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Genetic factors in the amyloid diseases

Genetic factors in the amyloid diseases
Literature review current through: Sep 2023.
This topic last updated: Apr 11, 2022.

INTRODUCTION — Amyloidosis is the general term used to refer to the extracellular tissue deposition of highly ordered fibrils composed of low molecular weight subunits of a variety of proteins, many of which, in their native form, circulate as normal constituents of plasma. Amyloid deposits may result in a wide range of clinical manifestations depending upon their type, location, and amount. In the genesis of amyloid deposits, previously soluble precursor peptides undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration, allowing them to stack as protofilaments in a twisted fibrillar configuration [1-4]. During fibrillogenesis, amyloid P component, apolipoprotein (Apo) E, and glycosaminoglycans contribute to the formation and persistence of amyloid deposits. These components are found in all amyloid deposits, regardless of the protein type, and therefore serve as universal amyloid signatures [5].

At least 38 different human protein precursors of amyloid fibrils are known. Some are produced at the site of amyloid formation (localized amyloid) and some circulate in the blood to deposit in a variety of tissues and organs (systemic amyloidosis). Amyloid has a characteristic gross pathologic and microscopic appearance, demonstrating birefringence under polarized light microscopy of Congo red stained tissue, which may have a typical "apple-green" dichroic appearance [6].

Over 500 variants and polymorphisms have been associated with heritable and acquired forms of amyloidosis, affecting genes for amyloid subunit proteins and their precursors, proteins implicated in autoinflammatory diseases in which AA amyloid may occur and presenilins (table 1).

The genetic contributions to various types of amyloidosis will be reviewed here. An overview of the amyloidoses, including pathology, fibrillogenesis, clinical manifestations, diagnosis, and therapies, is presented separately, as is a discussion of the genetics of Alzheimer disease (AD). (See "Overview of amyloidosis" and "Genetics of Alzheimer disease".)

TYPES OF GENETIC ABNORMALITIES IN AMYLOIDOSES — The importance of heredity in the amyloid diseases has been recognized for many years [7]; some amyloid disorders appear to be entirely due to heritable abnormalities in precursor proteins and are inherited in an autosomal dominant fashion. In addition, the expression of acquired amyloidoses may also be affected by genetically determined factors. The name "hereditary" rather than "familial" is recommended by the International Society of Amyloidosis (ISA) for amyloid diseases associated with mutations in the amyloidogenic protein itself, thereby making it prone to amyloidogenesis. By contrast, in "familial" amyloidoses associated with autoinflammatory diseases, the genetic abnormality affects protein(s) involved in modulation of the inflammatory response, which, in turn, creates an environment that is permissive for AA development [8].

Genetic abnormalities that have been identified as contributors to amyloidogenesis include (table 2):

Sequence variants, which increase the amyloidogenicity of the protein precursor, in some instances by destabilizing a native fold in the molecule and in others by increasing the intrinsic aggregation rate.

Variants that alter ligand binding or facilitate proteolytic cleavage.

Sequence variants that cause premature or late stop of translation, facilitating the accumulation of amyloidogenic variants.

Genetically determined post-translational modifications.

Variants in genes for non-amyloidogenic proteins can play a role in amyloid development. Examples include variants causing systemic autoinflammatory diseases that may be complicated by acquired AA amyloidosis and presenilin variants in early-onset Alzheimer disease (AD).

Apolipoprotein (Apo) misfolding has a more general role in the pathogenesis of amyloid diseases, as indicated by the observations that both wild-type and variant proteins may form amyloid fibrils, that specific Apo are part of the protein milieu for a variety of types of amyloidosis (as revealed by mass spectroscopy; eg, ApoE, ApoJ, and ApoAIV), and in the growing number of forms of hereditary amyloid (ApoAI, ApoAII, ApoCII, and ApoCIII) that may be causes of early-onset familial disease [9].

AUTOSOMAL DOMINANT HEREDITARY AMYLOIDOSES

Genetic mechanisms — The various autosomal dominant hereditary amyloidoses are typically associated with missense variants, although variants resulting in deletions and stop codons have also been described. The pathogenic point variant usually affects the part of the precursor molecule that is most aggregation prone; the whole precursor protein can be incorporated into the amyloid fibrils, or domains may be eliminated either prior to or after fibril formation [10-12]. Examining the fibrillogenic potential of recombinant proteins or synthetic peptides has demonstrated that the variant is often intrinsically more unstable and fibrillogenic in vitro than the wild-type peptide [13-15]. A resource for the tabulation of variants associated with the systemic hereditary amyloidoses is Mutations in Hereditary Amyloidosis [16,17].

In three forms of hereditary amyloid disease (hereditary British dementia, hereditary Danish dementia, and apolipoprotein [Apo] AII nephropathy), variants at the site of stop codons lead to carboxyterminal extensions that are not expressed by the wild-type protein [18,19]. Fibril subunit proteins may include an aminoterminal portion of the precursor (eg, ApoAI), a carboxyterminal fragment (eg, fibrinogen A-alpha chain), or the entire molecule (eg, transthyretin [TTR]).

Detection of variants — Variant forms of amyloidogenic proteins have been defined serologically, by immunoblot/immunoelectrophoresis, in the past, but these are challenging techniques; mass spectroscopy offers another means of looking for abnormal precursors or metabolic products in blood [20-22]. Genetic testing for the single base substitution characteristic for the particular amyloid disease was usually carried out by directly sequencing the amplified exon of the relevant gene of interest or targeted panels [23].

