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Inheritance

1

Autosomal dominant HP:0000006

Every recognised precursor form is transmitted as an autosomal dominant trait: affected individuals are heterozygous for a variant in the precursor gene, and one variant allele suffices because the disease arises from the amyloidogenic behaviour of the variant protein rather than from loss of the normal protein's function. Penetrance is markedly variable and, for the fibrinogen forms, low enough that a family history of renal disease is absent in about half of patients - which is why apparently sporadic renal amyloid still warrants sequencing of the precursor genes. Lysozyme amyloidosis sits at the other end of the penetrance range, with a clear family history in every case of one referral cohort.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

PMID:12832750 SUPPORT Human Clinical

"These diseases are inherited in an autosomal dominant manner with variable penetrance, and can present clinically at any time from the teen years to old age, though usually in mid-adult life."

States both the autosomal dominant transmission and the variable penetrance and wide age range curated in this block.

PMID:19073821 SUPPORT Human Clinical

"Overall, a family history of renal disease or amyloidosis was absent in 46% patients with AFib, with all of the available evidence indicating that this was due to reduced penetrance"

Quantifies the incomplete penetrance in the largest single cohort and gives the reason a negative family history does not exclude the diagnosis.

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Subtypes

4

AApoAI amyloidosis (apolipoprotein A-I, APOA1) MONDO:0019731

APOA1 hgnc:600

Amyloidosis in which the fibril protein is a variant apolipoprotein A-I, the principal HDL apolipoprotein. It is the most clinically heterogeneous of the four forms: kidney, liver and heart are all involved in a substantial fraction of patients, and it is also the only form in which peripheral neuropathy is described, and then only with the Gly26Arg variant and only in some kindreds. The renal lesion is characteristically medullary and tubulointerstitial rather than glomerular, so urinalysis may be bland and the presentation a defective urine-concentrating capacity rather than heavy proteinuria. Progression to end-stage renal disease is the slowest of the four forms, with a median of about 15 years from diagnosis.

Show evidence (2 references)

PMID:35502644 SUPPORT Human Clinical

"Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively."

Quantifies the multi-visceral organ distribution that distinguishes AApoAI from the kidney-restricted AFib form.

PMID:16011983 SUPPORT Other

"Only the apolipoprotein AI glycine 26 arginine mutation may cause peripheral neuropathy and then in only some of the kindreds with this disease."

Establishes the single exception to the non-neuropathic character of this disease group, which belongs to the AApoAI subtype. Evidence source is OTHER because this is a review.

AApoAII amyloidosis (apolipoprotein A-II, APOA2) MONDO:0016533

APOA2 hgnc:601

The rarest of the four forms, described in only a handful of kindreds. The reported amyloidogenic variants are stop-codon mutations that abolish the normal termination signal and append a C-terminal extension of about 21 residues to apolipoprotein A-II; it is this extension, rather than a missense destabilisation of the native fold, that is thought to drive fibril formation. Presentation is renal, with glomerular amyloid and proteinuria.

Show evidence (2 references)

PMID:11703582 SUPPORT Human Clinical

"DNA analysis revealed heterozygosity for a G to C transversion at the second position of the stop-codon of apoA-II gene, suggesting a stop to serine substitution at codon 78."

Documents the stop-codon read-through mechanism that defines the reported amyloidogenic APOA2 alleles.

PMID:11703582 SUPPORT Human Clinical

"These results indicate that the patient's amyloid fibrils were derived from apoA-II and the amyloidogenesis is likely to be closely linked to the peptide extension at the C-terminus of variant apoA-II."

Attributes fibril formation specifically to the C-terminal peptide extension, the proximal molecular defect of this subtype.

AFib amyloidosis (fibrinogen A alpha-chain, FGA) MONDO:0019733

FGA hgnc:3661

Amyloidosis in which the fibril protein is a fragment of a variant fibrinogen A alpha-chain. It is the most common hereditary renal amyloidosis in the UK and the most nearly organ-restricted of the four forms: renal involvement leads to diagnosis in essentially every case, and clinically significant extra-renal disease is rare in the largest referral cohort even after years of follow-up. How organ-restricted it really is, is disputed - see the CONTROVERSY discussion on this entry. The renal histology is distinctive enough to be diagnostic - massive amyloid within grossly enlarged glomeruli with almost none in vessels or interstitium. Amyloidogenic variants cluster in the portion of exon 5 encoding the fibril subunit peptide, and E526V is by far the most frequent.

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom."

Establishes AFib as the most frequent precursor form among hereditary renal amyloidoses in the best-characterised referral population.

PMID:19073821 SUPPORT Human Clinical

"Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases."

Supports the kidney-dominant, adult-onset character curated for this subtype.

ALys amyloidosis (lysozyme, LYZ) MONDO:0019732

LYZ hgnc:6740

Amyloidosis in which the fibril protein is a variant lysozyme, the bacteriolytic enzyme made by hepatocytes, neutrophils and macrophages. Reported amyloidogenic alleles are missense substitutions of highly conserved residues (classically Ile56Thr and Asp67His) that destabilise the native fold; fibrils contain full-length variant lysozyme rather than a proteolytic fragment. The organ distribution is the broadest visceral pattern of the four forms - gastrointestinal tract, liver and kidney - and hepatic amyloid can be extensive enough to cause spontaneous liver rupture, a presentation not seen in the other subtypes. Natural history is slow and penetrance appears high.

Show evidence (2 references)

PMID:8464497 SUPPORT Human Clinical

"Affected individuals are heterozygous for point mutations in the lysozyme gene that cause substitution of highly conserved residues, namely threonine for isoleucine at position 56 in one family, and histidine for aspartic acid at residue 67 in the other."

The original identification of lysozyme as an amyloid fibril protein and of the two classic amyloidogenic substitutions.

PMID:21988333 SUPPORT Human Clinical

"Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history."

Defines the tri-organ visceral distribution and indolent course curated for this subtype.

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Discussions and Knowledge Gaps

3

Why do four different variant plasma proteins, all made chiefly by the liver and all converging on the same cross-beta fibril, deposit in such different places - fibrinogen A alpha-chain almost purely in glomeruli, apolipoprotein A-I in the renal medulla and heart, lysozyme across gut, liver and kidney?

KNOWLEDGE GAP gap_fva_precursor_organ_tropism

Attached to

pathophysiology#Precursor-Determined Visceral Organ Tropism

Organ tropism is the single most clinically consequential difference between the subtypes - it determines presentation, rate of progression and whether liver transplantation is worth its risk - and yet the mechanism that determines it is not established. Candidate explanations include differences in the size and charge of the fibrillogenic fragment, local proteolytic processing at the deposition site, differential binding to tissue glycosaminoglycans or basement membrane components, and hemodynamic filtration effects at the glomerulus. The evidence curated in this entry documents the tropism but not its cause, so the downstream nodes are deliberately silent about it.

Is AFib fibrinogen A alpha-chain amyloidosis a kidney-restricted disease, or a systemic one whose extra-renal deposits are simply not looked for?

CONTROVERSY controversy_fva_afib_organ_restriction

Attached to

has_subtypes#AFib pathophysiology#Precursor-Determined Visceral Organ Tropism

Two large UK series reach opposite conclusions from overlapping patient populations. Gillmore and colleagues, following 71 prospectively studied patients, found clinically significant extra-renal disease rare and no patient developing the echocardiographic picture of infiltrative amyloid cardiomyopathy - the basis for calling AFib the most organ-restricted of the four precursor forms. Stangou and colleagues, assessing 22 AFib patients specifically for combined liver-kidney transplantation and therefore obtaining vascular and endomyocardial tissue that the observational cohort did not, found variant fibrinogen amyloid in excised atheroma and endomyocardial biopsies and autonomic neuropathy in half, and conclude the disease is systemic. The disagreement is partly about ascertainment - you find myocardial amyloid if you biopsy myocardium - and it matters clinically, because cardiovascular amyloid is what can make a patient ineligible for the combined transplant that would otherwise be curative. This entry curates the kidney-dominant tropism as the general pattern, and records the systemic finding here rather than asserting either position as settled.

Show evidence (3 references)

PMID:19633201 SUPPORT Human Clinical

"Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement."

The transplant-assessment series' conclusion that AFib is systemic rather than kidney-restricted.

PMID:19633201 SUPPORT Human Clinical

"Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid."

The tissue finding behind the systemic claim, and the reason the disagreement is partly one of ascertainment.

PMID:19073821 REFUTE Human Clinical

"Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare."

The opposing position from the larger prospective cohort, on which this entry's kidney-dominant characterization rests.

Is every amyloidogenic APOA1 allele dominant, or can a variant require two copies? A homozygous p.Leu202Arg carrier developed cardiac amyloidosis while his heterozygous brother was unaffected.

OPEN QUESTION openq_fva_apoa1_recessive_cardiac_allele

Attached to

inheritance#Autosomal dominant has_subtypes#AApoAI

This entry curates autosomal dominant inheritance throughout, which is correct for every established allele in all four precursor genes. One 2024 report is the sole exception on record: a man born to consanguineous parents, homozygous for APOA1 p.Leu202Arg, with cardiac amyloidosis, whose heterozygous brother had no disease. One family cannot establish a recessive mechanism - an unaffected heterozygous sibling is also compatible with reduced penetrance or later onset in a dominant allele - so nothing in the inheritance block was changed. It is recorded here because if the observation holds up it would mean a homozygous-only amyloidogenic allele class exists, which changes how an APOA1 variant of uncertain significance should be interpreted in a heterozygote.

Show evidence (2 references)

DOI:10.1038/s41439-024-00288-7 SUPPORT Human Clinical

"Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1."

The single observation this question rests on. Graded PARTIAL because one consanguineous case is hypothesis-generating, not a demonstration of recessive inheritance.

DOI:10.1038/s41439-024-00288-7 SUPPORT Human Clinical

"ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner."

The same report's statement of the established dominant rule, which is what this entry curates and which the case is proposed as an exception to.

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Pathophysiology

6

Variant Plasma Protein Amyloidogenic Precursor

The proximal trigger is a germline heterozygous variant in one of four genes encoding abundant circulating plasma proteins - APOA1, APOA2, FGA or LYZ - all of which are synthesised chiefly by the liver and secreted into plasma. The variant protein circulates alongside its wild-type counterpart and is the protein recovered from the amyloid deposits, so the disease is a gain of amyloidogenic behaviour by the variant allele's product rather than a shortfall of the normal protein. The identity of the precursor is what partitions this disease into its four subtypes, because it sets the organ tropism, the histological pattern and the rate of progression. The precursor is also the therapeutic target: removing the organ that makes it (liver transplantation) is the only manoeuvre that stops new deposition.

hepatocyte CL:0000182

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Destabilization and Beta-Sheet Conversion of the Variant Precursor The circulating variant protein is the substrate on which conformational conversion acts.

Show evidence (2 references)

PMID:16011983 SUPPORT Other

"Mutations in a number of plasma proteins, including transthyretin, apolipoprotein AI, fibrinogen Aalpha-chain, lysozyme, and apolipoprotein AII, are associated with hereditary systemic amyloidosis."

Names the variant plasma proteins that constitute the substituted precursor node of the amyloidogenesis module for this disease. Evidence source is OTHER because this is a review.

PMID:12832750 SUPPORT Human Clinical

"The types that present with renal disease are usually associated with mutations in the genes for either apolipoprotein AI, apolipoprotein AII, lysozyme or fibrinogen A alpha-chain."

Restricts the precursor set specifically to the renal-presenting, visceral forms curated by this entry.

Destabilization and Beta-Sheet Conversion of the Variant Precursor

The variant precursor is thermodynamically less stable than the wild-type protein and, under physiological conditions, populates partly unfolded states that retain beta-sheet secondary structure while losing tertiary or higher order structure. These partly folded species self-associate into aggregation-prone oligomers, committing the precursor to the amyloid pathway. The molecular route to instability differs by precursor and is the one genuinely subtype-specific upstream step: missense substitution of conserved core residues in lysozyme; acquisition of an extra positive charge in apolipoprotein A-I; a C-terminal peptide extension from stop-codon read-through in apolipoprotein A-II; and, in the fibrinogen A alpha-chain, variants clustered in the exon-5 segment that becomes the fibril subunit peptide.

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Visceral Amyloid Fibril Formation and Extracellular Deposition

Show evidence (2 references)

PMID:12832750 SUPPORT Human Clinical

"The amyloidogenic variant proteins associated with hereditary amyloidosis are less stable than their normal wild type counterparts and even under physiological conditions can populate partly unfolded states, involving loss of tertiary or higher order structure, which readily aggregate with..."

Describes the destabilization-to-beta-sheet-aggregation step exactly as curated in this node.

PMID:9461086 SUPPORT Human Clinical

"All the previously reported amyloidogenic variants of apoA-I also carry an extra positive charge, indicating that this electrostatic change is likely to be relevant to the amyloidogenicity of apoA-I."

Gives the precursor-specific physicochemical route to instability for the AApoAI subtype.

Visceral Amyloid Fibril Formation and Extracellular Deposition

Beta-sheet oligomers nucleate and elongate into insoluble cross-beta amyloid fibrils that deposit in the extracellular space. The deposition is systemic in the sense that the precursor is a circulating plasma protein, but the clinically relevant deposits are visceral - kidney above all, with spleen, adrenal, liver and gut involved to varying degrees - and, unlike hereditary transthyretin amyloidosis, peripheral nerve and myocardium are largely spared. This node is the disease's convergence with every other amyloidosis and the key conformance target of the amyloidogenesis module.

amyloid fibril formation GO:1990000 ↑ INCREASED

kidney UBERON:0002113 liver UBERON:0002107 spleen UBERON:0002106

Downstream

Precursor-Determined Visceral Organ Tropism

Show evidence (2 references)

PMID:8464497 SUPPORT Human Clinical

"Hereditary non-neuropathic systemic amyloidosis (Ostertag-type) is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade."

The defining statement of the disease concept: visceral, rather than neural, extracellular amyloid deposition.

PMID:29142973 SUPPORT Human Clinical

"The deposition of amyloid fibrils in an extracellular space readily leads to progressive disruption of the structure and function of affected tissues and organs."

States the extracellular character of the deposit and its structural consequence, the module's central effector step.

Precursor-Determined Visceral Organ Tropism

Which viscera are affected, and where within them, is set by the identity of the precursor rather than by anything downstream. In AFib the deposit is almost purely glomerular, filling grossly enlarged glomeruli while sparing vessels and interstitium; in AApoAI the renal deposit is the mirror image, confined to non-glomerular medullary tissue and producing a tubulointerstitial nephritis with bland urinalysis, and liver and heart are also commonly involved; ALys deposits across gut, liver and kidney; AApoAII deposits in glomeruli. Curating this as its own node keeps the subtype-differentiating step explicit rather than dissolving it into the generic accumulation node, and it is the step that explains why the four forms have different presentations and prognoses despite an identical upstream mechanism.

renal glomerulus UBERON:0000074 renal medulla UBERON:0000362

Downstream

Progressive Visceral Amyloid Accumulation

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid."

