Panel testing recommended at Breda Genetics for this condition:
Summary
Amyloidoses are a group of rare disorders caused by extracellular deposition of insoluble fibers made of misfolded proteins, which take the name of “amyloid”. These deposits damage tissues and interfere with their normal function. Nowadays, more than 30 forms of amyloidosis are known, each caused by a different protein. Amyloidosis can be divided into “localized” when it affects a single organ, and “systemic” when more organs and tissues are affected. The vast majority of amyloidoses is systemic and mainly involves the heart, liver, spleen, central nervous system and kidneys. Amyloidoses are chronic and progressive disorders, whose clinical manifestation and severity depend on which organs are affected and to what extent. Some forms of amyloidosis are genetic and can be transmitted to progeny; in other cases can be secondary to other disorders such as infections, autoinflammatory syndromes and tumors. Diagnosis is confirmed through biopsy and microscopy of an affected organ. For some kind of amyloidosis specific treatments, depending on the origin of the disorder, exist.
Detailed clinical description
Among the most common forms of amyloidosis we find:
- Light chain amyloidosis (AL, also known as primary amyloidosis): this is the most common form of amyloidosis, it’s not of genetic origin, but derives from an abnormality of the plasma cell, cells of the bone marrow whose task is to produce antibodies. Indeed, the AL amyloidosis is due to excessive and uncontrolled production of the light chains of immunoglobulins, which tend to aggregate and drop off. Often, this form of amyloidosis is observed in patients affected by multiple myeloma. The main organs affected by this disorder are the kidneys (renal failure), the heart (cardiomyopathy), in some cases the central nervous system (as polyneuropathy), the liver and spleen.
- Secondary amyloidosis (AA, also known as reactive amyloidosis): like the previous one, this kind of amyloidosis has not a genetic origin and develops as a secondary effect of a chronic inflammation disease (such as rheumatoid arthritis, Chron disease or Familial Mediterranean Fever), of a tumor or of an infection. In this case, the protein that forms amyloid fibers is called serum amyloid A (SAA) that is produced by the liver in response to pro-inflammatory cytokines. The two main clinical manifestations of this kind of amyloidosis are proteinuria and/or hepatosplenomegaly. Other affected organs are lymph nodes and adrenal glands.
- Senile systemic amyloidosis: it is a form of amyloidosis associated with aging, due to the deposition of the wild-type protein transthyretin, mainly in the heart. The etiology is not well known but it is usually observed in men with more than 70 years.
- Hereditary (or familial) amyloidosis: this form of amyloidosis is due to genetic mutations in genes that code for certain protein which, when mutated, acquire the ability to aggregate and form amyloid fibers. Being of genetic origin, it can be transmitted to the offspring. Usually, it affects primarily the kidneys, heart and the central nervous system in the form of polyneuropathy. One of the most common hereditary amyloidosis in Italy is transthyretin-related amyloidosis, caused by mutations in the TTR gene. This form is clinically characterized by progressive sensory or motor peripheral neuropathy, cardiomyopathy, nephropathy, carpal tunnel syndrome and vitreous deposits.
Prevalence
Amyloidosis is a rare disease, but nowadays accurate data on the prevalence of systemic amyloidosis are not available. For instance, according to some estimation, the prevalence of systemic amyloidosis in the UK is about 1 person in 20 million. Regarding the hereditary amyloidosis TTR-related, it is estimated that it has a prevalence of 1/100.000 in the caucasian population of the United States, but it more common (up to 4%) in African Americans. Finally, in some geographic regions such as Portugal, Sweden, Japan, Germany and Finland, this condition is more common because of the presence of endemic foci.
Molecular genetics
As discussed above, only some forms of amyloidosis have a genetic origin.
Mutations in the APOA1, B2M, FGA e LYZ genes cause familial systemic nonneuropathic amyloidosis (B2M one such family reported). They follow an autosomal dominant inheritance.
Mutations in the GPNMB, IL31RA, OSRM genes cause primary localized cutaneous amyloidosis. GPNMB has an autosomal recessive inheritance, while IL31RA e OSRM has an autosomal dominant transmission. For IL31RA one such patient has been reported.