Transthyretin

Range of genetic variants — Multiple variants have been identified among patients with TTR amyloidosis. The gene for transthyretin (TTR or prealbumin), a protein involved in the transport of thyroxine and retinol (hence, TTR), is located on chromosome 18. Until now, at least 138 TTR variants have been described, including single variants, compound heterozygotes, and deletions. Nomenclature for missense variants due to a single nucleotide change was updated in 2014 to include the 20 amino acid signal peptide [16,17]. One hundred and thirty-three of these variant TTR gene products are amyloidogenic; five are classified as "non-amyloidogenic" but include variants that may represent common polymorphisms [24] or that in trans may in fact be protective from developing amyloidosis [25].

Variants have been identified in approximately 60 percent of residues in this 127 amino acid single chain molecule. Thirty-eight residues have more than one substitution associated with disease; these tend to occur at variant hotspots in the DNA sequence and along portions of the molecule known to adopt a beta-pleated sheet configuration from radiograph crystallography of wild-type TTR [26].

One variant, substitution of methionine for threonine at position 119 (T119M), appears to have a stabilizing effect on the TTR tetramer and confers relative protection from development of TTR amyloidosis. Milder disease has been reported in compound heterozygotes for this variant and for another (R104H) known amyloidogenic variant [27,28]. In addition, this substitution appeared to be associated with increased plasma levels of TTR compared with destabilizing variants. In the Copenhagen General Population Study and Copenhagen City Heart Study involving 68,602 participants, 10,636 of whom developed vascular disease, the T119M variant was associated with a decreased incidence of cerebrovascular disease and increased life expectancy [28]. A more recent study involving approximately 500,000 participants enrolled in the United Kingdom Biobank, however, failed to confirm this association [29].

Major TTR amyloidosis phenotypes — Transthyretin (TTR) amyloidosis can present with peripheral and/or autonomic neuropathy, infiltrative cardiomyopathy, vitreous amyloid, or leptomeningeal disease in any combination [30,31]. Some phenotype-genotype correlation is seen, with subgroups of variants associated with a more neuropathic presentation and others with a later-onset cardiac presentation that more closely resembles wild-type TTR amyloidosis [31]. There may also be non-amyloid associations: A registry-based study in Swedish patients with familial amyloid polyneuropathy (FAP) suggested that patients have increased risk for the development of non-Hodgkin lymphoma [32], and some variants may affect the binding of thyroxine (T4) by TTR, resulting in euthyroid hyperthyroidism (eg, TTR Met 119) [33].

Peripheral and autonomic neuropathy and central nervous system disease – The most common phenotype among the amyloidogenic TTR variants is peripheral neuropathy, usually a length-dependent sensorimotor polyneuropathy, which may also present as small fiber neuropathy and/or prominently feature carpal tunnel syndrome (CTS) [34]. CTS is specifically identified in 25 variants and may predate cardiomyopathy by many years within kindreds with a mixed phenotype [35]. Autonomic neuropathy (orthostasis, gastrointestinal dysmotility) is clinically significant in 40 variants and is likely subclinical in others [36]. Leptomeningeal amyloidosis has been reported in 10 variants, and other central nervous system (CNS) manifestations (dementia, cerebellar dysfunction with ataxia, or cerebral hemorrhage) have been reported in some variants [37].

Cardiomyopathy – The other main phenotype of TTR amyloidosis is cardiomyopathy, which is present in 106 different variants, and may be the sole organ system involved in 24 [30]. ATTR variant (ATTRv, formerly termed ATTRm, to indicate a mutant protein) cardiomyopathy is notably late onset in several variants (V20I, E42G, Q92K, T60A), making it an important consideration in the diagnosis of cardiomyopathy in older adults [38]. ATTRv is also sometimes known as hereditary ATTR (hATTR). Presentations for ATTR cardiomyopathy include biventricular infiltrative cardiomyopathy, heart failure with preserved ejection fraction, conduction defects (notably atrial fibrillation), and as a concomitant of severe aortic stenosis [39]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

Vitreous amyloid – Vitreous amyloid, reflecting production of TTR by the retinal epithelium, has been described with 26 variants, may be the presenting and only disease manifestation in 5, and may develop after liver transplantation as a late manifestation of disease [40-42].

Kidney disease may complicate other organ system involvement or be due to deposition of TTR amyloid in the kidney. The latter has been reported for 15 different TTR variants but has been best studied among individuals affected by the V30M variant, in whom kidney involvement has been associated with late-onset neuropathy, families with low-penetrance disease, and patients manifesting cardiac arrhythmias [43].

Additionally, occasional patients with a clinical presentation suggesting immunoglobulin light chain (AL) amyloidosis have been identified in whom the amyloid deposits result from hereditary TTR amyloidosis. (See 'Variable penetrance and expressivity in hereditary amyloidosis' below.)