Documents the glomerulus-restricted tropism of the AFib precursor.

PMID:16221867 SUPPORT Human Clinical

"This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits."

Establishes that the AApoAI precursor produces a different intrarenal distribution from the other forms, which is the claim this node makes.

Progressive Visceral Amyloid Accumulation

Because the liver keeps secreting the variant precursor throughout life, deposition is cumulative and the amyloid load in the affected viscera rises over years to decades. Accumulation, not any acute event, is what converts a subclinical deposit into organ failure, and it is why the disease is typically diagnosed in mid to late adult life despite the causal variant being present from conception. The corollary is therapeutic: interrupting supply of the precursor arrests accumulation and can allow existing deposits to regress.

kidney UBERON:0002113

Downstream

Progressive Renal Excretory Failure

Show evidence (2 references)

PMID:9461086 SUPPORT Human Clinical

"Two members of the current generation received renal transplants for end-stage renal failure 16 and 18 years ago, and remain very well clinically despite massive visceral amyloidosis."

Documents accumulation of a massive visceral amyloid burden over decades, and that the burden itself is tolerated once the failed organ is replaced.

PMID:35502644 SUPPORT Human Clinical

"Liver transplantation led to regression of amyloid in all four cases in whom serial 123I-SAP scintigraphy was performed."

Shows accumulation is supply-driven: removing the source of the variant precursor reverses the accumulated load.

Progressive Renal Excretory Failure

Amyloid replacement of glomerular or tubulointerstitial architecture manifests first as proteinuria and then as a steady decline in excretory function, ending in end-stage renal disease requiring dialysis or transplantation. The rate differs by precursor - roughly five years from proteinuria to end-stage disease in AFib, roughly fifteen years from diagnosis in AApoAI - but the endpoint is shared, and renal failure is the dominant cause of morbidity in every subtype. Survival is nonetheless far better than in AL amyloidosis, because extra-renal amyloid is limited and dialysis outcomes are comparable to those of other non-diabetic nephropathy.

kidney UBERON:0002113

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr."

Quantifies the progression from renal presentation to end-stage disease and the comparatively long survival that follows it.

PMID:35502644 SUPPORT Human Clinical

"median time from diagnosis to end-stage renal disease was 15.0 (95% CI: 10.0-20.0) years"

Gives the substantially slower renal decline of the AApoAI subtype, the contrast that makes progression rate precursor-dependent.

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Histopathology

2

Congo Red-Positive Amyloid Deposition

Congo red staining of the affected tissue shows acellular extracellular deposits that are birefringent under cross-polarized light. The cited renal series describes the colour as red-green; the classical textbook phrase is apple-green, and the two name the same optical finding. This establishes that the deposit is amyloid but says nothing about which protein it is made of, so typing by immunohistochemistry or mass spectrometry remains a separate and mandatory step.

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"Panel B shows red-green birefringence when the same section is viewed under cross-polarized light."

Documents the polarized-light birefringence of the Congo red-stained renal deposit in this disease.

Glomerulus-Restricted Amyloid Deposition

In the fibrinogen subtype the deposit fills grossly enlarged glomeruli and obliterates their architecture while leaving vessels and tubulointerstitium essentially clear. The pattern is distinctive enough to be actionable: seeing it should prompt FGA sequencing even in a patient with no family history, and it is the opposite of the medullary, non-glomerular pattern of the apolipoprotein A-I subtype.

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"the discovery of massive glomerular amyloid, particularly in the absence of significant extraglomerular amyloid, should always prompt a search for a mutation"

States the actionable inference this histopathological pattern licenses - the sentence continues "in the fibrinogen Aa-chain gene", trimmed here only because the cached text spells the chain with a Greek alpha.

PMID:29142973 SUPPORT Human Clinical

"In 5 subjects, extensive amyloid deposits were found solely within the glomeruli, which stained specifically with antibodies to fibrinogen A alpha chain"

Independent confirmation of the glomerulus-restricted distribution with precursor-specific staining.

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Pathograph

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Phenotypes

13

Cardiovascular 1

Hypertension FREQUENT HP:0000822

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"Seventy-two percent of patients had previously been diagnosed with hypertension or were hypertensive at the time of discovery of proteinuria"

Quantifies the frequency of hypertension at presentation.

Genitourinary 3

Proteinuria VERY_FREQUENT HP:0000093

Show evidence (3 references)

PMID:19073821 SUPPORT Human Clinical

"A proteinuric presentation followed by progression to ESRD within 5 yr was typical of AFib."

Establishes proteinuria as the typical presenting phenotype.

PMID:29142973 SUPPORT Human Clinical

"Six patients presented with proteinuria, hypertension, and/or lower limb edema and underwent detailed clinical and laboratory investigations."

Independent case series confirming proteinuria as the mode of presentation.

PMID:39417966 SUPPORT Human Clinical

"All patients showed incipient symptoms including proteinuria"

Systematic review of 46 reported AFib cases finding proteinuria in every patient at onset.

End-Stage Renal Disease FREQUENT Stage 5 chronic kidney disease HP:0003774

Course: PROGRESSIVE

Show evidence (3 references)

PMID:19073821 SUPPORT Human Clinical

"At censor, a total of 44 (62%) patients had reached ESRD, having commenced renal replacement therapy at a median age of 60 yr"

Quantifies progression to end-stage renal disease in the largest reported cohort.

PMID:21988333 SUPPORT Human Clinical

"Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx)."

Confirms the same renal endpoint in the lysozyme subtype.

PMID:39417966 SUPPORT Human Clinical

"10 (21.7%) patients progressed to end-stage renal disease (ESRD) or received renal replacement therapy (including dialysis and kidney transplantation) within 1 year"

Quantifies the pace of progression to end-stage renal disease across pooled AFib case reports.

Polyuria HP:0000103

Show evidence (1 reference)

PMID:16221867 SUPPORT Human Clinical

"defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria"

Reports polyuria and defective urine concentration as part of the AApoAI renal phenotype.

Metabolism 3

Edema FREQUENT HP:0000969

Show evidence (2 references)

PMID:39417966 SUPPORT Human Clinical

"13 (28.3%) patients presented with nephrotic syndrome, 9 (19.6%) had edema in both lower limbs, and 4 (8.7%) had palpebral edema."

Quantifies lower-limb and palpebral edema as presenting features across pooled AFib cases.

PMID:29142973 SUPPORT Human Clinical

"Six patients presented with proteinuria, hypertension, and/or lower limb edema and underwent detailed clinical and laboratory investigations."

Independent series listing lower-limb edema among the presenting features.

Gastrointestinal Amyloid Involvement Amyloid deposition HP:0011034

Show evidence (2 references)

PMID:21988333 SUPPORT Human Clinical

"Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy."

Documents prevalent, endoscopically visible gastrointestinal amyloid in the lysozyme subtype.

PMID:25217048 SUPPORT Human Clinical

"All affected individuals suffered with prevailing gastrointestinal symptoms leading to the diagnosis of ALys."

An entire nine-member ALys kindred in which gastrointestinal disease, not renal disease, was the presenting problem.

Splenic Amyloid Deposition HP:0011034

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"showed renal amyloid in every patient who had not already reached ESRD, and asymptomatic splenic and adrenal amyloid deposits in 89 and 21% of patients, respectively"

Quantifies asymptomatic splenic and adrenal amyloid detected by scintigraphy.

Other 6

Renal Amyloidosis VERY_FREQUENT HP:0001917

Show evidence (2 references)

PMID:12832750 SUPPORT Human Clinical

"the renal histology is very characteristic showing substantial accumulation of amyloid within enlarged glomeruli, but none in blood vessels or the interstitium"

Describes the renal amyloid deposit and its characteristic distribution in the fibrinogen form.

PMID:35502644 SUPPORT Human Clinical

"Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg, n = 28)."

Establishes renal amyloid as effectively universal in the commonest AApoAI genotype.

Nephrotic Syndrome FREQUENT HP:0000100

Show evidence (2 references)

PMID:39417966 SUPPORT Human Clinical

"13 (28.3%) patients presented with nephrotic syndrome, 9 (19.6%) had edema in both lower limbs, and 4 (8.7%) had palpebral edema."

Quantifies nephrotic-range presentation across 46 pooled AFib cases.

PMID:35502644 SUPPORT Human Clinical

"patients with renal amyloidosis had a median creatinine of 159 µmol/L and median urinary protein of 0.3 g/24 h at the time of diagnosis of AApoAI amyloidosis"

Bounds the phenotype to the glomerular precursor forms by showing that the AApoAI subtype is characteristically sub-nephrotic. Graded PARTIAL because it constrains rather than establishes the phenotype.

Tubulointerstitial Nephritis HP:0001970

Show evidence (1 reference)

PMID:16221867 SUPPORT Human Clinical

"The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria."

Directly describes the tubulointerstitial presentation curated here and restricted to the AApoAI subtype.

Hepatic Amyloid Deposition Hepatic amyloidosis HP:0012280

Show evidence (2 references)

PMID:21988333 SUPPORT Human Clinical

"All symptomatic ALys individuals had hepatic amyloid."

Establishes universal hepatic amyloid among symptomatic lysozyme amyloidosis patients.

PMID:15131802 SUPPORT Human Clinical

"We investigated both phenotypic and genotypic aspects of apolipoprotein A-I amyloidosis unexpectedly disclosed by liver biopsy in 13 unrelated individuals with asymptomatic, persistent elevation of alkaline phosphatase and gamma-glutamyltransferase levels."

Shows hepatic amyloid in AApoAI presenting silently as a cholestatic enzyme abnormality.

Gastrointestinal Inflammation HP:0004386

Show evidence (2 references)

PMID:25217048 SUPPORT Human Clinical

"8/9 had non specific upper gastrointestinal symptoms and 3/9 had rectocolic inflammation evoking inflammatory bowel disease."

Reports the inflammatory-bowel-disease-like colitis and its frequency within the described kindred.

PMID:25217048 SUPPORT Human Clinical

"Amyloidosis should be considered in atypical or treatment resistant, upper or lower chronic gastrointestinal symptoms."

States the misdiagnosis risk that makes this phenotype worth curating separately from the amyloid deposit itself.

Cardiac Amyloid Involvement OCCASIONAL Cardiac amyloidosis HP:0030843

Show evidence (2 references)

PMID:35502644 SUPPORT Human Clinical

"Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively."

Quantifies cardiac involvement in the AApoAI subtype.

PMID:19073821 SUPPORT Human Clinical

"No patient developed the typical electrocardiographic and echocardiographic features of restrictive diastolic filling, thickened ventricular walls, and reduced QRS voltages to suggest an infiltrative amyloid cardiomyopathy during follow up."

Supports the subtype restriction of this phenotype by reporting the absence of cardiac amyloid in the fibrinogen cohort. Graded PARTIAL because it bounds rather than establishes the phenotype.

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Genetic Associations

4

APOA1 (Heterozygous variants in APOA1, which encodes the major HDL apolipoprotein, cause AApoAI amyloidosis. The amyloidogenic alleles are structurally diverse - missense substitutions, in-frame deletions and frameshifts - but the reported ones share the acquisition of an extra positive charge in the mature protein, which is thought to underlie their amyloidogenicity. Gly26Arg is the most frequently encountered variant and the only one associated with peripheral neuropathy; Leu75Pro accounts for several Italian kindreds and presents with a hepatic and renal picture.)

Gene: APOA1 hgnc:600 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:9461086 SUPPORT Human Clinical

"among living family members there was complete concordance between amyloidosis and the presence of a novel 9 base pair in-frame deletion mutation in exon 4 of the apoA-I gene"

Demonstrates co-segregation of an APOA1 variant with amyloidosis within a pedigree, the causal genetic claim.

PMID:15131802 SUPPORT Human Clinical

"A novel (Leu75Pro) heterozygous mutation in the apolipoprotein A-I gene was present in affected individuals but not in controls."

Case-control genetic evidence for a second amyloidogenic APOA1 allele.

APOA2 (Heterozygous stop-codon variants in APOA2 abolish normal translational termination and extend apolipoprotein A-II by roughly 21 C-terminal residues. The extended variant circulates alongside normal apolipoprotein A-II and is the fibril protein recovered from renal amyloid. Very few kindreds have been reported.)

Gene: APOA2 hgnc:601 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11703582 SUPPORT Human Clinical

"Western blot analysis and amino acid sequence analysis of the patient's plasma apoA-II showed both normal apoA-II and variant apoA-II with a 21-amino acid residue extension at the C-terminus."

Confirms the extended variant protein circulating in a patient with renal amyloidosis, tying the APOA2 allele to the amyloid.

FGA (Heterozygous variants in FGA, encoding the fibrinogen A alpha-chain, are the most common cause of hereditary renal amyloidosis in the United Kingdom. The amyloidogenic variants cluster in the region of exon 5 encoding the peptide fragment that forms the fibril subunit, and include both single-base substitutions and frameshifts; E526V dominates in British and northern European patients. Penetrance is low, so a negative family history is common and does not argue against the diagnosis. Allele class is not cosmetic: it tracks with how aggressive the renal disease is and therefore with whether an isolated kidney graft is enough or a combined liver-kidney transplant is warranted, since only the combined procedure removes the source of the variant protein. Pooled case data also show women presenting significantly earlier than men, for reasons that are not established.)

Gene: FGA hgnc:3661 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:19073821 SUPPORT Human Clinical

"64 patients were heterozygous for the previously reported single base substitution that altered the codon at position 526 of the mature protein from that for glutamic acid to valine"

Establishes the dominant FGA allele and its heterozygous state in the largest cohort.

PMID:29142973 SUPPORT Human Clinical

"2 frameshift mutations F521Sfs*27 and G519Efs*30 and 4 single base substitutions G555F, E526K, E524K, R554H"

Documents the allelic spectrum, including frameshift and substitution classes, in a second independent series.

PMID:39417966 SUPPORT Human Clinical

"We found the onset age to be lower in women than in men (P < 0.05)."

Reports the sex difference in age at onset across 46 pooled AFib cases.

+ 1 more reference

LYZ (Heterozygous missense variants in LYZ substitute highly conserved residues of human lysozyme (classically Ile56Thr and Asp67His), destabilising the native fold. Unlike the fibrinogen form, the fibril is composed of full-length variant lysozyme rather than a proteolytic fragment. Because lysozyme's structure and folding are known in atomic detail, this was the first hereditary amyloidosis to be used as a tractable structural model of amyloidogenesis.)

Gene: LYZ hgnc:6740 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:8464497 SUPPORT Human Clinical

"Amyloid fibrils from one individual were composed of the full-length Thr-56 variant lysozyme molecule."

