| 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** (pqac-00000000) | 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 (pqac-00000000, pqac-00000005) | No unified epidemiology or prognosis for the umbrella entity; evidence must be interpreted at subtype level (pqac-00000000) | Requires amyloid confirmation and subtype assignment; mass-spectrometry typing plus germline sequencing are central because hereditary cases may be misdiagnosed as AL (pqac-00000000) | No umbrella-specific therapy; management is subtype- and organ-specific, and evidence is sparse outside AFib and AApoAI transplant series (pqac-00000000, pqac-00000003) |
| AFib / FGA | Usually autosomal dominant; representative variants include **E526V/p.Glu545Val**, **R554L**, and frameshift variants such as **c.1673del (p.Lys558Argfs*10)** and **c.1639delA (p.Arg547Glyfs*21)** (pqac-00000001, pqac-00000002) | Predominantly renal amyloidosis with proteinuria, edema, hypertension, progressive CKD/ESKD; extra-renal liver/cardiac involvement can occur but is less prominent/variable (pqac-00000001, pqac-00000002) | 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 (pqac-00000001) | Renal biopsy with Congo red-positive deposits, proteomic typing/mass spectrometry, and **FGA** sequencing; careful review needed because private frameshifts can complicate typing (pqac-00000001) | 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 (pqac-00000001) |
| 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 (pqac-00000003, pqac-00000006, pqac-00000007) | 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 (pqac-00000003, pqac-00000006, pqac-00000007) | 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)** (pqac-00000003) | 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 (pqac-00000006, pqac-00000007) | 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 (pqac-00000003) |
| ALys / LYZ | Autosomal dominant hereditary systemic non-neuropathic amyloidosis; representative variants include **Asp67His** and **p.Trp82Arg** (pqac-00000000) | 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 (pqac-00000000) | 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 (pqac-00000000) | 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 (pqac-00000000) | 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 (pqac-00000000) |
| AApoAII / APOA2 | Hereditary systemic amyloidosis due to stop-codon mutations creating a **21-amino-acid C-terminal extension**; representative variants include **Stop78Ser** and **Stop78Arg** (pqac-00000004) | 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 (pqac-00000004) | 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 (pqac-00000004) | Renal biopsy with amyloid typing plus **APOA2** sequencing; mechanism is supported by demonstration of variant plasma apoA-II carrying a C-terminal extension (pqac-00000004) | 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 (pqac-00000004) |
| AB2M / B2M | Very rare hereditary systemic amyloidosis due to **D76N**; distinct from dialysis-related wild-type β2-microglobulin amyloidosis (pqac-00000005) | Multivisceral involvement including **liver, kidney, heart**; notably **spares bones and ligaments**, unlike dialysis-related β2M amyloidosis (pqac-00000005) | 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 (pqac-00000005) | 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 (pqac-00000005) | 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 (pqac-00000005) |


*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.*