Populations with increased prevalence of certain variants — Certain populations have an increased prevalence of specific variants. Examples include:

Portugal, Sweden, Japan, and other regions – In endemic areas of Portugal, 1 of every 600 people carries the TTR variant TTR Val30Met that can result in FAP [44]. The same variant is seen in some other countries such as Sweden and Japan [45,46]. In northern Sweden, the carrier frequency is 8.3-fold higher than in Portugal, but with a lower incidence and prevalence of amyloidosis due to a much lower penetrance (5 versus 87 percent) before age 40 [47]. Although haplotype analysis of contiguous TTR gene regions in Swedish, French, Portuguese, and Japanese carriers indicates common founders, these phenotypic differences highlight the importance of additional genetic and epigenetic factors in disease expression [48,49]. National FAP registers from Japan, France, and Italy, as well as the TTR Amyloidosis Outcome Survey (THAOS), have provided additional evidence for genetic and phenotypic heterogeneity for both hereditary and wild-type amyloid [50,51].

African American, Afro-Caribbean, and West African populations – Isolated cardiac amyloidosis presenting virtually exclusively as late-onset (age >65) disease is more common in African Americans than White Americans and White Europeans, and 3 to 4 percent of African Americans and some Afro-Caribbean populations are carriers for a potentially amyloidogenic substitution TTR Val122Ile. In addition, the carrier rate is >5 percent in some areas of West Africa. Although the prevalence of the Val122Ile variant is relatively high in these populations, it appears to have low penetrance for causing amyloid cardiomyopathy [52-55]. The male:female ratios reported for both wild-type and TTR Val122Ile have ranged up to 25:1; the basis for this sex bias remains to be fully explained. Homozygosity is associated with an earlier age of onset and female sex with a later age of onset and a less aggressive disease trajectory [56,57]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Types of amyloidosis'.)

Gelsolin — The Meretoja syndrome, also referred to as hereditary amyloidosis, Finnish type, results from variants in the gelsolin gene, which is located on chromosome 9 at q33.2; the most prevalent of these variants are associated with a characteristic triad of:

Lattice corneal dystrophy

Neuropathy with progressive facial paresis and largely sensory peripheral symptoms

Cutis laxa

Variants at codon 654 (residue 187) are called Meretoja substitutions, named after the ophthalmologist who first delineated the disease, and occur within the amyloidogenic fragment of gelsolin [11,15,20,58]. Meretoja syndrome is also referred to as familial amyloidosis, Finnish type, because of the striking clustering of the disease in the southern part of this country, where multiple families have been shown to share an ancestral haplotype [59].

The D187N variant has been found in Finnish, Japanese, American, Dutch, Portuguese, British, and Iranian families, and the D187Y variant was found in Danish, Czech, and Brazilian families with this phenotype; both interfere with calcium binding and increase proteolysis by furin to yield amyloidogenic fragments [15,20,60]. Variants at Glu580Lys and Met544Arg have also been described to have the Meretoja phenotype [61,62]. A novel presentation of fever, rash, and anemia with amyloidosis has been associated with an exon 10 variant [63]. Renal amyloid deposition appears common, but renal dysfunction in hereditary gelsolin amyloidosis is rare and has mostly been described in homozygotes; however, two novel variants, G194R and N211K, were reported to be associated with renal amyloidosis in patients without corneal lattice dystrophy or neuropathies [64].

Apolipoprotein AI — Apo amyloidosis may be hereditary or acquired, the latter due to wild-type protein in the senile forms of pathology that may occur in the aorta in association with atherosclerosis or (like wild-type ATTR) in the osteoarthritic joint [65]. ApoAI amyloidosis is the second most common hereditary systemic amyloidosis, and 22 pathogenic variants in the gene, which is located on chromosome 11, have been described, most of which are single amino acid substitutions resulting from point variants; deletions and insertions may also be associated with amyloid deposition [16,23].

Clinical manifestations of ApoAI amyloidosis vary with the location of variant within the approximately 93 residue fragments that form the fibril protein [12]. Variants in the 75 aminoterminal residues manifest as an interstitial and medullary nephropathy (11 variants) and/or as hepatic involvement (5 variants), and may be early or late onset in nature [66]. A deletion at position 107 (Lys 107 del [pLys 131 del]) is strikingly associated with angina and accelerated atherosclerosis. Glu34Lys was found to present with retinal, glomerular, and hepatic involvement, making it amenable to hepatorenal transplantation [65]. Cutaneous amyloid deposits (two variants), cardiomyopathy (seven variants), neuropathy/CTS (four variants), or laryngeal/palatal dysfunction (six variants) are more characteristic of variants beyond residue 90 and may present as localized amyloid involving the larynx or skin [23,67]. Hot spots for amyloidogenesis include residues 14 to 22 and the 121 to 142 segment that is particularly susceptible to proteolysis [65].

Apolipoprotein AII — Variants in the gene for ApoAII, which is located on chromosome 1, may cause amyloidosis [18,23,68,69]. Four stop-codon variants have been described at residue 78 in exon 4, leading to a 21 residue extension at the C-terminus of the molecule, with full-length mutant ApoAII depositing as amyloid. The clinical phenotype is a slowly progressive renal (glomerular and interstitial amyloid) disease, with other organ system involvement being less prominent.

Apolipoproteins CII and CIII — Rare cases of amyloidosis affecting the kidney have been described due to variants in the genes for apolipoproteins CII and CIII [70,71]. The gene for ApoCII is located on chromosome 19, and the protein is known from previous studies to be able to generate amyloidogenic peptides. In 2017, there was the first report of nodular glomerular and interstitial amyloid associated with a missense variant Glu69Val [70], with the average age of onset of 70; another variant associated with renal amyloidosis has subsequently been reported from the United States (Lys41Thr) [70,72].