Directly identifies full-length variant lysozyme as the fibril protein, establishing LYZ causation and the fibril composition claim.

PMID:21988333 SUPPORT Human Clinical

"Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages."

Identifies the LYZ gene product as the amyloidogenic precursor and names its cellular sources, which is why hepatectomy alone does not fully abolish precursor supply in this subtype.

💊

Medical Actions

5

Kidney Transplantation

Action: Kidney Transplantation NCIT:C15265

Renal transplantation is the standard treatment for end-stage renal disease in this group and gives good medium-term outcomes, but it does not address the source of the circulating variant precursor, so amyloid can recur in the graft. In the fibrinogen subtype recurrent amyloid caused graft loss after roughly six to seven years in several patients; in the apolipoprotein A-I subtype, where deposition is far slower, allograft survival has been much longer.

Mechanism Target:

RESTORES Progressive Renal Excretory Failure — Restores excretory function by replacing the failed organ, without altering upstream precursor supply - so the mechanism keeps running and amyloid eventually re-deposits in the graft.

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"Renal transplantation in AFib is associated with recurrence of amyloid in the graft and with resultant loss of transplant kidneys after a median of 6.7 yr, although one kidney continued to function after 12.2 yr."

Shows the graft restores excretory function but that ongoing precursor supply eventually re-deposits amyloid in it.

Show evidence (1 reference)

PMID:35502644 SUPPORT Human Clinical

"Post-renal transplantation, median allograft survival was 22.0 (13.0-31.0) years."

Documents the favourable renal allograft survival that makes transplantation the treatment of choice in the AApoAI subtype.

Liver Transplantation

Action: Liver Transplantation NCIT:C15271

Because the amyloidogenic precursors are synthesised chiefly by the liver, orthotopic liver transplantation removes the source of the circulating variant protein and is the only intervention that stops further deposition; existing deposits can then regress. It is used pre-emptively or, in lysozyme amyloidosis, urgently for spontaneous hepatic rupture. Lysozyme is also made by neutrophils and macrophages, so hepatectomy does not abolish precursor supply as completely in that subtype as it does for the apolipoproteins and fibrinogen.

Mechanism Target:

INHIBITS Variant Plasma Protein Amyloidogenic Precursor — Removes the hepatic source of the variant precursor, cutting supply at the trigger node rather than treating a downstream consequence.

Show evidence (1 reference)

PMID:35502644 SUPPORT Human Clinical

"Liver transplantation led to regression of amyloid in all four cases in whom serial 123I-SAP scintigraphy was performed."

Demonstrates that removing the precursor source reverses accumulated amyloid, which is the mechanistic claim for targeting this node.

Show evidence (2 references)

PMID:21988333 SUPPORT Human Clinical

"Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively."

Documents both the emergency and pre-emptive indications for liver transplantation in lysozyme amyloidosis.

PMID:19633201 SUPPORT Human Clinical

"Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation."

Argues for pre-emptive isolated liver transplantation on the mechanistic ground that it removes the precursor before the kidney is lost.

Combined Liver-Kidney Transplantation

Action: Organ Transplantation NCIT:C15289

Simultaneous hepatorenal transplantation both replaces the failed kidney and removes the hepatic source of the amyloidogenic precursor, so it prevents amyloid recurrence in the renal allograft. It carries greater perioperative risk than isolated renal transplantation, and because isolated renal grafts last several years before recurrent amyloid becomes limiting, it is generally reserved for younger, fitter patients.

Mechanism Target:

INHIBITS Progressive Visceral Amyloid Accumulation — Combines organ replacement with elimination of precursor supply, arresting further accumulation rather than merely replacing the failed organ.

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"A further six patients in this series have undergone combined hepatorenal transplantation at King's College Hospital, London, which was performed preemptively in three patients."

Documents the combined procedure in this disease, including pre-emptive use before renal replacement is strictly required.

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"it has been our practice to recommend consideration of combined liver and kidney transplantation only in younger, fitter patients with this disease"

States the patient-selection caveat curated in this treatment's description.

PMID:19633201 SUPPORT Human Clinical

"Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up."

Reports absence of recurrent amyloid after combined transplantation, the outcome that distinguishes it from isolated renal transplantation.

Renal Replacement Therapy

Action: Hemodialysis NCIT:C15248

Dialysis for end-stage renal disease. Outcomes in this disease are notably better than in AL amyloidosis and comparable to those of age-matched patients with other non-diabetic nephropathies, because extra-renal amyloid is limited and the natural history is slow.

Mechanism Target:

BYPASSES Progressive Renal Excretory Failure — Substitutes extracorporeally for lost excretory function; it has no effect on precursor supply or amyloid deposition.

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"Estimated median survival from commencement of renal replacement therapy by Kaplan-Meier analysis was 8.2 yr"

Quantifies survival on renal replacement therapy in this disease.

Symptomatic and Supportive Management

Action: Supportive Care NCIT:C15747

There is no amyloid-specific pharmacotherapy for any of the four precursor forms. In particular, none of the transthyretin-directed stabilisers or gene-silencing agents applies here, because the precursor is a different protein. Management outside transplantation is symptomatic - blood-pressure and proteinuria control, treatment of gastrointestinal bleeding, and surveillance of organ function.

Show evidence (1 reference)

PMID:21988333 SUPPORT Human Clinical

"There is currently no amyloid-specific therapy for the condition which is managed symptomatically."

States the absence of disease-modifying pharmacotherapy that this treatment entry records.

🔬

Biochemical Markers

2

Cholestatic Liver Enzyme Elevation (Persistently elevated)

Show evidence (1 reference)

PMID:15131802 SUPPORT Human Clinical

"These findings suggest that specific staining for amyloid should be performed on liver biopsy of individuals with asymptomatic chronic elevation of alkaline phosphatase and gamma-glutamyltransferase levels."

States the diagnostic recommendation that follows from this biochemical abnormality being the presenting abnormality.

Gamma-Glutamyltransferase Elevation (Persistently elevated)

Show evidence (1 reference)

PMID:15131802 SUPPORT Human Clinical

"apolipoprotein A-I amyloidosis unexpectedly disclosed by liver biopsy in 13 unrelated individuals with asymptomatic, persistent elevation of alkaline phosphatase and gamma-glutamyltransferase levels"

Documents the persistent gamma-glutamyltransferase elevation in the cohort in which the diagnosis was made this way.

🔬

Diagnosis

3

Renal biopsy with amyloid typing

Congo red staining of a renal biopsy establishes amyloid; the intrarenal distribution then narrows the precursor, since massive glomerular amyloid with spared vessels and interstitium is characteristic of the fibrinogen form. Immunohistochemistry with antibodies to the candidate fibril proteins types the deposit in most but not all cases, and laser microdissection with mass spectrometry resolves the remainder. Typing failure is common enough that a negative immunohistochemical result does not exclude a hereditary form.

Show evidence (2 references)

PMID:19073821 SUPPORT Human Clinical

"The diagnosis of amyloidosis was made by kidney biopsy in 64 patients and by serum amyloid P component (SAP) scintigraphy in conjunction with genetic analysis in the context of renal dysfunction and a known family history of AFib in seven patients."

Establishes kidney biopsy as the primary diagnostic modality in this disease, with scintigraphy plus genetics as the alternative route.

PMID:29142973 SUPPORT Human Clinical

"Clinical awareness and suspicion of hereditary amyloidosis corroborated by genetic analysis and adequate typing using combined immunohistochemistry and laser microdissection and mass spectrometry is valuable to avoid misdiagnosis, especially when a family history of amyloidosis is absent."

States the combined histological, immunohistochemical, proteomic and genetic diagnostic strategy curated here.

Sequencing of amyloidogenic precursor genes

Because the clinical picture is non-specific and penetrance is variable, DNA analysis of APOA1, APOA2, FGA and LYZ is required to establish the hereditary form and identify the precursor. A detectable plasma cell dyscrasia does not exclude a hereditary amyloidosis and does not remove the need for sequencing.

Show evidence (2 references)

PMID:12832750 SUPPORT Human Clinical

"DNA analysis is now performed routinely in UK National Amyloidosis Centre in patients with systemic amyloidosis in whom AA or AL fibril type cannot be definitively verified."

Establishes routine precursor-gene sequencing as the diagnostic step for untyped systemic amyloid.

PMID:19073821 SUPPORT Human Clinical

"the presence of a plasma cell dyscrasia in a patient with systemic amyloidosis, as was detected in 10% of the current cohort using the very sensitive techniques now available, neither excludes AFib nor proves AL-type amyloidosis, and does not alter the requirement for DNA analysis"

States explicitly that a coexisting paraprotein does not remove the requirement for genetic testing.

Serum amyloid P component scintigraphy

Radiolabelled SAP scintigraphy maps whole-body visceral amyloid load non-invasively, is diagnostic in patients in whom biopsy is not obtained, and is the tool that demonstrates regression of amyloid after removal of the precursor source by liver transplantation.

Show evidence (1 reference)

PMID:19073821 SUPPORT Human Clinical

"Radiolabeled SAP scintigraphy was diagnostic of amyloidosis in each of 63 patients who underwent the procedure."

Establishes the diagnostic yield of SAP scintigraphy in this disease.

📊

Prevalence

2

Patients with systemic amyloidosis, United Kingdom national series 1987-2012

Unknown Unknown AFib

A denominator-based figure, but a denominator of amyloidosis patients rather than of the general population: 87 of 5100 patients evaluated at the UK national amyloidosis service over 25 years had AFib amyloidosis. It bounds how often the commonest precursor form turns up in an amyloidosis clinic, not how common the disease is in a population, so no rate per 100,000 is derived from it. measure_type is UNKNOWN rather than PERIOD_PREVALENCE for the same reason, and matches the sibling record below: PrevalenceMeasureEnum's values all presuppose a population denominator, and neither of these two records has one.

Show evidence (1 reference)

PMID:39417966 SUPPORT Human Clinical

"evaluated 5100 patients with British national amyloidosis between 1987 and 2012 and discovered that only 87 (1.7%) patients had AFib amyloidosis"

Gives the numerator and denominator behind the AFib share of a national amyloidosis cohort.

Patients with apparently sporadic systemic amyloidosis, United Kingdom

Unknown Unknown

Not a population prevalence. This records the fraction of patients presenting with apparently sporadic systemic amyloid who in fact have hereditary fibrinogen A alpha-chain amyloidosis, which is the number that matters clinically because it sets the threshold for genetic testing. No general-population rate is curated: the two records here both have a denominator of amyloidosis patients, not of a population, and the Orphanet epidemiology record (ORPHA:85450) could not be quoted because the Orphadata bulk XML needed to generate a citable cache entry is not present in this checkout. MONDO carries the rare-disease subsets for this class.

Show evidence (1 reference)

PMID:12832750 SUPPORT Human Clinical

"we have lately demonstrated that five percent of patients with apparent sporadic amyloid have hereditary fibrinogen A alpha-chain amyloidosis associated with the valine 526 variant"

Gives the measured fraction of apparently sporadic amyloid that is in fact hereditary AFib.

🔀

Differential Diagnoses

1

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

AL Amyloidosis

Overlapping Features Systemic amyloidosis from a clonal immunoglobulin light chain. This is the diagnosis familial visceral amyloidosis is most often mistaken for, and the error has consequences: patients have received cytotoxic chemotherapy for presumed AL disease before the hereditary form was recognised. A monoclonal protein is common enough in older patients to be incidental, so its presence does not settle the question.

Distinguishing Features

Precursor-gene sequencing (APOA1, APOA2, FGA, LYZ) establishes the hereditary form; amyloid typing by immunohistochemistry, or by laser microdissection with mass spectrometry when immunohistochemistry is non-definitive, identifies the fibril protein.
Renal histology is informative: massive amyloid within grossly enlarged glomeruli with almost none in vessels or interstitium suggests fibrinogen A alpha-chain amyloidosis.
Survival is far longer in the hereditary visceral forms than in untreated AL amyloidosis, and clinically significant extra-renal amyloid is much less common.

Show evidence (3 references)

PMID:12832750 SUPPORT Human Clinical

"The clinical phenotype of hereditary renal amyloid is non-specific and is readily misdiagnosed as acquired AL amyloidosis."

States the misdiagnosis risk that makes AL amyloidosis the principal differential.

PMID:19073821 SUPPORT Human Clinical

"Chemotherapy comprising autologous stem cell transplantation was administered for presumed AL amyloidosis in one such patient before the correct diagnosis of AFib was achieved."

Documents the clinical harm of the misdiagnosis: cytotoxic therapy given for presumed AL amyloidosis.

PMID:39417966 SUPPORT Human Clinical

"among the 46 patients, seven were misdiagnosed with immunoglobulin light chain amyloidosis (AL). After chemotherapy and stem-cell transplantation, renal function in these patients deteriorated."

Quantifies how often the misdiagnosis happens (7 of 46 pooled AFib cases) and reports that the resulting treatment worsened renal function.

