Alternative titles; symbols
SNOMEDCT: 66451004; ORPHA: 314652, 85450, 93560, 93561, 93562; DO: 0050636;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.3 | Amyloidosis, hereditary systemic 2 | 105200 | Autosomal dominant | 3 | FGA | 134820 |
A number sign (#) is used with this entry because of the evidence that hereditary systemic amyloidosis-2 (AMYLD2) is caused by heterozygous mutation in the fibrinogen alpha-chain gene (FGA; 134820) on chromosome 4q31.
Systemic amyloidosis is a rare protein misfolding and deposition disorder caused by extracellular deposition of amyloid and leading to progressive organ failure. Amyloid is composed of highly organized proteinaceous, insoluble, and degradation-resistant fibrils. Hereditary systemic amyloidosis-2 (AMYLD2), resulting from mutation in the FGA gene, is the most common form of hereditary renal amyloidosis. The kidneys are the major affected organ, presenting with proteinuria. Other less frequently involved organs include liver, heart, autonomic nerve, and, rarely, peripheral nerve. A strong family history of coronary or vascular disease is also frequently seen (summary by Muchtar et al., 2021).
The various forms of hereditary systemic amyloidosis that do not have peripheral neuropathy as part of the clinical syndrome have been referred to as 'Ostertag type' in reference to a German family described by Benno Ostertag (1932) in which several members died with renal amyloidosis. Since the form of hereditary amyloidosis caused by mutation in the FGA gene is the most common in Europe and has a clinical presentation with hypertension and proteinuria, Benson (2005) considered it a very good candidate for being the original amyloidosis described by Ostertag.
For a discussion of genetic heterogeneity of hereditary systemic amyloidosis, see AMYLD1 (105210).
Ostertag (1932, 1950) reported on a family with visceral amyloidosis. A woman, 3 of her children, and 1 of her grandchildren were affected with chronic nephropathy, arterial hypertension, and hepatosplenomegaly. Albuminuria, hematuria and pitting edema were early signs. The age of onset was variable. Death occurred about 10 years after onset. The visceral involvement by amyloid was found to be extensive.
Maxwell and Kimbell (1936) described 3 brothers who died of visceral, especially renal, amyloidosis in their 40s. Chronic weakness, edema, proteinuria, and hepatosplenomegaly were features. McKusick (1974) followed up on the family reported by Maxwell and Kimbell (1936). The father of the 3 affected brothers died at age 72 after an automobile accident and their mother died suddenly at age 87 after being in apparent good health. A son of one of the brothers had frequent bouts of unexplained fever in childhood (as did his father and 2 uncles), accompanied at times by nonspecific rash. At the age of 35, proteinuria was discovered and renal amyloidosis was diagnosed by renal biopsy. For 2 years thereafter he displayed the nephrotic syndrome, followed in the next 2 years by uremia from which he died at age 39. Autopsy revealed amyloidosis, most striking in the kidneys but also involving the adrenal glands and spleen. Although some features of the family of Maxwell and Kimbell (1936) are similar to those of urticaria, deafness and amyloidosis (191900), no deafness was present in their family. Weiss and Page (1974) reported a family with 2 definite and 4 probable cases in 3 generations.
Mornaghi et al. (1981, 1982) reported rapidly progressive biopsy-proved renal amyloidosis in 3 brothers, aged 49, 52 and 55, of Irish-American origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum or urine protein, or any underlying chronic disease. Immunoperoxidase staining of 1 pulmonary and 1 renal biopsy specimen was negative for amyloid A (AA), amyloid L (AL) and prealbumin. The authors concluded that the disorder in the 3 brothers closely resembled that described by Ostertag (1932).
Libbey and Talbert (1987) described a case of nephropathic amyloidosis, presumably of the Ostertag type. In their case, the amyloid showed no staining for light chains or prealbumin. Involvement of the liver was associated with cholestasis. The details of their patient's family history were not given by Libbey and Talbert (1987).
Benson et al. (1993) reported a 3-generation Peruvian family in which 3 members who died of renal amyloidosis had a mutation in the FGA gene. The propositus was a 50-year-old man who had developed nephrotic syndrome and azotemia at age 36. At age 40 he received a cadaver renal transplant which 8 years later showed diffuse amyloid involvement of glomeruli on biopsy. He died at age 50 after a second renal allograft; autopsy demonstrated diffuse glomerular amyloid in the first renal transplant with focal interstitial calcification, chronic inflammation, and multifocal hyaline tubular degeneration, and interstitial lymphocytes and plasma cells consistent with mild acute rejection in the second transplant. The original kidneys showed much less amyloid deposition than the first transplant. Amyloid deposition was also present in spleen, but not in liver. The patient's sister and son died at ages 28 and 24 years, respectively, of renal amyloidosis. Benson et al. (1993) noted that the histologic appearance of the kidneys of these individuals was very similar to the description and figures presented by Ostertag (1950).