The gene for ApoCIII is on chromosome 11q23-24 as part of a gene cluster with ApoAI and ApoAIV. The Asp25Val variant has been found to be markedly fibrillogenic and associated with severe renal amyloidosis and hypotriglyceridemia in a French family [71].

Lysozyme — Nine variants in the lysozyme gene, which is located on chromosome 12, have been associated with several amyloid phenotypes, including sicca syndrome (three out of nine), renal (six out of nine), hepatic/gastrointestinal (six out of nine), and cardiac (three out of nine) amyloid disease of variable onset [13,73,74]. A novel variant in an American family of Swedish ancestry described chronic abdominal pain, diarrhea, weight loss, malabsorption, and sicca syndrome as common manifestations without apparent renal disease [75], and a complex T88N/W130R variant was associated with significant cardiac involvement [76].

Fibrinogen A-alpha — Variants in the fibrinogen alpha chain gene, which is located on chromosome 4, have been associated with a late-onset renal amyloidosis that is strikingly glomerular, without interstitial or vascular involvement; 15 variants have been described, all clustered near the 5' end of exon 5 and resulting in this clinical phenotype. It is the most common cause of hereditary amyloidosis in the United Kingdom (>70 patients reported) [77]. By contrast, a lower incidence has been reported in the United States [78]. Overall, only 46 percent of patients with fibrinogen alpha amyloidosis (AFib) have a family history, the majority of cases being sporadic. The rate of progression of AFib amyloid is slow compared with AL amyloid but greater than that seen in ApoAI or lysozyme-type amyloid. Additionally, occasional patients with a clinical presentation suggesting AL amyloidosis have been identified in whom the amyloid deposits result from hereditary AFib amyloidosis. (See 'Variable penetrance and expressivity in hereditary amyloidosis' below.)

The progression to end-stage kidney disease from presentation of renal disease is 4.6 years. Similarly, the time to recurrence in a renal allograft is 4.9 to 6.0 years, and the median transplant survival is 7.3 years. Since virtually all fibrinogen is synthesized in the liver, double allograft (liver-kidney) has also been attempted, albeit with significant perioperative morbidity and mortality [78-80]. (See "Renal amyloidosis".)

Cystatin C — One variant has been described in the cystatin gene, which is located on chromosome 20. This variant is associated with massive amyloid angiopathy, cerebral hemorrhage (Icelandic type), and a fatal outcome in the third to fourth decades of life in approximately 50 percent of affected persons [14,81].

Beta-2 microglobulin — Variant forms of the gene beta-2m for beta-2 microglobulin (beta-2m), which is located on chromosome 15, have been identified as a rare cause of hereditary amyloidosis [82,83]. However, most patients with beta-2m amyloidosis have the wild-type form of beta-2m as the major subunit of the amyloid complicating chronic hemo- or peritoneal dialysis. In the latter situation, defective renal clearance in such patients causes persistent high circulating levels. (See "Dialysis-related amyloidosis".)

The hereditary beta-2m amyloidoses include a novel dominantly inherited Asp76Asn variant of beta-2m, described in association with systemic amyloidosis in a French family, in whom it was manifested as gastrointestinal disease, autonomic neuropathy, and sicca syndrome [82]. In these patients, beta-2m levels in blood were normal, and the variant molecule was found to have striking intrinsic amyloidogenicity in vitro. Another amyloidogenic beta2m variant (V27M) was identified in the amyloid of a patient on hemodialysis [83].

Hereditary AL amyloidosis — A hereditary form of immunoglobulin light chain (AL) amyloidosis has been very rarely described, unlike the far more common AL amyloidosis often associated with plasma cell dyscrasias. An extended family, multiple members of which had progressive renal amyloidosis, has been described in which each affected member was found to have a single point variant in the constant region of the immunoglobulin kappa light chain [84]. These patients had no evidence of plasma cell dyscrasia, and indeed V-kappa peptides identified in the amyloid came from three different subgroups. This is in contradistinction to very rare instances of more than one member of a family being affected by myeloma and/or AL amyloid, where the amyloid subunit protein is clonal and has only a single V-region sequence.

VARIABLE PENETRANCE AND EXPRESSIVITY IN HEREDITARY AMYLOIDOSIS — Clinical features, age at onset, and progression of disease may be uniform among members of the same kindred carrying specific amyloidogenic variants. However, a consistent course is not universal. Rarely, individuals with an amyloidogenic variant (homozygous or heterozygous) may remain relatively asymptomatic or may have late onset or more severe disease [85-90]. Variations in clinical manifestations of disease between different kindreds carrying the same variants suggest an important role for modifier genes and/or possibly environmental factors in disease expression.

As examples:

Uniform expression – As an example of highly consistent clinical phenotypic expression in family members, in a large kindred of persons with Finnish type of hereditary amyloidosis (caused by a variant in the gelsolin gene), early signs of corneal lattice dystrophy were apparent by the third or fourth decade of life. The characteristic facies, due to cranial neuropathy and cutis laxa, most apparent around the eyes, developed progressively in the fifth and sixth decades [91]. (See 'Gelsolin' above.)