{ }

Source YAML

click to show

name: Familial Visceral Amyloidosis
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
description: >-
  Familial visceral amyloidosis - the Ostertag-type hereditary non-neuropathic
  systemic amyloidosis - is an autosomal dominant disease in which a germline
  variant in a circulating, hepatically synthesised plasma protein renders that
  protein amyloidogenic, so that it misfolds and deposits as extracellular
  amyloid predominantly in the viscera (kidney above all, and also liver, spleen,
  adrenal and gastrointestinal tract) rather than in peripheral nerve or heart.
  Four precursor proteins define the recognised forms: apolipoprotein A-I
  (AApoAI, APOA1), apolipoprotein A-II (AApoAII, APOA2), fibrinogen A alpha-chain
  (AFib, FGA) and lysozyme (ALys, LYZ). Whatever the precursor, the presentation
  is proteinuria and slowly progressive renal impairment culminating in end-stage
  renal disease, typically over years to decades, with a natural history far
  slower than acquired AL amyloidosis. Penetrance is variable and a family
  history is often absent, so the disease is routinely mistaken for sporadic AL
  amyloidosis; distinguishing the two matters because chemotherapy is useless
  here and because organ transplantation - renal, and in selected patients
  combined hepatorenal, which removes the source of the circulating variant - is
  the only intervention that alters the course.
parents:
- Genetic Disease
- Protein Misfolding Disease
disease_term:
  preferred_term: familial visceral amyloidosis
  term:
    id: MONDO:0007099
    label: familial visceral amyloidosis
synonyms:
- Ostertag type amyloidosis
- Hereditary non-neuropathic systemic amyloidosis
- Familial renal amyloidosis
- Hereditary renal amyloidosis
- Familial amyloid nephropathy
- German type amyloidosis

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Every recognised precursor form is transmitted as an autosomal dominant
    trait: affected individuals are heterozygous for a variant in the precursor
    gene, and one variant allele suffices because the disease arises from the
    amyloidogenic behaviour of the variant protein rather than from loss of the
    normal protein's function. Penetrance is markedly variable and, for the
    fibrinogen forms, low enough that a family history of renal disease is absent
    in about half of patients - which is why apparently sporadic renal amyloid
    still warrants sequencing of the precursor genes. Lysozyme amyloidosis sits
    at the other end of the penetrance range, with a clear family history in
    every case of one referral cohort.
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These diseases are inherited in an autosomal dominant manner with variable
      penetrance, and can present clinically at any time from the teen years to
      old age, though usually in mid-adult life.
    explanation: >-
      States both the autosomal dominant transmission and the variable penetrance
      and wide age range curated in this block.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, a family history of renal disease or amyloidosis was absent in 46%
      patients with AFib, with all of the available evidence indicating that this
      was due to reduced penetrance
    explanation: >-
      Quantifies the incomplete penetrance in the largest single cohort and gives
      the reason a negative family history does not exclude the diagnosis.

has_subtypes:
- name: AApoAI
  display_name: AApoAI amyloidosis (apolipoprotein A-I, APOA1)
  subtype_term:
    preferred_term: AApoAI amyloidosis
    term:
      id: MONDO:0019731
      label: AApoAI amyloidosis
  classification: precursor_protein
  description: >-
    Amyloidosis in which the fibril protein is a variant apolipoprotein A-I, the
    principal HDL apolipoprotein. It is the most clinically heterogeneous of the
    four forms: kidney, liver and heart are all involved in a substantial
    fraction of patients, and it is also the only form in which peripheral
    neuropathy is described, and then only with the Gly26Arg variant and only in
    some kindreds. The renal lesion is characteristically medullary and
    tubulointerstitial rather than glomerular, so urinalysis may be bland and the
    presentation a defective urine-concentrating capacity rather than heavy
    proteinuria. Progression to end-stage renal disease is the slowest of the
    four forms, with a median of about 15 years from diagnosis.
  genes:
  - preferred_term: APOA1
    term:
      id: hgnc:600
      label: APOA1
  evidence:
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Involvement of the kidneys, liver and heart by amyloid was detected in 81%,
      67% and 28% of patients, respectively.
    explanation: >-
      Quantifies the multi-visceral organ distribution that distinguishes AApoAI
      from the kidney-restricted AFib form.
  - reference: PMID:16011983
    reference_title: "Ostertag revisited: the inherited systemic amyloidoses without neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Only the apolipoprotein AI glycine 26 arginine mutation may cause
      peripheral neuropathy and then in only some of the kindreds with this
      disease.
    explanation: >-
      Establishes the single exception to the non-neuropathic character of this
      disease group, which belongs to the AApoAI subtype. Evidence source is
      OTHER because this is a review.

- name: AApoAII
  display_name: AApoAII amyloidosis (apolipoprotein A-II, APOA2)
  subtype_term:
    preferred_term: apolipoprotein A-II amyloidosis
    term:
      id: MONDO:0016533
      label: apolipoprotein A-II amyloidosis
  classification: precursor_protein
  description: >-
    The rarest of the four forms, described in only a handful of kindreds. The
    reported amyloidogenic variants are stop-codon mutations that abolish the
    normal termination signal and append a C-terminal extension of about 21
    residues to apolipoprotein A-II; it is this extension, rather than a missense
    destabilisation of the native fold, that is thought to drive fibril
    formation. Presentation is renal, with glomerular amyloid and proteinuria.
  genes:
  - preferred_term: APOA2
    term:
      id: hgnc:601
      label: APOA2
  evidence:
  - reference: PMID:11703582
    reference_title: Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA analysis revealed heterozygosity for a G to C transversion at the
      second position of the stop-codon of apoA-II gene, suggesting a stop to
      serine substitution at codon 78.
    explanation: >-
      Documents the stop-codon read-through mechanism that defines the reported
      amyloidogenic APOA2 alleles.
  - reference: PMID:11703582
    reference_title: Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that the patient's amyloid fibrils were derived from
      apoA-II and the amyloidogenesis is likely to be closely linked to the
      peptide extension at the C-terminus of variant apoA-II.
    explanation: >-
      Attributes fibril formation specifically to the C-terminal peptide
      extension, the proximal molecular defect of this subtype.

- name: AFib
  display_name: AFib amyloidosis (fibrinogen A alpha-chain, FGA)
  subtype_term:
    preferred_term: AFib amyloidosis
    term:
      id: MONDO:0019733
      label: AFib amyloidosis
  classification: precursor_protein
  description: >-
    Amyloidosis in which the fibril protein is a fragment of a variant fibrinogen
    A alpha-chain. It is the most common hereditary renal amyloidosis in the UK
    and the most nearly organ-restricted of the four forms: renal involvement
    leads to diagnosis in essentially every case, and clinically significant
    extra-renal disease is rare in the largest referral cohort even after years
    of follow-up. How organ-restricted it really is, is disputed - see the
    CONTROVERSY discussion on this entry. The renal histology is
    distinctive enough to be diagnostic - massive amyloid within grossly enlarged
    glomeruli with almost none in vessels or interstitium. Amyloidogenic variants
    cluster in the portion of exon 5 encoding the fibril subunit peptide, and
    E526V is by far the most frequent.
  genes:
  - preferred_term: FGA
    term:
      id: hgnc:3661
      label: FGA
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the fibrinogen A alpha-chain gene are the most common cause of
      hereditary renal amyloidosis in the United Kingdom.
    explanation: >-
      Establishes AFib as the most frequent precursor form among hereditary renal
      amyloidoses in the best-characterised referral population.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median age at presentation was 58 yr, and renal involvement led to
      diagnosis in all cases.
    explanation: >-
      Supports the kidney-dominant, adult-onset character curated for this
      subtype.

- name: ALys
  display_name: ALys amyloidosis (lysozyme, LYZ)
  subtype_term:
    preferred_term: ALys amyloidosis
    term:
      id: MONDO:0019732
      label: ALys amyloidosis
  classification: precursor_protein
  description: >-
    Amyloidosis in which the fibril protein is a variant lysozyme, the
    bacteriolytic enzyme made by hepatocytes, neutrophils and macrophages.
    Reported amyloidogenic alleles are missense substitutions of highly conserved
    residues (classically Ile56Thr and Asp67His) that destabilise the native
    fold; fibrils contain full-length variant lysozyme rather than a proteolytic
    fragment. The organ distribution is the broadest visceral pattern of the four
    forms - gastrointestinal tract, liver and kidney - and hepatic amyloid can be
    extensive enough to cause spontaneous liver rupture, a presentation not seen
    in the other subtypes. Natural history is slow and penetrance appears high.
  genes:
  - preferred_term: LYZ
    term:
      id: hgnc:6740
      label: LYZ
  evidence:
  - reference: PMID:8464497
    reference_title: Human lysozyme gene mutations cause hereditary systemic amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals are heterozygous for point mutations in the lysozyme
      gene that cause substitution of highly conserved residues, namely threonine
      for isoleucine at position 56 in one family, and histidine for aspartic
      acid at residue 67 in the other.
    explanation: >-
      The original identification of lysozyme as an amyloid fibril protein and of
      the two classic amyloidogenic substitutions.
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which
      has a slow natural history.
    explanation: >-
      Defines the tri-organ visceral distribution and indolent course curated for
      this subtype.

pathophysiology:
- name: Variant Plasma Protein Amyloidogenic Precursor
  description: >-
    The proximal trigger is a germline heterozygous variant in one of four genes
    encoding abundant circulating plasma proteins - APOA1, APOA2, FGA or LYZ -
    all of which are synthesised chiefly by the liver and secreted into plasma.
    The variant protein circulates alongside its wild-type counterpart and is the
    protein recovered from the amyloid deposits, so the disease is a gain of
    amyloidogenic behaviour by the variant allele's product rather than a
    shortfall of the normal protein. The identity of the precursor is what
    partitions this disease into its four subtypes, because it sets the organ
    tropism, the histological pattern and the rate of progression. The precursor
    is also the therapeutic target: removing the organ that makes it (liver
    transplantation) is the only manoeuvre that stops new deposition.
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16011983
    reference_title: "Ostertag revisited: the inherited systemic amyloidoses without neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in a number of plasma proteins, including transthyretin,
      apolipoprotein AI, fibrinogen Aalpha-chain, lysozyme, and apolipoprotein
      AII, are associated with hereditary systemic amyloidosis.
    explanation: >-
      Names the variant plasma proteins that constitute the substituted precursor
      node of the amyloidogenesis module for this disease. Evidence source is
      OTHER because this is a review.
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The types that present with renal disease are usually associated with
      mutations in the genes for either apolipoprotein AI, apolipoprotein AII,
      lysozyme or fibrinogen A alpha-chain.
    explanation: >-
      Restricts the precursor set specifically to the renal-presenting, visceral
      forms curated by this entry.
  downstream:
  - target: Destabilization and Beta-Sheet Conversion of the Variant Precursor
    causal_link_type: DIRECT
    description: >-
      The circulating variant protein is the substrate on which conformational
      conversion acts.

- name: Destabilization and Beta-Sheet Conversion of the Variant Precursor
  description: >-
    The variant precursor is thermodynamically less stable than the wild-type
    protein and, under physiological conditions, populates partly unfolded states
    that retain beta-sheet secondary structure while losing tertiary or higher
    order structure. These partly folded species self-associate into
    aggregation-prone oligomers, committing the precursor to the amyloid pathway.
    The molecular route to instability differs by precursor and is the one
    genuinely subtype-specific upstream step: missense substitution of conserved
    core residues in lysozyme; acquisition of an extra positive charge in
    apolipoprotein A-I; a C-terminal peptide extension from stop-codon
    read-through in apolipoprotein A-II; and, in the fibrinogen A alpha-chain,
    variants clustered in the exon-5 segment that becomes the fibril subunit
    peptide.
  conforms_to: amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization
  role: amplifier
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amyloidogenic variant proteins associated with hereditary amyloidosis
      are less stable than their normal wild type counterparts and even under
      physiological conditions can populate partly unfolded states, involving
      loss of tertiary or higher order structure, which readily aggregate with
      retention of beta-sheet secondary structure into protofilaments and
      fibrils.
    explanation: >-
      Describes the destabilization-to-beta-sheet-aggregation step exactly as
      curated in this node.
  - reference: PMID:9461086
    reference_title: Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the previously reported amyloidogenic variants of apoA-I also carry an
      extra positive charge, indicating that this electrostatic change is likely
      to be relevant to the amyloidogenicity of apoA-I.
    explanation: >-
      Gives the precursor-specific physicochemical route to instability for the
      AApoAI subtype.
  downstream:
  - target: Visceral Amyloid Fibril Formation and Extracellular Deposition
    causal_link_type: DIRECT

- name: Visceral Amyloid Fibril Formation and Extracellular Deposition
  description: >-
    Beta-sheet oligomers nucleate and elongate into insoluble cross-beta amyloid
    fibrils that deposit in the extracellular space. The deposition is systemic
    in the sense that the precursor is a circulating plasma protein, but the
    clinically relevant deposits are visceral - kidney above all, with spleen,
    adrenal, liver and gut involved to varying degrees - and, unlike hereditary
    transthyretin amyloidosis, peripheral nerve and myocardium are largely
    spared. This node is the disease's convergence with every other amyloidosis
    and the key conformance target of the amyloidogenesis module.
  conforms_to: amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition
  role: central_effector
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  evidence:
  - reference: PMID:8464497
    reference_title: Human lysozyme gene mutations cause hereditary systemic amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary non-neuropathic systemic amyloidosis (Ostertag-type) is a rare
      autosomal dominant disease in which amyloid deposition in the viscera is
      usually fatal by the fifth decade.
    explanation: >-
      The defining statement of the disease concept: visceral, rather than
      neural, extracellular amyloid deposition.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deposition of amyloid fibrils in an extracellular space readily leads
      to progressive disruption of the structure and function of affected tissues
      and organs.
    explanation: >-
      States the extracellular character of the deposit and its structural
      consequence, the module's central effector step.
  downstream:
  - target: Precursor-Determined Visceral Organ Tropism
    causal_link_type: DIRECT

- name: Precursor-Determined Visceral Organ Tropism
  description: >-
    Which viscera are affected, and where within them, is set by the identity of
    the precursor rather than by anything downstream. In AFib the deposit is
    almost purely glomerular, filling grossly enlarged glomeruli while sparing
    vessels and interstitium; in AApoAI the renal deposit is the mirror image,
    confined to non-glomerular medullary tissue and producing a
    tubulointerstitial nephritis with bland urinalysis, and liver and heart are
    also commonly involved; ALys deposits across gut, liver and kidney; AApoAII
    deposits in glomeruli. Curating this as its own node keeps the
    subtype-differentiating step explicit rather than dissolving it into the
    generic accumulation node, and it is the step that explains why the four
    forms have different presentations and prognoses despite an identical
    upstream mechanism.
  role: modifier
  biological_scale: TISSUE
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  - preferred_term: renal medulla
    term:
      id: UBERON:0000362
      label: renal medulla
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal histology was characteristic: striking glomerular enlargement with
      almost complete obliteration of the normal architecture by amyloid
      deposition and little or no vascular or interstitial amyloid.
    explanation: >-
      Documents the glomerulus-restricted tropism of the AFib precursor.
  - reference: PMID:16221867
    reference_title: "Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This location of apolipoprotein A-I amyloid differs sharply from other
      systemic amyloidoses that are mainly characterized by glomerular and
      vascular deposits.
    explanation: >-
      Establishes that the AApoAI precursor produces a different intrarenal
      distribution from the other forms, which is the claim this node makes.
  downstream:
  - target: Progressive Visceral Amyloid Accumulation
    causal_link_type: DIRECT

- name: Progressive Visceral Amyloid Accumulation
  description: >-
    Because the liver keeps secreting the variant precursor throughout life,
    deposition is cumulative and the amyloid load in the affected viscera rises
    over years to decades. Accumulation, not any acute event, is what converts a
    subclinical deposit into organ failure, and it is why the disease is
    typically diagnosed in mid to late adult life despite the causal variant
    being present from conception. The corollary is therapeutic: interrupting
    supply of the precursor arrests accumulation and can allow existing deposits
    to regress.
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  role: effector
  biological_scale: TISSUE
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:9461086
    reference_title: Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two members of the current generation received renal transplants for
      end-stage renal failure 16 and 18 years ago, and remain very well
      clinically despite massive visceral amyloidosis.
    explanation: >-
      Documents accumulation of a massive visceral amyloid burden over decades,
      and that the burden itself is tolerated once the failed organ is replaced.
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver transplantation led to regression of amyloid in all four cases in
      whom serial 123I-SAP scintigraphy was performed.
    explanation: >-
      Shows accumulation is supply-driven: removing the source of the variant
      precursor reverses the accumulated load.
  downstream:
  - target: Progressive Renal Excretory Failure
    causal_link_type: DIRECT