Mutations in the GSN gene cause the Finnish type of amyloidosis, which has an autosomal dominant inheritance.
Mutations in the CST3, ITM2B, PRNP and APP genes cause cerebral amyloid angiopathy and have an autosomal dominant inheritance.
Finally, heterozygous mutations in the TTR gene cause TTR-related hereditary amyloidosis, which is autosomal dominant. To date, more than 130 mutations in the TTR are known to be associated with this condition. Most mutations fall in exons 2,3 and 4 of the gene and no large deletions/duplications have been reported so far. Among the most common mutations, we find the c.148G>A (p.Val50Met) variant, which is observed especially in Finnish, Swedish and Japanese patients and the p.Val142Ile variant, observed in about 5% of populations in some areas of West Africa. It should be noted that the variant p.Thr139Met has a protective effect in compound heterozygous patients with another pathogenic mutation in TTR.
Treatment
The type of treatment for amyloidosis depends on the underlying disorder and on the affected organs. In addition to specific treatments, supportive treatments are often combined to limit damages of the already damaged tissue.
For AL amyloidosis, many drugs used for multiple myeloma (such as chemotherapy) are used for treatment, with the aim to erase “crazy” plasma cells. Hematopoietic stem cell transplantation can also be used in these cases.
Treatment for transthyretin amyloidosis requires a multidisciplinary approach, with the aim of preventing further deposition of amyloid on one hand, and on the other to treat the signs resulting from the damage already present. In the last years, many therapies have been developed to treat mainly the first stages of the disorder. Among these we find:
- Orthotopic liver transplantation, which is based on the notion that the liver is the main producer of transthyretin. However, from the studies conducted over the last 30 years, it seems that this treatment is effective against neuropathy, but fails to block cardiac deposition of amyloid.
- Tetramer stabilizers. Transthyretin has a homotetrameric structure, i.e. it’s made of 4 subunits. Dissociation of these subunits is the basis for amyloid fibers aggregation and deposit. Tetramer stabilizers, such as Tafamidis and Diflunisal, stabilize the tetrameric native structure and prevent disintegration and accumulation.
- Gene silencing therapy: these are state-of-the-art therapies that aim to reduce the amount of mutated protein through the use of antisense oligonucleotides. To date, Patisiran has been approved in Europe for the treatment of patients with stage 1 or 2 polyneuropathy.
Treatment for AA amyloidosis consists of the treatment of primary disorder, with antiinflammatory, immunosuppressive or chemotherapy drugs, depending on its origin.
Genetic testing strategy
The most important step in the diagnosis of amyloidosis is the distinction between the various forms, for which there are specific treatments. If there is a suspicion of a hereditary form, confirmation is always recommended by analyzing a Next-Generation Sequencing panel that includes all the genes associated with this disease. Breda Genetics offers the analysis of genes for hereditary amyloidosis through multi-gene panels based on exome (EXOME 60MB) or whole genome (WHOLE GENOME) sequencing.
Panel testing recommended at Breda Genetics for this condition:
References
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Faiman B, Richards T. Diagnosis and Treatment of AL and ATTR Amyloidosis. J Adv Pract Oncol. 2021 Apr;12(3):329-332. doi: 10.6004/jadpro.2021.12.3.24. Epub 2021 Apr 1. PMID: 34084586; PMCID: PMC8087231.
Adam RD, Coriu D, Jercan A, Bădeliţă S, Popescu BA, Damy T, Jurcuţ R. Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature. ESC Heart Fail. 2021 Jun 5. doi: 10.1002/ehf2.13443. Epub ahead of print. PMID: 34089308.
Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. 2020 Nov 14. doi: 10.1007/s10072-020-04889-2. Epub ahead of print. PMID: 33188616.
Lahuerta Pueyo C, Aibar Arregui MÁ, Gracia Gutierrez A, Bueno Juana E, Menao Guillén S. Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data. Eur J Hum Genet. 2019 May;27(5):783-791. doi: 10.1038/s41431-019-0337-1. Epub 2019 Jan 25. PMID: 30683924;