Variable expression – The transthyretin (TTR) Met (30) substitution, which accounts for approximately 60 percent of cases of hereditary amyloid polyneuropathy worldwide due to TTR, may have an onset at different ages or with varying clinical presentations when sampled among large groups of affected patients in Portugal, Sweden, or Japan. Haplotype analysis indicates multiple founders responsible for disease in different endemic geographic areas [47,92].

In addition, anticipation of age at onset, with age at onset becoming younger in patients of successive generations, has been described in pedigrees with TTR Met (30) from two high-prevalence areas in Japan [93]. In a study of 77 Swedish families, potentially higher penetrance has been described when inherited down the maternal rather than the paternal line [47].

Occasional kindreds have been described in which the onset of neuropathy or cardiomyopathy associated with TTR variants occurs late in life [47,86,89,94].

Of more interest has been TTR I122, associated with late-onset amyloid cardiomyopathy, which is a common polymorphism virtually, but not entirely, unique to groups with African ancestry [95]. It has been estimated that 3.9 percent of African Americans (ie, 1.3 million people) are carriers for this variant TTR molecule and are, therefore, at risk for the development of cardiac amyloid [94,95]. (See 'Populations with increased prevalence of certain variants' above and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

Confusion with AL amyloidosis – Phenotypically, there is a considerable overlap between immunoglobulin light chain (AL) and ATTR variant (ATTRv) amyloidosis, with both being associated with cardiomyopathy and peripheral neuropathy. Moreover, a substantial proportion of patients with ATTR also have monoclonal gammopathy of undetermined significance (MGUS). In one study, 49 percent of patients with cardiac ATTRv amyloidosis were shown to have a concurrent MGUS [96]. Therefore, sporadic cases of hereditary amyloidoses may be confused with AL amyloidosis, a complication of a plasma cell dyscrasia. This was illustrated in a study of 350 patients suspected of having AL amyloidosis by clinical and laboratory findings and the absence of a family history; 34 (9.7 percent) had a mutant gene for an "amyloidogenic" protein, most often involving fibrinogen A-alpha or TTR [77]. The presence of low concentrations of monoclonal immunoglobulins (less than 0.2 g/dL) in 8 of these 34 patients contributed to the misdiagnosis. Recognition of these heritable conditions is important, since treatment for AL amyloidosis (eg, chemotherapy) has no role in the treatment of the hereditary disorders [97]. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

ROLE OF GENETIC DETERMINANTS OF AA AMYLOIDOSIS — Multiple genetic factors may influence the expression of AA amyloid. As examples, in early studies, the frequency of amyloid complicating disorders such as leprosy was noted to sometimes vary strikingly between leprosaria [98]; the frequency of AA amyloid complicating juvenile and adult rheumatoid arthritis (RA) and tuberculosis varied between populations [99,100]; and surveys have indicated a higher incidence of AA amyloidosis among patients with RA in Japan and Finland than in the United States [101]. Genetic factors may have relevance to reports of a declining incidence of AA amyloidosis complicating RA in some populations (eg, Finland) and not others (eg, Japan), as well as varying incidences of subclinical versus clinical disease, and time to develop overt amyloid [102].

AA amyloidosis complicating chronic inflammatory diseases is a useful model to explore additional genetic contributors in amyloidosis as it remains more prevalent than the individual types of hereditary amyloidosis, and the fibril precursor protein, serum amyloid A protein (SAA), shows much less variability than the clonal light chains that form AL amyloidosis.

The genetics of both the underlying inflammatory disorders and the acute phase amyloidogenic protein, SAA, are relevant:

Role of genes influencing inflammatory disease rates – The population prevalence of AA amyloidosis is significantly increased in specific ethnic groups with higher variant carrier rates in genes predisposing to autoinflammatory diseases [103]. For example, carrier rates for MEFV variants have been reported in up to 1 in 5 among Armenian individuals, 1 in 6 among the North African Jewish population, 1 in 8 among Iraqi individuals, and 1 in 12 among the Ashkenazi Jewish population [104]. Increased prevalence of certain MEFV variants in certain populations has been related to heightened resistance to Yersinia pestis [105]. These diseases may rarely present as what has been termed "phenotype 2," in which (usually) renal amyloid is found without any indication of symptoms of periodic fever [106,107]. (See 'AA amyloid and the inherited systemic autoinflammatory diseases' below.)

In a large database of patients with AA amyloidosis evaluated in the United Kingdom Amyloidosis Referral Center in 2007, approximately 9 percent were associated with known autoinflammatory disease, and approximately 6 percent were found to have "idiopathic" AA, occurring in the absence of any apparent underlying inflammatory disease [108]. These observations may also have relevance to the greatly increased incidence of AA as a cause of renal amyloid in Turkey and Armenia, where carrier rates for pathogenic variants in MEFV are high, and autoinflammatory diseases such as familial Mediterranean fever (FMF) and Behçet syndrome are quite prevalent [109]. In this study, surprisingly, country of living was the most important factor in developing AA amyloidosis (rather than FMF genotype), and this may suggest a major role for unknown environmental factors.