- name: Progressive Renal Excretory Failure
  description: >-
    Amyloid replacement of glomerular or tubulointerstitial architecture
    manifests first as proteinuria and then as a steady decline in excretory
    function, ending in end-stage renal disease requiring dialysis or
    transplantation. The rate differs by precursor - roughly five years from
    proteinuria to end-stage disease in AFib, roughly fifteen years from
    diagnosis in AApoAI - but the endpoint is shared, and renal failure is the
    dominant cause of morbidity in every subtype. Survival is nonetheless far
    better than in AL amyloidosis, because extra-renal amyloid is limited and
    dialysis outcomes are comparable to those of other non-diabetic nephropathy.
  conforms_to: amyloidogenesis#Organ Dysfunction
  role: outcome
  biological_scale: ORGANISM
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median time from presentation to ESRD was 4.6 yr, and the estimated median
      patient survival from presentation was 15.2 yr.
    explanation: >-
      Quantifies the progression from renal presentation to end-stage disease and
      the comparatively long survival that follows it.
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      median time from diagnosis to end-stage renal disease was 15.0 (95% CI:
      10.0-20.0) years
    explanation: >-
      Gives the substantially slower renal decline of the AApoAI subtype, the
      contrast that makes progression rate precursor-dependent.

phenotypes:
- category: Renal
  name: Proteinuria
  description: >-
    Proteinuria is the presenting abnormality in most patients and the finding
    that leads to renal biopsy and diagnosis. In the fibrinogen form it is
    universal at presentation; in the apolipoprotein A-I form it may be mild and
    tubular rather than nephrotic-range, because the deposit is medullary rather
    than glomerular.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A proteinuric presentation followed by progression to ESRD within 5 yr was
      typical of AFib.
    explanation: >-
      Establishes proteinuria as the typical presenting phenotype.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six patients presented with proteinuria, hypertension, and/or lower limb
      edema and underwent detailed clinical and laboratory investigations.
    explanation: >-
      Independent case series confirming proteinuria as the mode of presentation.
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed incipient symptoms including proteinuria
    explanation: >-
      Systematic review of 46 reported AFib cases finding proteinuria in every
      patient at onset.

- category: Renal
  name: Renal Amyloidosis
  description: >-
    Amyloid deposition within the kidney is the defining organ lesion of this
    disease and is present in essentially every symptomatic patient regardless of
    precursor. Its intrarenal distribution differs by subtype (glomerular in AFib
    and AApoAII, medullary and tubulointerstitial in AApoAI), which is what makes
    renal histology informative about the underlying gene.
  phenotype_term:
    preferred_term: Renal amyloidosis
    term:
      id: HP:0001917
      label: Renal amyloidosis
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the renal histology is very characteristic showing substantial accumulation
      of amyloid within enlarged glomeruli, but none in blood vessels or the
      interstitium
    explanation: >-
      Describes the renal amyloid deposit and its characteristic distribution in
      the fibrinogen form.
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal amyloidosis was universal in association with the most commonly
      identified variant (Gly26Arg, n = 28).
    explanation: >-
      Establishes renal amyloid as effectively universal in the commonest AApoAI
      genotype.

- category: Renal
  name: End-Stage Renal Disease
  description: >-
    Progressive loss of excretory function culminating in dialysis dependence or
    the need for transplantation. This is the dominant clinical outcome of the
    disease in every subtype; the time course differs, being fastest in AFib
    (median under five years from proteinuria) and slowest in AApoAI.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At censor, a total of 44 (62%) patients had reached ESRD, having commenced
      renal replacement therapy at a median age of 60 yr
    explanation: >-
      Quantifies progression to end-stage renal disease in the largest reported
      cohort.
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients had progressive amyloidotic renal dysfunction culminating in
      end-stage renal failure, three of whom underwent renal transplantation
      (RTx).
    explanation: >-
      Confirms the same renal endpoint in the lysozyme subtype.
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      10 (21.7%) patients progressed to end-stage renal disease (ESRD) or
      received renal replacement therapy (including dialysis and kidney
      transplantation) within 1 year
    explanation: >-
      Quantifies the pace of progression to end-stage renal disease across
      pooled AFib case reports.

- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Around a quarter of reported AFib patients present in the nephrotic range
    rather than with isolated proteinuria. This is the presentation that most
    resembles AL amyloidosis and it is where the misdiagnosis usually happens.
    Note the contrast with the apolipoprotein A-I subtype, where median protein
    excretion at diagnosis was only 0.3 g per 24 hours despite universal renal
    amyloid: nephrotic-range proteinuria is a feature of the glomerular
    precursor forms, not of the medullary AApoAI lesion.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  frequency: FREQUENT
  subtypes:
  - AFib
  evidence:
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 (28.3%) patients presented with nephrotic syndrome, 9 (19.6%) had edema
      in both lower limbs, and 4 (8.7%) had palpebral edema.
    explanation: >-
      Quantifies nephrotic-range presentation across 46 pooled AFib cases.
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with renal amyloidosis had a median creatinine of 159 µmol/L and
      median urinary protein of 0.3 g/24 h at the time of diagnosis of AApoAI
      amyloidosis
    explanation: >-
      Bounds the phenotype to the glomerular precursor forms by showing that the
      AApoAI subtype is characteristically sub-nephrotic. Graded PARTIAL because
      it constrains rather than establishes the phenotype.

- category: Renal
  name: Edema
  description: >-
    Peripheral and periorbital edema follow the loss of protein in the urine and
    are often the symptom that brings the patient to attention, ahead of any
    measured decline in kidney function.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  frequency: FREQUENT
  subtypes:
  - AFib
  evidence:
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 (28.3%) patients presented with nephrotic syndrome, 9 (19.6%) had edema
      in both lower limbs, and 4 (8.7%) had palpebral edema.
    explanation: >-
      Quantifies lower-limb and palpebral edema as presenting features across
      pooled AFib cases.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six patients presented with proteinuria, hypertension, and/or lower limb
      edema and underwent detailed clinical and laboratory investigations.
    explanation: >-
      Independent series listing lower-limb edema among the presenting features.

- category: Renal
  name: Tubulointerstitial Nephritis
  description: >-
    The characteristic renal presentation of the apolipoprotein A-I subtype:
    medullary, non-glomerular amyloid producing defective urine concentration,
    polyuria and only mild tubular proteinuria with a bland urinalysis. This is
    the presentation most likely to be missed, because it does not look like
    amyloid nephropathy.
  phenotype_term:
    preferred_term: Tubulointerstitial nephritis
    term:
      id: HP:0001970
      label: Tubulointerstitial nephritis
  subtypes:
  - AApoAI
  evidence:
  - reference: PMID:16221867
    reference_title: "Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The renal presentation was consistent with a tubulointerstitial disease, as
      suggested by the findings of defective urine-concentrating capacity,
      moderate polyuria, negative urinalysis, and mild tubular proteinuria.
    explanation: >-
      Directly describes the tubulointerstitial presentation curated here and
      restricted to the AApoAI subtype.

- category: Renal
  name: Polyuria
  description: >-
    Polyuria from impaired urinary concentration, reflecting medullary amyloid in
    apolipoprotein A-I amyloidosis rather than glomerular injury.
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
  subtypes:
  - AApoAI
  evidence:
  - reference: PMID:16221867
    reference_title: "Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      defective urine-concentrating capacity, moderate polyuria, negative
      urinalysis, and mild tubular proteinuria
    explanation: >-
      Reports polyuria and defective urine concentration as part of the AApoAI
      renal phenotype.

- category: Cardiovascular
  name: Hypertension
  description: >-
    Hypertension is common at or before the discovery of proteinuria and is part
    of the usual renal presentation rather than a marker of cardiac amyloid.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  frequency: FREQUENT
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-two percent of patients had previously been diagnosed with
      hypertension or were hypertensive at the time of discovery of proteinuria
    explanation: >-
      Quantifies the frequency of hypertension at presentation.

- category: Hepatic
  name: Hepatic Amyloid Deposition
  description: >-
    Liver involvement is prominent in the lysozyme and apolipoprotein A-I
    subtypes and is rare in the fibrinogen subtype. It may be clinically silent
    and detected only as an unexplained persistent cholestatic liver enzyme
    elevation, which is how several apolipoprotein A-I kindreds were first
    identified.
  phenotype_term:
    preferred_term: Hepatic amyloidosis
    term:
      id: HP:0012280
      label: Hepatic amyloidosis
  subtypes:
  - AApoAI
  - ALys
  evidence:
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All symptomatic ALys individuals had hepatic amyloid.
    explanation: >-
      Establishes universal hepatic amyloid among symptomatic lysozyme
      amyloidosis patients.
  - reference: PMID:15131802
    reference_title: Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated both phenotypic and genotypic aspects of apolipoprotein A-I
      amyloidosis unexpectedly disclosed by liver biopsy in 13 unrelated
      individuals with asymptomatic, persistent elevation of alkaline phosphatase
      and gamma-glutamyltransferase levels.
    explanation: >-
      Shows hepatic amyloid in AApoAI presenting silently as a cholestatic enzyme
      abnormality.

- category: Gastrointestinal
  name: Gastrointestinal Amyloid Involvement
  description: >-
    Macroscopically visible amyloid lesions throughout the gastrointestinal tract
    are characteristic of the lysozyme subtype and can be the presenting problem,
    ahead of any renal disease. Gastrointestinal involvement is not a feature of
    the fibrinogen subtype. HPO has no gastrointestinal-specific amyloid class,
    so the generic Amyloid deposition term is bound here and the anatomical site
    is carried by the phenotype name and description.
  phenotype_term:
    preferred_term: Gastrointestinal amyloid deposition
    term:
      id: HP:0011034
      label: Amyloid deposition
  subtypes:
  - ALys
  evidence:
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically
      visible amyloidotic lesions were present in nine of 10 patients who
      underwent GI endoscopy.
    explanation: >-
      Documents prevalent, endoscopically visible gastrointestinal amyloid in the
      lysozyme subtype.
  - reference: PMID:25217048
    reference_title: A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals suffered with prevailing gastrointestinal symptoms
      leading to the diagnosis of ALys.
    explanation: >-
      An entire nine-member ALys kindred in which gastrointestinal disease, not
      renal disease, was the presenting problem.

- category: Gastrointestinal
  name: Gastrointestinal Inflammation
  description: >-
    A minority of lysozyme amyloidosis patients have rectocolic inflammation that
    looks like inflammatory bowel disease, which is a route to misdiagnosis: the
    colitis is treated on its own terms and the underlying amyloidosis is missed
    until the disease is atypical or refractory enough to prompt a search for
    amyloid. Reported in three of nine affected members of a single p.Trp82Arg
    kindred, so the proportion should not be generalised.
  phenotype_term:
    preferred_term: Gastrointestinal inflammation
    term:
      id: HP:0004386
      label: Gastrointestinal inflammation
  subtypes:
  - ALys
  evidence:
  - reference: PMID:25217048
    reference_title: A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8/9 had non specific upper gastrointestinal symptoms and 3/9 had rectocolic
      inflammation evoking inflammatory bowel disease.
    explanation: >-
      Reports the inflammatory-bowel-disease-like colitis and its frequency
      within the described kindred.
  - reference: PMID:25217048
    reference_title: A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloidosis should be considered in atypical or treatment resistant, upper
      or lower chronic gastrointestinal symptoms.
    explanation: >-
      States the misdiagnosis risk that makes this phenotype worth curating
      separately from the amyloid deposit itself.

- category: Hematologic
  name: Splenic Amyloid Deposition
  description: >-
    Splenic amyloid is detected by serum amyloid P component scintigraphy in the
    large majority of patients with the fibrinogen subtype but is asymptomatic,
    an illustration of how far visceral amyloid load can outrun clinical
    manifestations outside the kidney.
  phenotype_term:
    preferred_term: Splenic amyloid deposition
    term:
      id: HP:0011034
      label: Amyloid deposition
  subtypes:
  - AFib
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed renal amyloid in every patient who had not already reached ESRD, and
      asymptomatic splenic and adrenal amyloid deposits in 89 and 21% of
      patients, respectively
    explanation: >-
      Quantifies asymptomatic splenic and adrenal amyloid detected by
      scintigraphy.

- category: Cardiovascular
  name: Cardiac Amyloid Involvement
  description: >-
    Cardiac involvement separates the subtypes sharply and is the clearest
    contrast with hereditary transthyretin amyloidosis. Roughly a quarter of
    apolipoprotein A-I patients have cardiac amyloid, whereas in the fibrinogen
    subtype infiltrative cardiomyopathy is essentially absent even on prolonged
    follow-up.
  phenotype_term:
    preferred_term: Cardiac amyloidosis
    term:
      id: HP:0030843
      label: Cardiac amyloidosis
  frequency: OCCASIONAL
  subtypes:
  - AApoAI
  evidence:
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Involvement of the kidneys, liver and heart by amyloid was detected in 81%,
      67% and 28% of patients, respectively.
    explanation: >-
      Quantifies cardiac involvement in the AApoAI subtype.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No patient developed the typical electrocardiographic and echocardiographic
      features of restrictive diastolic filling, thickened ventricular walls, and
      reduced QRS voltages to suggest an infiltrative amyloid cardiomyopathy
      during follow up.
    explanation: >-
      Supports the subtype restriction of this phenotype by reporting the absence
      of cardiac amyloid in the fibrinogen cohort. Graded PARTIAL because it
      bounds rather than establishes the phenotype.

biochemical:
- name: Cholestatic Liver Enzyme Elevation
  notes: >-
    A persistent, asymptomatic rise in alkaline phosphatase and
    gamma-glutamyltransferase, with hepatic amyloid found only when the liver is
    biopsied. This is not a minor laboratory footnote: it is how an entire cohort
    of Italian apolipoprotein A-I kindreds was discovered, in people who had no
    renal complaint and no family history to prompt the question. It matters for
    diagnosis because the alternative route in - proteinuria - can be absent or
    trivial in the AApoAI subtype, whose renal deposit is medullary.
  biomarker_term:
    preferred_term: Serum Alkaline Phosphatase Measurement
    term:
      id: NCIT:C61016
      label: Serum Alkaline Phosphatase Measurement
  presence: Persistently elevated
  subtypes:
  - AApoAI
  evidence:
  - reference: PMID:15131802
    reference_title: Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that specific staining for amyloid should be
      performed on liver biopsy of individuals with asymptomatic chronic
      elevation of alkaline phosphatase and gamma-glutamyltransferase levels.
    explanation: >-
      States the diagnostic recommendation that follows from this biochemical
      abnormality being the presenting abnormality.

