outside larger AFib/AApoAI series.

Low or unavailable: global prevalence/incidence, penetrance estimates, carrier frequencies, sex ratio, unified survival, protective factors, modifier genes, pharmacogenomics, epigenetics, disease-specific omics signatures, validated quality-of-life statistics, natural veterinary homologues, and interventional-trial efficacy. These fields should be stored as not established, not as negative biological findings.

References

1. (OpenTargets Search: familial visceral amyloidosis): Open Targets Query (familial visceral amyloidosis, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (stoppini2015systemicamyloidosislessons pages 1-2): Monica Stoppini and Vittorio Bellotti. Systemic amyloidosis: lessons from β2-microglobulin. Apr 2015. URL: https://doi.org/10.1074/jbc.r115.639799, doi:10.1074/jbc.r115.639799. This article has 115 citations and is from a domain leading peer-reviewed journal.

3. (cohen2024prognosticmarkersand pages 194-199): OC Cohen. Prognostic markers and management strategies in systemic amyloidosis. Unknown journal, 2024.

4. (he2025clinicalmanifestationsdiagnosis pages 1-2): Linying He, Jiahui Zhou, Miner Wang, Jianxiang Chen, Chang Liu, Jiazhen Shi, Yanxia Rui, and Henglan Wu. Clinical manifestations, diagnosis and treatment of hereditary fibrinogen aα-chain renal amyloidosis: one case report and systematic review. International Urology and Nephrology, 57:517-533, Oct 2025. URL: https://doi.org/10.1007/s11255-024-04236-w, doi:10.1007/s11255-024-04236-w. This article has 1 citations and is from a peer-reviewed journal.

5. (escaleira2022fibrinogenaalphachain pages 14-17): JPR da Cruz Escaleira. Fibrinogen a alpha-chain amyloidosis: the landscape of dialysis and kidney transplantation in patients with the fga p. glu545val variant and portuguese ancestry. Unknown journal, 2022.

6. (yagi2024theapoa1p.leu202arg pages 1-3): Shusuke Yagi, Ryosuke Miyamoto, Masayoshi Tasaki, Hiroyuki Morino, Ryuji Otani, Muneyuki Kadota, Takayuki Ise, Hiroki Yamazaki, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Daiju Fukuda, Mitsuharu Ueda, and Masataka Sata. The apoa1 p.leu202arg variant potentially causes autosomal recessive cardiac amyloidosis. Human Genome Variation, Aug 2024. URL: https://doi.org/10.1038/s41439-024-00288-7, doi:10.1038/s41439-024-00288-7. This article has 3 citations.

7. (moutafi2019anewgenetic pages 1-2): Myrto Moutafi, Dimitrios C. Ziogas, Spyros Michopoulos, Tina Bagratuni, Vassiliki Vasileiou, Laura Verga, Giampaolo Merlini, Giovanni Palladini, Charis Matsouka, Meletios A. Dimopoulos, and Efstathios Kastritis. A new genetic variant of hereditary apolipoprotein a-i amyloidosis: a case-report followed by discussion of diagnostic challenges and therapeutic options. BMC Medical Genetics, Jan 2019. URL: https://doi.org/10.1186/s12881-019-0755-5, doi:10.1186/s12881-019-0755-5. This article has 18 citations and is from a peer-reviewed journal.

8. (chabert2019atransgenicmouse pages 1-2): Michèle Chabert, Xavier Rousset, Magali Colombat, Michel Lacasa, Hermine Kakanakou, Mathilde Bourderioux, Pierre Brousset, Odile Burlet-Schiltz, Juris J. Liepnieks, Barbara Kluve-Beckerman, Gilles Lambert, François P. Châtelet, Merrill D. Benson, and Athina D. Kalopissis. A transgenic mouse model reproduces human hereditary systemic amyloidosis. Kidney international, 96:628-641, Sep 2019. URL: https://doi.org/10.1016/j.kint.2019.03.013, doi:10.1016/j.kint.2019.03.013. This article has 2 citations and is from a highest quality peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Every term resolved, and every label the report gave matched.