Role of SAA gene polymorphisms – The presence of certain alleles of SAA can influence disease expression. AA forms by proteolysis from one of two human acute-phase SAA proteins (SAA1 and SAA2), encoded by members of a gene family on chromosome 11. The SAA1 gene has five alleles (1.1 to 1.5), and the SAA2 gene has two (2.1 to 2.2), based on amino acid substitutions at positions 52, 57, and 60 of the molecule for SAA1 and at position 71 for SAA2. (See "Pathogenesis of AA amyloidosis".)

Among European individuals, the incidence of AA amyloid appears to be increased in persons homozygous for the 1.1 allele [110]. By contrast, the 1.1 allele appears to have an inhibitory effect on the development of AA amyloidosis in Japan and East Asia, where homozygosity of the 1.3 allele correlates positively with renal AA, and an additional single nucleotide polymorphism (SNP) at the 5' flanking region of SAA1 also confers increased risk [111]. SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5' flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of the SAA1 gene, were associated with susceptibility to FMF in the Japanese population [112]. Studies from Turkey have shown that the 1.1 allele is a significant risk factor for AA amyloid complicating Behçet syndrome, and an association between the SAA 1-13T/C polymorphism and amyloidosis in FMF patients has been found [113,114]. Conversely, the SAA 1 beta/beta polymorphism was associated with relative protection against AA amyloidosis in Armenian FMF patients homozygous for MEFV M694V [115]. Additional studies are necessary to reconcile these observations and to establish the significance of SAA polymorphisms as predictive risk factors for the development of AA amyloidosis in FMF.

Non-genetic determinants of AA amyloidosis – Non-genetic factors, particularly early diagnosis and treatment in the case of the autoinflammatory disorders, affects the risk of development of AA amyloidosis. Historically, AA amyloid was reported to complicate these diseases with frequencies varying from greater than 60 percent in untreated FMF in certain ethnic populations (eg, Turkish people) to 25 percent in the tumor necrosis factor receptor-1 (TNFR1) associated periodic syndrome (TRAPS) and the cryopyrin-associated periodic syndrome (CAPS), and to less than 5 percent in mevalonate kinase deficiency (MKD) [116]. These rates have decreased dramatically with the advent of earlier diagnosis and the availability of highly effective targeted therapies for these disorders. (See 'AA amyloid and the inherited systemic autoinflammatory diseases' below and "The autoinflammatory diseases: An overview".)

Obesity was added as a significant susceptibility factor for idiopathic AA amyloidosis as the list of conditions associated with AA amyloidosis continues to expand [117]. However, no association with an identifiable underlying disease can be seen in up to 19 percent of patients diagnosed with AA amyloidosis [8].

AA AMYLOID AND THE INHERITED SYSTEMIC AUTOINFLAMMATORY DISEASES

Familial Mediterranean fever — AA amyloidosis occurs in patients with familial Mediterranean fever (FMF), where its occurrence is influenced by genetic factors that influence the development of FMF itself and of amyloidosis in the patients with FMF, but most importantly, by the timing and effectiveness of treatment for the autoinflammatory disorder. FMF is characterized by recurrent episodes of painful serositis associated with fever and sometimes arthritis, typically lasting two to four days. The responsible molecule is pyrin, a neutrophil, mononuclear, and dendritic cell-specific protein that has an important role in regulation of apoptosis and inflammation [118-120]. Pyrin is encoded by a single gene (MEFV) on chromosome 16p. Amyloid in these patients typically presents as nephropathy, which may follow a period of active disease (phenotype 1) or which may be the apparent presenting manifestation (phenotype 2) [107,121,122]. FMF and the genetics of FMF itself are discussed in more detail separately. (See 'Role of genetic determinants of AA amyloidosis' above and "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Long-term complications' and "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis".)

The prevalence of specific MEFV variants (particularly homozygous M694V) correlates positively with the incidence and severity of disease and AA amyloid in some populations [109,123-126]. It is important to note that severe disease and AA amyloidosis can occur in a variety of genotypes, and variability in expression of the same variant between populations, and even within families, suggests a significant effect for environment and other genes [127]. Several modifying genetic factors influence disease expression, including male sex, SAA1 polymorphisms, and major histocompatibility complex class 1-related gene A [128,129]. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis".)

The most frequent variant associated with amyloidosis in some (but not all) studies is homozygous M694V, followed by M690I/M694V compound and M694V heterozygous genotypes [130,131]. R202Q and M680I may also be associated. MEFV M694V homozygosity is also associated with more severe disease and poor responsiveness to colchicine.

Variants at positions M680 and M694 are associated with earlier onset of FMF, with more severe disease, and with an increased incidence of AA amyloidosis in all ethnic groups; homozygosity for the M694V variant is significantly associated with phenotype 2 presentation of AA amyloidosis. Phenotype 2 presents as AA amyloidosis in an otherwise asymptomatic individual with MEFV genetics consistent with FMF and/or a family history of FMF. AA amyloidosis has also been described in a typical dominant disease in association with an M694del variant in White Northern European patients, and 3 T577 variants in British, Turkish, and Dutch patients [132].