- name: Gamma-Glutamyltransferase Elevation
  notes: >-
    Raised gamma-glutamyltransferase accompanies the alkaline phosphatase rise
    and is part of the same cholestatic pattern; the two are reported together
    and neither on its own is specific.
  biomarker_term:
    preferred_term: Gamma Glutamyl Transpeptidase Measurement
    term:
      id: NCIT:C64847
      label: Gamma Glutamyl Transpeptidase Measurement
  presence: Persistently elevated
  subtypes:
  - AApoAI
  evidence:
  - reference: PMID:15131802
    reference_title: Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      apolipoprotein A-I amyloidosis unexpectedly disclosed by liver biopsy in 13
      unrelated individuals with asymptomatic, persistent elevation of alkaline
      phosphatase and gamma-glutamyltransferase levels
    explanation: >-
      Documents the persistent gamma-glutamyltransferase elevation in the cohort
      in which the diagnosis was made this way.

histopathology:
- name: Congo Red-Positive Amyloid Deposition
  description: >-
    Congo red staining of the affected tissue shows acellular extracellular
    deposits that are birefringent under cross-polarized light. The cited renal
    series describes the colour as red-green; the classical textbook phrase is
    apple-green, and the two name the same optical finding. This establishes that
    the deposit is amyloid but says nothing about which protein it is made of, so
    typing by immunohistochemistry or mass spectrometry remains a separate and
    mandatory step.
  diagnostic: true
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Panel B shows red-green birefringence when the same section is viewed under
      cross-polarized light.
    explanation: >-
      Documents the polarized-light birefringence of the Congo red-stained renal
      deposit in this disease.

- name: Glomerulus-Restricted Amyloid Deposition
  description: >-
    In the fibrinogen subtype the deposit fills grossly enlarged glomeruli and
    obliterates their architecture while leaving vessels and tubulointerstitium
    essentially clear. The pattern is distinctive enough to be actionable: seeing
    it should prompt FGA sequencing even in a patient with no family history, and
    it is the opposite of the medullary, non-glomerular pattern of the
    apolipoprotein A-I subtype.
  diagnostic: true
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  subtype: AFib
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the discovery of massive glomerular amyloid, particularly in the absence of
      significant extraglomerular amyloid, should always prompt a search for a
      mutation
    explanation: >-
      States the actionable inference this histopathological pattern licenses -
      the sentence continues "in the fibrinogen Aa-chain gene", trimmed here only
      because the cached text spells the chain with a Greek alpha.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 5 subjects, extensive amyloid deposits were found solely within the
      glomeruli, which stained specifically with antibodies to fibrinogen A alpha
      chain
    explanation: >-
      Independent confirmation of the glomerulus-restricted distribution with
      precursor-specific staining.

genetic:
- name: APOA1
  gene_term:
    preferred_term: APOA1
    term:
      id: hgnc:600
      label: APOA1
  relationship_type: CAUSATIVE
  subtype: AApoAI
  association: >-
    Heterozygous variants in APOA1, which encodes the major HDL apolipoprotein,
    cause AApoAI amyloidosis. The amyloidogenic alleles are structurally diverse
    - missense substitutions, in-frame deletions and frameshifts - but the
    reported ones share the acquisition of an extra positive charge in the mature
    protein, which is thought to underlie their amyloidogenicity. Gly26Arg is the
    most frequently encountered variant and the only one associated with
    peripheral neuropathy; Leu75Pro accounts for several Italian kindreds and
    presents with a hepatic and renal picture.
  evidence:
  - reference: PMID:9461086
    reference_title: Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among living family members there was complete concordance between
      amyloidosis and the presence of a novel 9 base pair in-frame deletion
      mutation in exon 4 of the apoA-I gene
    explanation: >-
      Demonstrates co-segregation of an APOA1 variant with amyloidosis within a
      pedigree, the causal genetic claim.
  - reference: PMID:15131802
    reference_title: Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel (Leu75Pro) heterozygous mutation in the apolipoprotein A-I gene was
      present in affected individuals but not in controls.
    explanation: >-
      Case-control genetic evidence for a second amyloidogenic APOA1 allele.

- name: APOA2
  gene_term:
    preferred_term: APOA2
    term:
      id: hgnc:601
      label: APOA2
  relationship_type: CAUSATIVE
  subtype: AApoAII
  association: >-
    Heterozygous stop-codon variants in APOA2 abolish normal translational
    termination and extend apolipoprotein A-II by roughly 21 C-terminal residues.
    The extended variant circulates alongside normal apolipoprotein A-II and is
    the fibril protein recovered from renal amyloid. Very few kindreds have been
    reported.
  evidence:
  - reference: PMID:11703582
    reference_title: Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot analysis and amino acid sequence analysis of the patient's
      plasma apoA-II showed both normal apoA-II and variant apoA-II with a
      21-amino acid residue extension at the C-terminus.
    explanation: >-
      Confirms the extended variant protein circulating in a patient with renal
      amyloidosis, tying the APOA2 allele to the amyloid.

- name: FGA
  gene_term:
    preferred_term: FGA
    term:
      id: hgnc:3661
      label: FGA
  relationship_type: CAUSATIVE
  subtype: AFib
  association: >-
    Heterozygous variants in FGA, encoding the fibrinogen A alpha-chain, are the
    most common cause of hereditary renal amyloidosis in the United Kingdom. The
    amyloidogenic variants cluster in the region of exon 5 encoding the peptide
    fragment that forms the fibril subunit, and include both single-base
    substitutions and frameshifts; E526V dominates in British and northern
    European patients. Penetrance is low, so a negative family history is common
    and does not argue against the diagnosis. Allele class is not cosmetic: it
    tracks with how aggressive the renal disease is and therefore with whether an
    isolated kidney graft is enough or a combined liver-kidney transplant is
    warranted, since only the combined procedure removes the source of the
    variant protein. Pooled case data also show women presenting significantly
    earlier than men, for reasons that are not established.
  frequency: >-
    Most common cause of hereditary renal amyloidosis in the UK; E526V accounted
    for 64 of 71 patients in the largest reported cohort.
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      64 patients were heterozygous for the previously reported single base
      substitution that altered the codon at position 526 of the mature protein
      from that for glutamic acid to valine
    explanation: >-
      Establishes the dominant FGA allele and its heterozygous state in the
      largest cohort.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 frameshift mutations F521Sfs*27 and G519Efs*30 and 4 single base
      substitutions G555F, E526K, E524K, R554H
    explanation: >-
      Documents the allelic spectrum, including frameshift and substitution
      classes, in a second independent series.
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found the onset age to be lower in women than in men (P < 0.05).
    explanation: >-
      Reports the sex difference in age at onset across 46 pooled AFib cases.
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among them, 6 (37.5%) patients had disease recurrence after
      transplantation
    explanation: >-
      Quantifies post-transplant amyloid recurrence, the outcome that makes
      allele class and transplant strategy a joined-up decision.

- name: LYZ
  gene_term:
    preferred_term: LYZ
    term:
      id: hgnc:6740
      label: LYZ
  relationship_type: CAUSATIVE
  subtype: ALys
  association: >-
    Heterozygous missense variants in LYZ substitute highly conserved residues of
    human lysozyme (classically Ile56Thr and Asp67His), destabilising the native
    fold. Unlike the fibrinogen form, the fibril is composed of full-length
    variant lysozyme rather than a proteolytic fragment. Because lysozyme's
    structure and folding are known in atomic detail, this was the first
    hereditary amyloidosis to be used as a tractable structural model of
    amyloidogenesis.
  evidence:
  - reference: PMID:8464497
    reference_title: Human lysozyme gene mutations cause hereditary systemic amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid fibrils from one individual were composed of the full-length Thr-56
      variant lysozyme molecule.
    explanation: >-
      Directly identifies full-length variant lysozyme as the fibril protein,
      establishing LYZ causation and the fibril composition claim.
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lysozyme, which is the amyloidogenic precursor protein in ALys, is a
      ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and
      macrophages.
    explanation: >-
      Identifies the LYZ gene product as the amyloidogenic precursor and names its
      cellular sources, which is why hepatectomy alone does not fully abolish
      precursor supply in this subtype.

diagnosis:
- name: Renal biopsy with amyloid typing
  description: >-
    Congo red staining of a renal biopsy establishes amyloid; the intrarenal
    distribution then narrows the precursor, since massive glomerular amyloid
    with spared vessels and interstitium is characteristic of the fibrinogen
    form. Immunohistochemistry with antibodies to the candidate fibril proteins
    types the deposit in most but not all cases, and laser microdissection with
    mass spectrometry resolves the remainder. Typing failure is common enough
    that a negative immunohistochemical result does not exclude a hereditary
    form.
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of amyloidosis was made by kidney biopsy in 64 patients and
      by serum amyloid P component (SAP) scintigraphy in conjunction with genetic
      analysis in the context of renal dysfunction and a known family history of
      AFib in seven patients.
    explanation: >-
      Establishes kidney biopsy as the primary diagnostic modality in this
      disease, with scintigraphy plus genetics as the alternative route.
  - reference: PMID:29142973
    reference_title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical awareness and suspicion of hereditary amyloidosis corroborated by
      genetic analysis and adequate typing using combined immunohistochemistry
      and laser microdissection and mass spectrometry is valuable to avoid
      misdiagnosis, especially when a family history of amyloidosis is absent.
    explanation: >-
      States the combined histological, immunohistochemical, proteomic and
      genetic diagnostic strategy curated here.

- name: Sequencing of amyloidogenic precursor genes
  description: >-
    Because the clinical picture is non-specific and penetrance is variable, DNA
    analysis of APOA1, APOA2, FGA and LYZ is required to establish the hereditary
    form and identify the precursor. A detectable plasma cell dyscrasia does not
    exclude a hereditary amyloidosis and does not remove the need for sequencing.
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA analysis is now performed routinely in UK National Amyloidosis Centre
      in patients with systemic amyloidosis in whom AA or AL fibril type cannot
      be definitively verified.
    explanation: >-
      Establishes routine precursor-gene sequencing as the diagnostic step for
      untyped systemic amyloid.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of a plasma cell dyscrasia in a patient with systemic
      amyloidosis, as was detected in 10% of the current cohort using the very
      sensitive techniques now available, neither excludes AFib nor proves
      AL-type amyloidosis, and does not alter the requirement for DNA analysis
    explanation: >-
      States explicitly that a coexisting paraprotein does not remove the
      requirement for genetic testing.

- name: Serum amyloid P component scintigraphy
  description: >-
    Radiolabelled SAP scintigraphy maps whole-body visceral amyloid load
    non-invasively, is diagnostic in patients in whom biopsy is not obtained, and
    is the tool that demonstrates regression of amyloid after removal of the
    precursor source by liver transplantation.
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiolabeled SAP scintigraphy was diagnostic of amyloidosis in each of 63
      patients who underwent the procedure.
    explanation: >-
      Establishes the diagnostic yield of SAP scintigraphy in this disease.

treatments:
- name: Kidney Transplantation
  description: >-
    Renal transplantation is the standard treatment for end-stage renal disease
    in this group and gives good medium-term outcomes, but it does not address
    the source of the circulating variant precursor, so amyloid can recur in the
    graft. In the fibrinogen subtype recurrent amyloid caused graft loss after
    roughly six to seven years in several patients; in the apolipoprotein A-I
    subtype, where deposition is far slower, allograft survival has been much
    longer.
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Progressive Renal Excretory Failure
    treatment_effect: RESTORES
    description: >-
      Restores excretory function by replacing the failed organ, without altering
      upstream precursor supply - so the mechanism keeps running and amyloid
      eventually re-deposits in the graft.
    evidence:
    - reference: PMID:19073821
      reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renal transplantation in AFib is associated with recurrence of amyloid in
        the graft and with resultant loss of transplant kidneys after a median of
        6.7 yr, although one kidney continued to function after 12.2 yr.
      explanation: >-
        Shows the graft restores excretory function but that ongoing precursor
        supply eventually re-deposits amyloid in it.
  evidence:
  - reference: PMID:35502644
    reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Post-renal transplantation, median allograft survival was 22.0 (13.0-31.0)
      years.
    explanation: >-
      Documents the favourable renal allograft survival that makes
      transplantation the treatment of choice in the AApoAI subtype.

- name: Liver Transplantation
  description: >-
    Because the amyloidogenic precursors are synthesised chiefly by the liver,
    orthotopic liver transplantation removes the source of the circulating
    variant protein and is the only intervention that stops further deposition;
    existing deposits can then regress. It is used pre-emptively or, in lysozyme
    amyloidosis, urgently for spontaneous hepatic rupture. Lysozyme is also made
    by neutrophils and macrophages, so hepatectomy does not abolish precursor
    supply as completely in that subtype as it does for the apolipoproteins and
    fibrinogen.
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Variant Plasma Protein Amyloidogenic Precursor
    treatment_effect: INHIBITS
    description: >-
      Removes the hepatic source of the variant precursor, cutting supply at the
      trigger node rather than treating a downstream consequence.
    evidence:
    - reference: PMID:35502644
      reference_title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Liver transplantation led to regression of amyloid in all four cases in
        whom serial 123I-SAP scintigraphy was performed.
      explanation: >-
        Demonstrates that removing the precursor source reverses accumulated
        amyloid, which is the mechanistic claim for targeting this node.
  evidence:
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients received orthotopic liver transplants (OLT), three for
      spontaneous hepatic rupture and one case, who had extensive hepatic amyloid
      and a strong family history of hepatic rupture, pre-emptively.
    explanation: >-
      Documents both the emergency and pre-emptive indications for liver
      transplantation in lysozyme amyloidosis.
  - reference: PMID:19633201
    reference_title: "Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data encourage evaluation of preemptive solitary liver transplantation
      early in the course of amyloid nephropathy to prevent hemodialysis and
      kidney transplantation.
    explanation: >-
      Argues for pre-emptive isolated liver transplantation on the mechanistic
      ground that it removes the precursor before the kidney is lost.

- name: Combined Liver-Kidney Transplantation
  description: >-
    Simultaneous hepatorenal transplantation both replaces the failed kidney and
    removes the hepatic source of the amyloidogenic precursor, so it prevents
    amyloid recurrence in the renal allograft. It carries greater perioperative
    risk than isolated renal transplantation, and because isolated renal grafts
    last several years before recurrent amyloid becomes limiting, it is generally
    reserved for younger, fitter patients.
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Progressive Visceral Amyloid Accumulation
    treatment_effect: INHIBITS
    description: >-
      Combines organ replacement with elimination of precursor supply, arresting
      further accumulation rather than merely replacing the failed organ.
    evidence:
    - reference: PMID:19073821
      reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A further six patients in this series have undergone combined hepatorenal
        transplantation at King's College Hospital, London, which was performed
        preemptively in three patients.
      explanation: >-
        Documents the combined procedure in this disease, including pre-emptive
        use before renal replacement is strictly required.
  evidence:
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it has been our practice to recommend consideration of combined liver and
      kidney transplantation only in younger, fitter patients with this disease
    explanation: >-
      States the patient-selection caveat curated in this treatment's
      description.
  - reference: PMID:19633201
    reference_title: "Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of 9 patients who underwent LKT are alive (67%), with good allograft
      function and no amyloidosis at median 67 months (range, 33-155 months) of
      follow-up.
    explanation: >-
      Reports absence of recurrent amyloid after combined transplantation, the
      outcome that distinguishes it from isolated renal transplantation.

