HAEM5:Immunoglobulin-related (AL) amyloidosis: Difference between revisions

*The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion<ref name=":6" />

*Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients<ref name=":8" />

</blockquote>

==Sites of Involvement==

Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0" /><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>.

</blockquote>

* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine<ref name=":2" />. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years<ref name=":3" /><ref name=":4" /><ref name=":17" />. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease<ref name=":15" /><ref>{{Cite journal|last=Warsame|first=R|last2=Kumar|first2=S K|last3=Gertz|first3=M A|last4=Lacy|first4=M Q|last5=Buadi|first5=F K|last6=Hayman|first6=S R|last7=Leung|first7=N|last8=Dingli|first8=D|last9=Lust|first9=J A|date=2015|title=Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death|url=http://www.nature.com/articles/bcj201534|journal=Blood Cancer Journal|language=en|volume=5|issue=5|pages=e310–e310|doi=10.1038/bcj.2015.34|issn=2044-5385|pmc=PMC4423220|pmid=25933374}}</ref><ref>{{Cite journal|last=Tahir|first=Usman A.|last2=Doros|first2=Gheorghe|last3=Kim|first3=John S.|last4=Connors|first4=Lawreen H.|last5=Seldin|first5=David C.|last6=Sam|first6=Flora|date=2019|title=Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure|url=http://www.nature.com/articles/s41598-019-44912-x|journal=Scientific Reports|language=en|volume=9|issue=1|doi=10.1038/s41598-019-44912-x|issn=2045-2322|pmc=PMC6561903|pmid=31189919}}</ref>.

To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits<ref name=":16" /><ref>{{Cite journal|last=Jd|first=Gillmore|last2=Pn|first2=Hawkins|last3=Mb|first3=Pepys|date=1997|title=Amyloidosis: a review of recent diagnostic and therapeutic developments|url=https://pubmed.ncbi.nlm.nih.gov/9375734/|language=en|pmid=9375734}}</ref>. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia<ref name=":2" />. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies<ref name=":2" /><ref>National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). <nowiki>https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf</nowiki> Accessed July 20th, 2020.</ref>. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens<ref name=":14" /><ref name=":4" /><ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Kunz|first3=Christina|last4=Granzow|first4=Martin|last5=Benner|first5=Axel|last6=Seckinger|first6=Anja|last7=Kimmich|first7=Christoph|last8=Goldschmidt|first8=Hartmut|last9=Ho|first9=Anthony D.|date=2015|title=Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens|url=http://ascopubs.org/doi/10.1200/JCO.2014.57.4947|journal=Journal of Clinical Oncology|language=en|volume=33|issue=12|pages=1371–1378|doi=10.1200/JCO.2014.57.4947|issn=0732-183X}}</ref>.

</blockquote>

==Individual Region Genomic Gain / Loss / LOH==

|}

Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref name=":18">{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>.

</blockquote>

==Characteristic Chromosomal Patterns==

|}

Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>.

</blockquote>

==Gene Mutations (SNV / INDEL)==

Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients<ref name=":12" /><ref>{{Cite journal|last=López-Corral|first=L|last2=Sarasquete|first2=M E|last3=Beà|first3=S|last4=García-Sanz|first4=R|last5=Mateos|first5=M V|last6=Corchete|first6=L A|last7=Sayagués|first7=J M|last8=García|first8=E M|last9=Bladé|first9=J|date=2012|title=SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status|url=http://www.nature.com/articles/leu2012128|journal=Leukemia|language=en|volume=26|issue=12|pages=2521–2529|doi=10.1038/leu.2012.128|issn=0887-6924}}</ref><ref name=":13" /><ref>{{Cite journal|last=Weinhold|first=N|last2=Försti|first2=A|last3=da Silva Filho|first3=M I|last4=Nickel|first4=J|last5=Campo|first5=C|last6=Hoffmann|first6=P|last7=Nöthen|first7=M M|last8=Hose|first8=D|last9=Goldschmidt|first9=H|date=2014|title=Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma|url=http://www.nature.com/articles/leu2014208|journal=Leukemia|language=en|volume=28|issue=11|pages=2254–2256|doi=10.1038/leu.2014.208|issn=0887-6924}}</ref>. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (''CDH1'') and RCAN family member 3 (''RCAN''), and the pro-apoptotic genes GLI pathogenesis related 1 (''GLIPR1'') and Fas cell surface death receptor (''FAS'') were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (''IFITM1'') gene known to be associated with the development of aggressive solid tumors was observed<ref name=":13" /><ref>{{Cite journal|last=Yu|first=Fang|last2=Xie|first2=Dan|last3=Ng|first3=Samuel S.|last4=Lum|first4=Ching Tung|last5=Cai|first5=Mu-Yan|last6=Cheung|first6=William K.|last7=Kung|first7=Hsiang-Fu|last8=Lin|first8=Guimiao|last9=Wang|first9=Xiaomei|date=2015|title=IFITM1 promotes the metastasis of human colorectal cancer via CAV-1|url=https://linkinghub.elsevier.com/retrieve/pii/S0304383515005005|journal=Cancer Letters|language=en|volume=368|issue=1|pages=135–143|doi=10.1016/j.canlet.2015.07.034}}</ref>

Genetic analysis may be used to distinguish AL amyloidosis from hereditary amyloidosis. Testing for mutations in the transthyretin, fibrinogen Aα‐chain, lysozyme or apolipoprotein A-I genes are associated with hereditary disease. Genetic testing is often necessary as clinical features between diseases may be indistinguishable and family history evaluations may not be reflective given reduced penetrance<ref>{{Cite journal|last=Lachmann|first=Helen J.|last2=Booth|first2=David R.|last3=Booth|first3=Susanne E.|last4=Bybee|first4=Alison|last5=Gilbertson|first5=Janet A.|last6=Gillmore|first6=Julian D.|last7=Pepys|first7=Mark B.|last8=Hawkins|first8=Philip N.|date=2002|title=Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis|url=http://www.nejm.org/doi/abs/10.1056/NEJMoa013354|journal=New England Journal of Medicine|language=en|volume=346|issue=23|pages=1786–1791|doi=10.1056/NEJMoa013354|issn=0028-4793}}</ref><ref>{{Cite journal|last=Li|first=Danyang|last2=Liu|first2=Dan|last3=Xu|first3=Hui|last4=Yu|first4=Xiao-juan|last5=Zhou|first5=Fu-de|last6=Zhao|first6=Ming-hui|last7=Wang|first7=Su-xia|date=2019|title=Typing of hereditary renal amyloidosis presenting with isolated glomerular amyloid deposition|url=https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1667-5|journal=BMC Nephrology|language=en|volume=20|issue=1|doi=10.1186/s12882-019-1667-5|issn=1471-2369|pmc=PMC6929319|pmid=31870425}}</ref>.  

</blockquote>

==Epigenomic Alterations==