Tumor necrosis factor receptor-1 associated periodic syndrome — The tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS) is a dominantly inherited disease characterized by recurrent febrile episodes lasting one to four weeks, serositis, myalgia, rash, and periorbital edema; muscle and fascia may be inflamed. It can be complicated by AA amyloidosis. The relevant gene (TNFR1) has been mapped to chromosome 12. TRAPS and its genetics and pathogenesis are discussed in detail separately. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

AA amyloid may complicate TRAPS with an estimated prevalence of 14 to 25 percent, with considerable variability between families [133]. Variants affecting cysteine residues are accompanied by a higher risk for amyloid than non-cysteine variants [134,135]. Two familial cases of severe amyloidosis were associated with a non-cysteine variant T50M. Homozygous SAA1.1 is also significantly associated with AA amyloidosis in TRAPS patients. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)", section on 'Secondary (AA) amyloidosis'.)

Cryopyrin-associated periodic syndromes — AA amyloidosis can occur as a complication of cryopyrin-associated periodic syndromes (CAPS), which are characterized by periodic fever, urticaria, arthralgia, and deafness with variable degrees of chronic meningitis and joint involvement. Mild to mid-spectrum CAPS is transmitted as an autosomal dominant trait. The disease is due to variants in the cryopyrin gene (NLRP3) on chromosome 1q44 [136]. Variants in this gene are also associated with the severe CAPS phenotypes of neonatal multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and articular (CINCA) syndromes that are generally sporadic diseases due to de novo variant. Broad spectrum of disease and variable age of onset relate in part to a significant incidence of somatic mosaicism. CAPS and its genetics and pathogenesis are described in detail separately. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Cryopyrin-associated periodic syndromes'.)

The incidence of AA amyloid has been reported to be approximately 25 percent in Muckle-Wells syndrome (MWS), approximately 20 percent in CINCA/NOMID, and approximately 2 percent in familial cold autoinflammatory syndrome (FCAS). Heterozygosity for both V198M and R260W was found in one MWS family. An N475K knock-in mouse recapitulated CAPS and developed amyloid. Cryopyrinopathies are responsive to treatment with interleukin 1 receptor antagonist (IL-1ra) and other IL-1-beta antagonists [137]. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Cryopyrin-associated periodic syndromes' and "Cryopyrin-associated periodic syndromes and related disorders", section on 'Treatment of cryopyrinopathies'.)

Mevalonate kinase deficiency — Mevalonate kinase deficiency (MKD), which is also known as hyper-immunoglobulin D (IgD) syndrome (HIDS) in its less severe form, is an autosomal recessive hereditary disease associated with variants in the mevalonate kinase (MVK) gene on chromosome 12 and may be rarely (2 to 4 percent) associated with AA amyloidosis [138]. MKD is considered a pyrin inflammasomopathy because of the effect of variants on the pyrin regulatory factor RhoA [115]. The genetics and pathophysiology of HIDS and related conditions and its clinical manifestations are discussed in detail separately. (See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

In a review of 114 cases of MKD, AA amyloidosis was found in 5 patients, significantly associated with V377I/I268T compound heterozygosity [139]. In a review of 20 cases of AA complicating MKD, 18 were compound heterozygotes [140]. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'Hyperimmunoglobulin D syndrome'.)

Coexpression of allelic variants of different autoinflammatory diseases and AA amyloidosis — Allelic variants of two different autoinflammatory diseases may co-associate in some patients presenting with an autoinflammatory disease phenotype, and low penetrance allelic variants have been identified with apparent increased frequency among patients with AA amyloidosis with the advent of whole genome sequencing [141-143].

OCULAR AMYLOIDS — Amyloidosis of the eye may be an organ-specific manifestation of a systemic disease or may be localized to this organ; examples of the former include lattice dystrophy type II in familial amyloidosis, Finnish type, due to mutant gelsolin [15,20,91], and amyloidosis, which may be a prominent feature among some kindred associated with mutant transthyretin (TTR) molecules and retinal amyloid with apolipoprotein (Apo) AI variants [17,42,65].

Various phenotypes of corneal amyloidosis occur [144-147]. These phenotypes have been related to variants of gelsolin in lattice corneal dystrophy, type 3, as seen in familial amyloidosis, Finnish type (see 'Gelsolin' above); and to 28 variants of the tumor-associated calcium signal transducer 2 (TACSTD2) gene on chromosome 1 in gelatinous drop dystrophy. Additionally, they can present as a result of >50 variants of a gene product variously called keratoepithelin, transforming growth factor beta-induced protein (TGFB1), or BIGH3 on chromosome 5 in lattice corneal dystrophy type 1, granular corneal dystrophies (GCD) type 1 (characterized by amorphous aggregates), GCD type 2 (characterized by a combination of amyloid and amorphous aggregates), and Thiel-Behnke corneal dystrophy (TBCD; in which curly fibers form in the superficial corneal stroma).

LOCALIZED AMYLOIDS ASSOCIATED WITH GENETIC DISORDERS — There are a number of genetic diseases that manifest organ-specific or localized amyloids. These include Alzheimer disease (AD) (see "Genetics of Alzheimer disease"), hereditary cerebral hemorrhage with amyloidosis (HCHWA) syndromes (cystatin C, Bri2), and the lattice corneal dystrophies (see 'Autosomal dominant hereditary amyloidoses' above and 'Ocular amyloids' above). Additional examples include amyloid due to calcitonin associated with medullary carcinoma of the thyroid [148] and cutaneous lichen amyloidosis, associated with familial medullary carcinoma of the thyroid and multiple endocrine neoplasia syndrome 2A (MEN2A) [149-151]. Hypertrichosis of the scalp with amyloid deposition has been associated with nonsense variants of the CDSN gene encoding corneodesmosin on chromosome 6; these variants occur in the middle of the coding region, resulting in a truncated protein that is aggregation-prone [152,153].

