| Type | Precursor Protein | Gene(s) | Etiology | Main Organs Affected | Typical Age of Onset | Inheritance | Key Epidemiology | Primary Treatment Approaches |
|---|---|---|---|---|---|---|---|---|
| AL amyloidosis | Monoclonal immunoglobulin light chains (κ or λ) | Immunoglobulin light-chain loci; recurrent plasma-cell cytogenetic abnormalities include t(11;14), 1q21 gain | Clonal plasma-cell disorder with misfolded light-chain production and extracellular fibril deposition; often arises from MGUS/smoldering myeloma and ~10% also meet criteria for multiple myeloma (pqac-00000004, pqac-00000005, pqac-00000003) | Heart, kidney, liver, GI tract, peripheral/autonomic nerves, soft tissue; ~70% have multiorgan involvement at diagnosis (pqac-00000005, pqac-00000007, pqac-00000008) | Usually adult/older adult; age >65–70 years is adverse prognostic factor (pqac-00000003, pqac-00000004) | Not classically inherited; acquired clonal hematologic disease | Incidence ≈1 per 100,000 person-years; ~3,500–4,500 new US cases/year; also reported as ~10 per million/year (pqac-00000004, pqac-00000005) | First-line daratumumab + bortezomib/cyclophosphamide/dexamethasone (D-VCd); bortezomib-based regimens; selected patients receive autologous stem-cell transplantation; supportive organ care (pqac-00000024, pqac-00000026, pqac-00000029) |
| ATTR variant (ATTRv, hereditary transthyretin amyloidosis) | Mutant transthyretin | **TTR** (chromosome 18); >140–150 pathogenic variants; key variants include p.Val50Met/Val30Met and p.Val142Ile/Val122Ile (pqac-00000013, pqac-00000015, pqac-00000018) | Destabilizing missense TTR variants reduce tetramer stability, causing monomer misfolding and amyloid fibril deposition; phenotype may be neuropathic, cardiac, or mixed (pqac-00000013, pqac-00000015, pqac-00000018) | Peripheral/autonomic nerves, heart, GI tract, kidneys, eyes, leptomeninges/CNS (pqac-00000006, pqac-00000010) | Early-onset in endemic areas often 2nd–5th decade; late-onset usually after 50 years and often 7th–8th decade in non-endemic regions (pqac-00000006, pqac-00000046) | Autosomal dominant with incomplete/variable penetrance; parent-of-origin effects reported for Val30Met/Val50Met (pqac-00000013, pqac-00000014, pqac-00000017) | Global prevalence estimated ~10,186 affected persons (range 5,000–38,000); endemic clusters in Portugal, Sweden, Brazil, Japan; Val122Ile present in ~3–4% of African Americans (pqac-00000046, pqac-00000017, pqac-00000018) | TTR stabilizers (tafamidis; diflunisal off-label; acoramidis for cardiomyopathy), gene silencers (patisiran, vutrisiran, inotersen, eplontersen), emerging CRISPR gene editing (NTLA-2001), supportive multidisciplinary care (pqac-00000021, pqac-00000023, pqac-00000027) |
| ATTR wild-type (ATTRwt) | Wild-type transthyretin | **TTR** (wild-type sequence) | Age-related destabilization/misfolding of native TTR without pathogenic coding mutation; predominantly cardiac deposition (pqac-00000001, pqac-00000052, pqac-00000053) | Heart (restrictive/infiltrative cardiomyopathy), conduction system; can be associated with carpal tunnel syndrome and other musculoskeletal manifestations in broader ATTR spectrum (pqac-00000001, pqac-00000012) | Older adults, predominantly elderly men; often >70–80 years (pqac-00000001, pqac-00000047, pqac-00000049) | Non-Mendelian; no inherited pathogenic variant required | US ATTR prevalence reported as 6.1/million overall in systematic review; 2-year mortality in wild-type ATTR-CM ~10–30%; autopsy deposits in ~25% of people aged ≥85 years (pqac-00000047, pqac-00000048, pqac-00000052) | Tafamidis is established disease-modifying therapy; acoramidis now approved for ATTR-CM; investigational/expanding roles for gene silencers and gene editing in cardiomyopathy; supportive HF care/diuretics (pqac-00000021, pqac-00000022, pqac-00000027) |
| AA amyloidosis | Serum amyloid A (SAA) protein | **SAA1** and related SAA loci as susceptibility modifiers; SAA1.1 homozygosity increases risk in some populations (pqac-00000002) | Chronic inflammatory states drive sustained SAA overproduction and secondary fibril deposition; causes include chronic infection, inflammatory arthritis, FMF, immunodeficiency; ~20% idiopathic/unknown cause (pqac-00000002, pqac-00000034) | Kidney predominates; also liver, GI tract, heart less commonly, and other organs depending on inflammatory burden (pqac-00000002, pqac-00000034) | Usually adults, median diagnosis age ~50–70 years (pqac-00000002) | Not usually Mendelian; underlying inflammatory disorders may be genetic (e.g., FMF), and SAA genotype modifies risk (pqac-00000002) | Incidence ~1–2 cases per million person-years in developed countries; now ~2.9% of all amyloidosis cases; slight male predominance (pqac-00000002) | Control underlying inflammation and reduce SAA: biologics such as IL-6 inhibition (tocilizumab), IL-1 inhibition (anakinra), other anti-inflammatory therapy; kidney transplantation for ESRD in selected patients (pqac-00000002, pqac-00000034) |


*Table: This table compares the four major systemic amyloidosis categories across precursor protein, genetics, etiology, organ involvement, onset, epidemiology, and current treatment strategy. It is useful as a compact disease-knowledge-base reference grounded in the gathered evidence.*