- name: Renal Replacement Therapy
  description: >-
    Dialysis for end-stage renal disease. Outcomes in this disease are notably
    better than in AL amyloidosis and comparable to those of age-matched patients
    with other non-diabetic nephropathies, because extra-renal amyloid is limited
    and the natural history is slow.
  treatment_term:
    preferred_term: Hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Progressive Renal Excretory Failure
    treatment_effect: BYPASSES
    description: >-
      Substitutes extracorporeally for lost excretory function; it has no effect
      on precursor supply or amyloid deposition.
    evidence:
    - reference: PMID:19073821
      reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Estimated median survival from commencement of renal replacement therapy
        by Kaplan-Meier analysis was 8.2 yr
      explanation: >-
        Quantifies survival on renal replacement therapy in this disease.

- name: Symptomatic and Supportive Management
  description: >-
    There is no amyloid-specific pharmacotherapy for any of the four precursor
    forms. In particular, none of the transthyretin-directed stabilisers or
    gene-silencing agents applies here, because the precursor is a different
    protein. Management outside transplantation is symptomatic - blood-pressure
    and proteinuria control, treatment of gastrointestinal bleeding, and
    surveillance of organ function.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:21988333
    reference_title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is currently no amyloid-specific therapy for the condition which is
      managed symptomatically.
    explanation: >-
      States the absence of disease-modifying pharmacotherapy that this treatment
      entry records.

differential_diagnoses:
- name: AL Amyloidosis
  description: >-
    Systemic amyloidosis from a clonal immunoglobulin light chain. This is the
    diagnosis familial visceral amyloidosis is most often mistaken for, and the
    error has consequences: patients have received cytotoxic chemotherapy for
    presumed AL disease before the hereditary form was recognised. A monoclonal
    protein is common enough in older patients to be incidental, so its presence
    does not settle the question.
  distinguishing_features:
  - >-
    Precursor-gene sequencing (APOA1, APOA2, FGA, LYZ) establishes the hereditary
    form; amyloid typing by immunohistochemistry, or by laser microdissection
    with mass spectrometry when immunohistochemistry is non-definitive,
    identifies the fibril protein.
  - >-
    Renal histology is informative: massive amyloid within grossly enlarged
    glomeruli with almost none in vessels or interstitium suggests fibrinogen A
    alpha-chain amyloidosis.
  - >-
    Survival is far longer in the hereditary visceral forms than in untreated AL
    amyloidosis, and clinically significant extra-renal amyloid is much less
    common.
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype of hereditary renal amyloid is non-specific and is
      readily misdiagnosed as acquired AL amyloidosis.
    explanation: >-
      States the misdiagnosis risk that makes AL amyloidosis the principal
      differential.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chemotherapy comprising autologous stem cell transplantation was
      administered for presumed AL amyloidosis in one such patient before the
      correct diagnosis of AFib was achieved.
    explanation: >-
      Documents the clinical harm of the misdiagnosis: cytotoxic therapy given
      for presumed AL amyloidosis.
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among the 46 patients, seven were misdiagnosed with immunoglobulin light
      chain amyloidosis (AL). After chemotherapy and stem-cell transplantation,
      renal function in these patients deteriorated.
    explanation: >-
      Quantifies how often the misdiagnosis happens (7 of 46 pooled AFib cases)
      and reports that the resulting treatment worsened renal function.

prevalence:
- subtype: AFib
  population: Patients with systemic amyloidosis, United Kingdom national series 1987-2012
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A denominator-based figure, but a denominator of amyloidosis patients rather
    than of the general population: 87 of 5100 patients evaluated at the UK
    national amyloidosis service over 25 years had AFib amyloidosis. It bounds
    how often the commonest precursor form turns up in an amyloidosis clinic, not
    how common the disease is in a population, so no rate per 100,000 is derived
    from it. measure_type is UNKNOWN rather than PERIOD_PREVALENCE for the same
    reason, and matches the sibling record below: PrevalenceMeasureEnum's values
    all presuppose a population denominator, and neither of these two records
    has one.
  evidence:
  - reference: PMID:39417966
    reference_title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      evaluated 5100 patients with British national amyloidosis between 1987 and
      2012 and discovered that only 87 (1.7%) patients had AFib amyloidosis
    explanation: >-
      Gives the numerator and denominator behind the AFib share of a national
      amyloidosis cohort.
- population: Patients with apparently sporadic systemic amyloidosis, United Kingdom
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Not a population prevalence. This records the fraction of patients presenting
    with apparently sporadic systemic amyloid who in fact have hereditary
    fibrinogen A alpha-chain amyloidosis, which is the number that matters
    clinically because it sets the threshold for genetic testing. No
    general-population rate is curated: the two records here both have a
    denominator of amyloidosis patients, not of a population, and the Orphanet
    epidemiology record (ORPHA:85450) could not be quoted because the Orphadata
    bulk XML needed to generate a citable cache entry is not present in this
    checkout. MONDO carries the rare-disease subsets for this class.
  evidence:
  - reference: PMID:12832750
    reference_title: Hereditary systemic amyloidosis with renal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have lately demonstrated that five percent of patients with apparent
      sporadic amyloid have hereditary fibrinogen A alpha-chain amyloidosis
      associated with the valine 526 variant
    explanation: >-
      Gives the measured fraction of apparently sporadic amyloid that is in fact
      hereditary AFib.

discussions:
- discussion_id: gap_fva_precursor_organ_tropism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do four different variant plasma proteins, all made chiefly by the liver
    and all converging on the same cross-beta fibril, deposit in such different
    places - fibrinogen A alpha-chain almost purely in glomeruli, apolipoprotein
    A-I in the renal medulla and heart, lysozyme across gut, liver and kidney?
  attaches_to:
  - pathophysiology#Precursor-Determined Visceral Organ Tropism
  rationale: >-
    Organ tropism is the single most clinically consequential difference between
    the subtypes - it determines presentation, rate of progression and whether
    liver transplantation is worth its risk - and yet the mechanism that
    determines it is not established. Candidate explanations include differences
    in the size and charge of the fibrillogenic fragment, local proteolytic
    processing at the deposition site, differential binding to tissue
    glycosaminoglycans or basement membrane components, and hemodynamic
    filtration effects at the glomerulus. The evidence curated in this entry
    documents the tropism but not its cause, so the downstream nodes are
    deliberately silent about it.

- discussion_id: controversy_fva_afib_organ_restriction
  kind: CONTROVERSY
  prompt: >-
    Is AFib fibrinogen A alpha-chain amyloidosis a kidney-restricted disease, or
    a systemic one whose extra-renal deposits are simply not looked for?
  attaches_to:
  - has_subtypes#AFib
  - pathophysiology#Precursor-Determined Visceral Organ Tropism
  rationale: >-
    Two large UK series reach opposite conclusions from overlapping patient
    populations. Gillmore and colleagues, following 71 prospectively studied
    patients, found clinically significant extra-renal disease rare and no
    patient developing the echocardiographic picture of infiltrative amyloid
    cardiomyopathy - the basis for calling AFib the most organ-restricted of the
    four precursor forms. Stangou and colleagues, assessing 22 AFib patients
    specifically for combined liver-kidney transplantation and therefore
    obtaining vascular and endomyocardial tissue that the observational cohort
    did not, found variant fibrinogen amyloid in excised atheroma and
    endomyocardial biopsies and autonomic neuropathy in half, and conclude the
    disease is systemic. The disagreement is partly about ascertainment - you
    find myocardial amyloid if you biopsy myocardium - and it matters clinically,
    because cardiovascular amyloid is what can make a patient ineligible for the
    combined transplant that would otherwise be curative. This entry curates the
    kidney-dominant tropism as the general pattern, and records the systemic
    finding here rather than asserting either position as settled.
  evidence:
  - reference: PMID:19633201
    reference_title: "Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fibrinogen amyloidosis is a systemic amyloid disease with visceral,
      vascular, cardiac, and neurologic involvement.
    explanation: >-
      The transplant-assessment series' conclusion that AFib is systemic rather
      than kidney-restricted.
  - reference: PMID:19633201
    reference_title: "Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vascular atheroma excised at endarterectomy and endomyocardial biopsies
      contained purely variant fibrinogen amyloid.
    explanation: >-
      The tissue finding behind the systemic claim, and the reason the
      disagreement is partly one of ascertainment.
  - reference: PMID:19073821
    reference_title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even after a median follow-up of 4 yr, clinically significant extra-renal
      disease was rare.
    explanation: >-
      The opposing position from the larger prospective cohort, on which this
      entry's kidney-dominant characterization rests.

- discussion_id: openq_fva_apoa1_recessive_cardiac_allele
  kind: OPEN_QUESTION
  prompt: >-
    Is every amyloidogenic APOA1 allele dominant, or can a variant require two
    copies? A homozygous p.Leu202Arg carrier developed cardiac amyloidosis while
    his heterozygous brother was unaffected.
  attaches_to:
  - inheritance#Autosomal dominant
  - has_subtypes#AApoAI
  rationale: >-
    This entry curates autosomal dominant inheritance throughout, which is
    correct for every established allele in all four precursor genes. One 2024
    report is the sole exception on record: a man born to consanguineous parents,
    homozygous for APOA1 p.Leu202Arg, with cardiac amyloidosis, whose
    heterozygous brother had no disease. One family cannot establish a recessive
    mechanism - an unaffected heterozygous sibling is also compatible with
    reduced penetrance or later onset in a dominant allele - so nothing in the
    inheritance block was changed. It is recorded here because if the observation
    holds up it would mean a homozygous-only amyloidogenic allele class exists,
    which changes how an APOA1 variant of uncertain significance should be
    interpreted in a heterozygote.
  evidence:
  - reference: DOI:10.1038/s41439-024-00288-7
    reference_title: The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was
      born to consanguineous parents and carried a homozygous variant of
      p.Leu202Arg in APOA1.
    explanation: >-
      The single observation this question rests on. Graded PARTIAL because one
      consanguineous case is hypothesis-generating, not a demonstration of
      recessive inheritance.
  - reference: DOI:10.1038/s41439-024-00288-7
    reference_title: The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are
      inherited in an autosomal dominant manner.
    explanation: >-
      The same report's statement of the established dominant rule, which is what
      this entry curates and which the case is proposed as an exception to.

notes: >-
  Concept decision (why this is a Disease entry with has_subtypes rather than a
  grouping). MONDO:0007099 (familial visceral amyloidosis, Ostertag type) has four
  MONDO children, one per precursor protein: AApoAI (MONDO:0019731), AApoAII
  (MONDO:0016533), AFib (MONDO:0019733) and ALys (MONDO:0019732). They share one
  reasonably conserved pathograph - a germline variant in a hepatically
  synthesised circulating plasma protein, destabilisation and beta-sheet
  conversion of that protein, cross-beta fibril formation, visceral
  (kidney-dominant, non-neuropathic, non-cardiac) deposition, cumulative
  accumulation, and progressive renal excretory failure - and they share their
  diagnostic pathway and their only disease-modifying treatment, which is removal
  of the precursor source by transplantation. What differs between them sits at
  one node, organ tropism, curated explicitly as
  "Precursor-Determined Visceral Organ Tropism". That is a subtype-level
  difference within one mechanism, not a union of unrelated diseases, so the
  entry is curated as a Disease root with has_subtypes, per the guidance in issue
  #9603.

  Relationship to kb/groupings/Hereditary_Systemic_Amyloidoses.yaml. That grouping
  is the broader systemic-hereditary union, scoped by MONDO:0018634
  (skos:broadMatch) and spanning the neuropathic and cardiac forms as well as
  these visceral ones; its rationale records the maintainer directive on issue
  #8655 not to create an umbrella kb/disorders/Hereditary_Amyloidosis.yaml. This
  entry does not contradict that directive. MONDO:0007099 is a narrower concept
  than MONDO:0018634 - it is precisely the non-neuropathic visceral subset, which
  is why a single conserved pathograph is available here and was not available at
  the MONDO:0018634 level. This entry is added to that grouping's members as a
  DISEASE member in the same change.

  Revisit condition. The grouping's rationale lists AApoAI, AApoAII, AFib and
  ALys as intended future standalone Disease entries. If any of them is later
  curated as its own kb/disorders/ file, this entry's corresponding has_subtypes
  block becomes a duplicate and should be reduced to a pointer, or this entry
  should be converted to a grouping at that time. Curating them standalone first
  was not chosen here because it would have left MONDO:0007099 itself - the
  concept the issue asks for, and the one clinicians use when they say
  "hereditary renal amyloidosis" - uncurated.

  Scope. Hereditary transthyretin amyloidosis (ATTRv) is deliberately excluded
  even though Benson's review discusses TTR alongside these precursors: it is
  neuropathic and cardiac rather than visceral, is not a MONDO child of
  MONDO:0007099, and is already curated as kb/disorders/ATTR_Amyloidosis.yaml.
  Gelsolin (AGel/Finnish-type) amyloidosis is likewise excluded and separately
  curated as kb/disorders/Finnish_Type_Amyloidosis.yaml; it is not a MONDO child
  of this class and its phenotype is corneal and cranial-nerve rather than
  visceral. The shared downstream mechanism is modelled once in
  kb/modules/amyloidogenesis.yaml and reached here via conforms_to.

  GeneReviews. PubMed searches for GeneReviews chapters covering fibrinogen A
  alpha-chain, apolipoprotein A-I, apolipoprotein A-II and lysozyme amyloidosis
  returned no results (searched 2026-08-28), so no GeneReviews baseline was
  available. The phenotype baseline is taken instead from the UK National
  Amyloidosis Centre cohort series (PMID:19073821 for AFib, PMID:35502644 for
  AApoAI, PMID:21988333 for ALys) and the Benson review (PMID:16011983).

  Hereditary beta-2-microglobulin amyloidosis (AB2M, B2M p.Asp76Asn) is a
  candidate fifth precursor form and is deliberately NOT curated as a subtype
  here. It is a visceral, non-osteoarticular hereditary systemic amyloidosis and
  the falcon deep-research report proposed it as a member, but it is not a MONDO
  child of MONDO:0007099, it was described long after the Ostertag concept was
  partitioned into the four precursor forms, and the reported literature is a
  small number of families. Adding it would extend the concept past its ontology
  grounding on the strength of a single review. Revisit if MONDO places it under
  this class.