Dysferlin-deficient muscular dystrophy and anoctamin 5 muscular dystrophy may both be associated with skeletal muscle amyloid deposits, as well as cardiomyopathy with delayed enhancement on cardiac magnetic resonance imaging (MRI) [154]; these conditions are discussed separately. (See "Musculoskeletal manifestations of amyloidosis", section on 'Dysferlin-deficient muscular dystrophy' and "Musculoskeletal manifestations of amyloidosis", section on 'Anoctamin 5 muscular dystrophy'.)

ALZHEIMER DISEASE AND ALZHEIMER AMYLOID PRECURSOR PROTEIN — More than 50 variants have been identified within the Alzheimer amyloid precursor protein gene (APP) from over 100 families with early-onset Alzheimer disease (AD) [155-158]. APP is located on chromosome 21 (21q21.3). The genetics of AD, including the role of the APP gene, presenilins, and apolipoprotein (Apo) E, are reviewed in detail separately. (See "Genetics of Alzheimer disease".)

Variants that have been associated with early-onset or familial cases of AD can occur in the gene for amyloid precursor protein (APP) that cluster within the amyloidogenic Alzheimer beta protein (A-beta) sequence [155,159]. In these cases, it is assumed that diversion of APP processing to an amyloid-producing pathway is the primary mechanism leading to accumulation of fibrillogenic A-beta peptides at the sites of pathology. Striking cerebrovascular amyloidosis has been associated with point mutations in the coding sequence of the A-beta protein sequence, as well as familial British dementia and familial Danish dementia (ABri2-related dementias), hereditary cerebral hemorrhage with amyloidosis of Icelandic type due to a mutation of the cystatin C gene (ACys), transthyretin amyloid (ATTR), and prion protein amyloidosis (APrP) [160].

SUMMARY

Amyloid formation – Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils that are insoluble polymers comprised of low molecular weight subunit proteins. These subunits are derived from soluble precursors, which undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration. Some amyloid disorders appear to be entirely due to heritable abnormalities in precursor proteins that render them intrinsically unstable, and the expression of acquired amyloidosis may be affected by genetically determined factors (table 1). (See 'Introduction' above.)

Types of genetic abnormalities in amyloidogenic proteins – Three types of genetic abnormalities have been identified in amyloidogenic proteins: polymorphisms, which are relatively frequent in specific populations; rare gene variants (eg, missense variants, deletions, and premature stop codons); and genetically determined post-translational modifications. In addition, variants in genes for non-amyloidogenic proteins can play a permissive role in amyloid development. (See 'Genetic mechanisms' above.)

Autosomal dominant hereditary amyloidoses – Among the familial diseases associated with missense variants, the point variant that correlates with clinical disease usually occurs in the part of the precursor molecule that actually forms the fibril subunit protein; other precursor domains may be eliminated by metabolism or may be digested away prior to or after fibril formation. Subunit protein variants associated with genetic amyloidoses may occur in genes for transthyretin (TTR), gelsolin, apolipoprotein (Apo) AI, ApoAII, fibrinogen A-alpha chain, lysozyme, beta-2 microglobulin (beta-2m), and cystatin C. (See 'Autosomal dominant hereditary amyloidoses' above.)

Variable disease expression – Clinical features, age at onset, and progression of disease may be uniform among members of a kindred carrying specific amyloidogenic variants. However, a uniform course is not universal. Rarely, individuals with an amyloidogenic variant (homozygous or heterozygous) may remain relatively asymptomatic, may have late-onset disease, or may have more severe disease. Variations in clinical manifestations between different kindreds carrying the same variants suggest an important role for modifier genes and/or possibly environmental factors in disease expression. (See 'Variable penetrance and expressivity in hereditary amyloidosis' above.)

AA amyloidosis

Complicating chronic infectious and systemic rheumatic disorders and related conditions – The frequency of AA amyloid complicating disorders such as leprosy, juvenile and adult rheumatoid arthritis (RA), and tuberculosis varies considerably between populations. Additional studies are necessary to reconcile these observations and to establish the significance of serum amyloid A (SAA) polymorphisms as predictive risk factors for the development of AA amyloid. (See 'Role of genetic determinants of AA amyloidosis' above.)

Complicating hereditary autoinflammatory diseases – AA amyloid complicates hereditary autoinflammatory diseases with varying frequencies: familial Mediterranean fever (FMF), tumor necrosis factor receptor-1 (TNFR1) associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and, rarely, mevalonate kinase deficiency (MKD). (See 'AA amyloid and the inherited systemic autoinflammatory diseases' above.)

Organ-specific and localized disease – Genetic forms of amyloidosis affecting the eye or skin may be an organ-specific manifestation of a systemic disease or may be localized to these organs. (See 'Ocular amyloids' above.)

Alzheimer disease – Numerous variants have been found to affect the Alzheimer amyloid precursor protein gene (APP) and the presenilin genes, which play a role in Alzheimer disease (AD). The genetics of AD are reviewed in detail separately. (See "Genetics of Alzheimer disease".)

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Topic 5590 Version 29.0

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