  Deep research. One falcon (Edison) run was performed
  (research/Familial_Visceral_Amyloidosis-deep-research-falcon.md); its
  reference validation resolved 11 of 11 identifiers with a 0.0 confabulation
  rate. Note that its relevance pass reports on_topic 1 of 11 with off_topic 0,
  which means most references were undecided rather than judged off topic. Its
  central recommendation - that MONDO:0007099 be treated as a legacy umbrella
  and the disease-level record point at precursor-defined subtype records rather
  than assign one prognosis to all forms - is what the has_subtypes structure and
  the per-subtype evidence in this entry implement. Claims taken from the report
  were re-verified against the cited abstracts before use; nothing is cited on
  the report's authority alone.

  PMID:16916739 (Lane et al., "Hereditary fibrinogen A alpha-chain amyloidosis")
  was fetched but its cache entry has no retrievable text, so nothing from it is
  quoted or cited here.

  Not curated for want of a verifiable source: the AFib allele-class onset
  gradient (roughly 57 years for E526V, 45 for R554L, 24.5 for frameshift
  alleles) and the E526V-versus-other post-transplant recurrence contrast (22%
  versus 83%). Both appear in the falcon report, attributed to a 32-patient
  French series, but neither number is present in any cached reference in this
  repository, and a deep-research report is a lead rather than a citation. What
  is curated instead is what the cached systematic review (PMID:39417966) does
  support: the pooled post-transplant recurrence rate, the sex difference in age
  at onset, and the allelic spectrum itself. If the French series is fetched
  later, the gradient belongs in the FGA genetic block, because it is what
  decides between an isolated kidney graft and a combined liver-kidney
  transplant.

  The transgenic APOA2 Stop78Ser mouse is the strongest disease-specific animal
  model in the literature and is not curated as an animal_models entry: its cache
  (DOI:10.1016/j.kint.2019.03.013) has content_type unavailable, so there is
  nothing quotable to attach to a modeled_mechanisms link.

references:
- reference: PMID:16011983
  title: "Ostertag revisited: the inherited systemic amyloidoses without neuropathy."
- reference: PMID:8464497
  title: Human lysozyme gene mutations cause hereditary systemic amyloidosis.
- reference: PMID:12832750
  title: Hereditary systemic amyloidosis with renal involvement.
- reference: PMID:19073821
  title: "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis."
- reference: PMID:29142973
  title: Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.
- reference: PMID:35502644
  title: The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.
- reference: PMID:16221867
  title: "Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis."
- reference: PMID:9461086
  title: Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.
- reference: PMID:15131802
  title: Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
- reference: PMID:21988333
  title: "Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation."
- reference: PMID:11703582
  title: Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.
- reference: PMID:19633201
  title: "Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation."
- reference: PMID:25217048
  title: A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.
- reference: PMID:39417966
  title: "Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review."
- reference: DOI:10.1038/s41439-024-00288-7
  title: The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis

📚

References & Deep Research

References

15

PMID:16011983

Ostertag revisited: the inherited systemic amyloidoses without neuropathy.

No top-level findings curated for this source.

PMID:8464497

Human lysozyme gene mutations cause hereditary systemic amyloidosis.

No top-level findings curated for this source.

PMID:12832750

Hereditary systemic amyloidosis with renal involvement.

No top-level findings curated for this source.

PMID:19073821

Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis.

No top-level findings curated for this source.

PMID:29142973

Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.

No top-level findings curated for this source.

PMID:35502644

The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.

No top-level findings curated for this source.

PMID:16221867

Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis.

No top-level findings curated for this source.

PMID:9461086

Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.

No top-level findings curated for this source.

PMID:15131802

Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.

No top-level findings curated for this source.

PMID:21988333

Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation.

No top-level findings curated for this source.

PMID:11703582

Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.

No top-level findings curated for this source.

PMID:19633201

Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation.

No top-level findings curated for this source.

PMID:25217048

A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.

No top-level findings curated for this source.

PMID:39417966

Clinical manifestations, diagnosis and treatment of hereditary fibrinogen Aα-chain renal amyloidosis: one case report and systematic review.

No top-level findings curated for this source.

DOI:10.1038/s41439-024-00288-7

The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Familial Visceral Amyloidosis: Disease-Characteristics Report

Edison Scientific Literature 21 citations 2026-08-28T17:07:40.192421

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.

Subtype	Inheritance / representative variants	Dominant organs and phenotype	Natural-history statistics	Definitive diagnosis	Treatment / evidence gaps
Familial visceral amyloidosis (MONDO:0007099)	Legacy/umbrella Mendelian systemic amyloidosis concept rather than a single molecular disease; associated targets include FGA, APOA1, LYZ, APOA2, B2M (OpenTargets Search: familial visceral amyloidosis)	Multivisceral amyloid deposition, but organ tropism differs strongly by subtype: kidney-predominant in AFib and many AApoAII cases; kidney/liver/heart in AApoAI; GI-predominant or renal/hepatic in ALys; visceral non-musculoskeletal pattern in hereditary B2M D76N (OpenTargets Search: familial visceral amyloidosis, stoppini2015systemicamyloidosislessons pages 1-2)	No unified epidemiology or prognosis for the umbrella entity; evidence must be interpreted at subtype level (OpenTargets Search: familial visceral amyloidosis)	Requires amyloid confirmation and subtype assignment; mass-spectrometry typing plus germline sequencing are central because hereditary cases may be misdiagnosed as AL (OpenTargets Search: familial visceral amyloidosis)	No umbrella-specific therapy; management is subtype- and organ-specific, and evidence is sparse outside AFib and AApoAI transplant series (OpenTargets Search: familial visceral amyloidosis, cohen2024prognosticmarkersand pages 194-199)
AFib / FGA	Usually autosomal dominant; representative variants include E526V/p.Glu545Val, R554L, and frameshift variants such as *c.1673del (p.Lys558Argfs10) and c.1639delA (p.Arg547Glyfs21)* (he2025clinicalmanifestationsdiagnosis pages 1-2, escaleira2022fibrinogenaalphachain pages 14-17)	Predominantly renal amyloidosis with proteinuria, edema, hypertension, progressive CKD/ESKD; extra-renal liver/cardiac involvement can occur but is less prominent/variable (he2025clinicalmanifestationsdiagnosis pages 1-2, escaleira2022fibrinogenaalphachain pages 14-17)	In 32 French patients, median diagnosis age 51.5 y; proteinuria 93%, hypertension 83%, kidney failure 68%; kidney disease onset averaged 57 y for E526V, 45 y for R554L, 24.5 y for frameshifts. In a 46-case review, 21.7% reached ESRD/RRT within 1 year and 39.1% within 1–5 years (he2025clinicalmanifestationsdiagnosis pages 1-2)	Renal biopsy with Congo red-positive deposits, proteomic typing/mass spectrometry, and FGA sequencing; careful review needed because private frameshifts can complicate typing (he2025clinicalmanifestationsdiagnosis pages 1-2)	Supportive antiproteinuric/antihypertensive care; dialysis for ESKD. Kidney transplant viable especially for E526V; recurrence after KT lower in E526V than non-E526V (22% vs 83%, P=0.03). Liver-kidney transplant may be preferred for frameshift/non-E526V disease; no recurrence observed after LKT in the French series. No approved subtype-specific drug therapy identified (he2025clinicalmanifestationsdiagnosis pages 1-2)
AApoAI / APOA1	Usually autosomal dominant; heterogeneous mutations including common Gly26Arg and novel c.251T>C (Leu→Pro in mature ApoA-I); 2024 report suggests a possible autosomal recessive cardiac form with p.Leu202Arg in one homozygous patient (cohen2024prognosticmarkersand pages 194-199, yagi2024theapoa1p.leu202arg pages 1-3, moutafi2019anewgenetic pages 1-2)	Kidneys, liver, and heart are major targets; phenotype depends partly on variant. Can present with slowly progressive renal disease, hepatomegaly, infiltrative liver disease, hypogonadism, and less often cardiac amyloidosis (cohen2024prognosticmarkersand pages 194-199, yagi2024theapoa1p.leu202arg pages 1-3, moutafi2019anewgenetic pages 1-2)	UK cohort: 57 patients, 14 APOA1 mutations; median presentation age 43 y; median delay to referral 3 y. Organ involvement: kidneys 81%, liver 67%, heart 28%. For renal disease, median creatinine 159 µmol/L, median proteinuria 0.3 g/24 h, median time from diagnosis to ESRD 15.0 y (95% CI 10.0–20.0). Renal amyloidosis was universal with Gly26Arg (n=28) (cohen2024prognosticmarkersand pages 194-199)	Tissue biopsy with Congo red; immunoelectron microscopy or LMD/LC-MS/MS for amyloid typing; germline APOA1 sequencing for confirmation, especially in atypical liver/cardiac presentations (yagi2024theapoa1p.leu202arg pages 1-3, moutafi2019anewgenetic pages 1-2)	Transplant outcomes are relatively favorable: in the UK cohort, 18 underwent renal transplantation, including 5 LKT and 2 HKT; median renal allograft survival 22.0 y (13.0–31.0). Liver transplantation led to regression of amyloid on serial SAP scintigraphy in all 4 imaged cases. No approved APOA1-targeted pharmacologic/gene-silencing therapy identified (cohen2024prognosticmarkersand pages 194-199)
ALys / LYZ	Autosomal dominant hereditary systemic non-neuropathic amyloidosis; representative variants include Asp67His and p.Trp82Arg (OpenTargets Search: familial visceral amyloidosis)	Heterogeneous phenotype with gastrointestinal, renal, and hepatic involvement; one 9-member family with p.Trp82Arg had predominantly mild upper-GI symptoms and some inflammatory-bowel-disease-like colitis without other organ involvement (OpenTargets Search: familial visceral amyloidosis)	In the reported family, 9 affected members carried heterozygous p.Trp82Arg; 8/9 had nonspecific upper-GI symptoms and 3/9 had rectocolic inflammation suggestive of inflammatory bowel disease. Older evidence notes some Asp67His and APOA1 Gly26Arg cases show slowly progressive renal impairment (OpenTargets Search: familial visceral amyloidosis)	Histologic confirmation of amyloid plus targeted LYZ mutation testing when GI disease is atypical/treatment-resistant and familial; subtype confirmation is important because hereditary amyloidosis may be mistaken for AL (OpenTargets Search: familial visceral amyloidosis)	No established disease-modifying drug therapy identified in gathered evidence. Management appears supportive and organ-directed; evidence for transplantation or systematic outcome data is limited in the gathered set (OpenTargets Search: familial visceral amyloidosis)
AApoAII / APOA2	Hereditary systemic amyloidosis due to stop-codon mutations creating a 21-amino-acid C-terminal extension; representative variants include Stop78Ser and Stop78Arg (chabert2019atransgenicmouse pages 1-2)	Primarily renal amyloidosis/proteinuria progressing to nephrotic syndrome and CKD; human kindreds also show systemic involvement, while the transgenic model developed renal, liver, heart, and spleen amyloid (chabert2019atransgenicmouse pages 1-2)	Human report: proteinuria noted at 42 y in a 46-year-old man with glomerular amyloid and heterozygous stop-codon mutation. Model-derived human summary in Chabert notes ~70% of patients develop nephrotic syndrome progressing to CKD/ESRD, but subtype-specific human cohorts remain very small (chabert2019atransgenicmouse pages 1-2)	Renal biopsy with amyloid typing plus APOA2 sequencing; mechanism is supported by demonstration of variant plasma apoA-II carrying a C-terminal extension (chabert2019atransgenicmouse pages 1-2)	No approved subtype-specific drug therapy identified. Evidence base is limited to rare kindreds/case reports and one transgenic model; transplant and long-term human outcome data are sparse in the gathered evidence (chabert2019atransgenicmouse pages 1-2)
AB2M / B2M	Very rare hereditary systemic amyloidosis due to D76N; distinct from dialysis-related wild-type β2-microglobulin amyloidosis (stoppini2015systemicamyloidosislessons pages 1-2)	Multivisceral involvement including liver, kidney, heart; notably spares bones and ligaments, unlike dialysis-related β2M amyloidosis (stoppini2015systemicamyloidosislessons pages 1-2)	Quantitative natural-history data were not found in the gathered evidence. Main established point is that hereditary D76N has a different tissue tropism from dialysis-related β2M disease (stoppini2015systemicamyloidosislessons pages 1-2)	Amyloid typing plus B2M sequencing are required to distinguish hereditary D76N disease from dialysis-related β2M amyloidosis; deposits in D76N reportedly lacked wild-type and N-terminally truncated β2M species seen in dialysis-related amyloid (stoppini2015systemicamyloidosislessons pages 1-2)	No established subtype-specific therapy or trial evidence identified in the gathered set. Evidence is limited to rare-family and mechanistic literature; prognosis and optimal intervention remain poorly defined (stoppini2015systemicamyloidosislessons pages 1-2)

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

Upstream germline variant in a secreted protein gene.
Hepatic or other physiological synthesis and release of the mutant precursor into blood.
Variant-dependent destabilization, abnormal proteolysis, or altered intermolecular interactions.
Oligomerization and formation of cross-β amyloid fibrils, often with serum amyloid P component and extracellular-matrix glycosaminoglycans.
Extracellular deposition in glomerular mesangium/capillary walls, interstitium, vessels, myocardium, liver, spleen, or GI wall.
Mechanical distortion, microvascular dysfunction, cellular stress, and impaired filtration/contractility/organ architecture.
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:

asymptomatic carrier;
biomarker abnormality—proteinuria, reduced eGFR, abnormal liver tests, BNP/troponin rise;
clinically apparent single-organ amyloidosis;
multiorgan or advanced organ dysfunction;
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

Recognize the organ syndrome: unexplained familial proteinuria/CKD, low-proteinuria renal dysfunction, hepatomegaly, infiltrative liver disease, cardiomyopathy, or familial refractory GI disease.
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.
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.
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.
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.
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

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)
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.
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)
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

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

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	1
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	19
Resolved	19
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	1
Terms named as a different term	0

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

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OpenScientist Report

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Familial Visceral Amyloidosis: Disease-Characteristics Report

Executive summary and curation warning

1. Disease information

Definition and synonyms

Evidence-source distinction

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

Causal factors

Risk and modifier factors

Environmental and protective factors

3. Phenotypes

AFib/FGA

AApoAI/APOA1

ALys/LYZ

AApoAII/APOA2

AB2M/B2M

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Suggested ontology annotations

7. Anatomy

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended workflow

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

General strategy

Transplantation

Trials and recent therapeutic development

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments, 2023–2024

Selected exact abstract quotations

Key publications and identifiers

Knowledge gaps and confidence assessment

Artifacts

Reference Validation

Term Validation