Uemichi et al. (1994) described 2 American families of Irish descent with hereditary renal amyloidosis and the same mutation in the FGA gene. Affected individuals presented with nonneuropathic nephropathic amyloidosis in the fifth to seventh decade of life. The propositus of the first family was noted to have proteinuria at age 43 years, which increased into the nephrotic range during the next 3 years. Amyloidosis was detected by renal biopsy. Liver biopsy at age 51 years detected amyloid in blood vessel walls only. He had no cardiac or neurologic symptoms. His father died of renal failure at age 69; autopsy showed amyloid in kidneys and spleen but not in liver or heart. His uncle had onset of severe generalized pruritus at age 59 years and died of renal dysfunction and pancytopenia at age 61. His cousin presented with proteinuria at age 61 years; amyloid deposition was shown on renal biopsy, renal dysfunction progressed rapidly within a year, and he was placed on hemodialysis. In the second family, renal biopsy detected amyloidosis in the 62-year-old propositus and her 70-year old brother. Echocardiogram in the sister detected left ventricular hypertrophy and thickening of the mitral valve, and while right heart myocardial biopsy showed bo evidence of cardiac amyloid in the brother, echocardiogram showed concentric left ventricular hypertrophy and a sparkling appearance suggestive of cardiac amyloid, as well as a heavily calcified aortic valve.
Uemichi et al. (1996) reported a family with hereditary renal amyloidosis and low plasma fibrinogen concentration and mutation in the FGA gene. Two of the 4 children of the propositus carried the mutation, and both had lower plasma fibrinogen concentrations than their sibs but had no clinical symptoms of amyloidosis in the second decade of life.
The transmission pattern of AMYLD2 in the family reported by Benson et al. (1993) was consistent with autosomal dominant inheritance.
In a Peruvian family in which a brother and sister and the son of the brother died from renal amyloidosis, Benson et al. (1993) identified a mutation in the fibrinogen A alpha polypeptide gene (FGA; 134820.0012).
In 2 large American kindreds of Irish descent with nephrotic syndrome due to renal amyloidosis, Uemichi et al. (1993, 1994) identified a missense mutation in the FGA gene (E526V; 134820.0013).
In an American kindred with hereditary renal amyloidosis, Uemichi et al. (1996) identified a 1-bp deletion in the FGA gene (134820.0016), causing a frameshift and termination sequence at codon 548.
In a French kindred with autosomal dominant hereditary renal amyloidosis, Hamidi Asl et al. (1997) identified a different 1-bp deletion in the FGA gene, also resulting in termination at codon 548 (134820.0018).
Systemic amyloidosis is the diagnosis in 2.5% of all renal biopsies, according to Davison (1985), and is the cause of death in more than 1 in 1,500 persons in the United Kingdom annually. Acquired monoclonal immunoglobulin light-chain amyloidosis (AL; see 254500), formerly known as primary amyloidosis, is the most common form of systemic amyloidosis and can respond to chemotherapy directed at the underlying plasma cell dyscrasia. Lachmann et al. (2002) studied 350 patients with systemic amyloidosis in whom a diagnosis of the AL type of the disorder had been suggested by clinical and laboratory data and by the apparent absence of a family history. They identified amyloidogenic mutations in 34 (9.7%) of the patients, all of whom had the diagnosis of hereditary amyloidosis confirmed by additional investigations. In 18 (5.1%) of the 350 patients, the E526V mutation in the FGA gene was identified; 13 of the patients had missense mutations in the transthyretin gene (176300); 2 patients had missense mutations in the APOA1 gene (107680); and 1 patient had the D67H mutation in the lysozyme gene (153450.0002). All 18 patients with the FGA E526V mutation were of northern European ancestry, and although none was aware of any relevant family history, genealogic studies revealed that 2 were cousins and that ancestors of 2 other patients lived in adjacent villages. A fifth patient retrospectively ascertained that her dizygotic twin had died of renal failure at the age of 76 years. The median age of the 18 patients at the time of presentation was 59 years; the youngest was in her thirties and the oldest was 78 years old. All presented with isolated renal dysfunction and proteinuria, and most had moderate hypertension; all had renal amyloid deposits, and splenic amyloid was present in all but 1 of the patients. Spontaneous splenic rupture occurred in 2 patients.
Bodin et al. (2010) demonstrated that administration of anti-human serum amyloid P component (SAP; 104770) antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-D-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits.
Alexander, F., Atkins, E. L. Familial renal amyloidosis: case reports, literature review and classification. Am. J. Med. 59: 121-128, 1975. [PubMed: 1138543] [Full Text: https://doi.org/10.1016/0002-9343(75)90329-0]
Benson, M. D., Liepnieks, J., Uemichi, T., Wheeler, G., Correa, R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nature Genet. 3: 252-255, 1993. [PubMed: 8097946] [Full Text: https://doi.org/10.1038/ng0393-252]
Benson, M. D. Ostertag revisited: the inherited systemic amyloidoses without neuropathy. Amyloid 12: 75-87, 2005. [PubMed: 16011983] [Full Text: https://doi.org/10.1080/13506120500106925]
Bodin, K., Ellmerich, S., Kahan, M. C., Tennent, G. A., Loesch, A., Gilbertson, J. A., Hutchinson, W. L., Mangione, P. P., Gallimore, J. R., Millar, D. J., Minogue, S., Dhillon, A. P., Taylor, G. W., Bradwell, A. R., Petrie, A., Gillmore, J. D., Bellotti, V., Botto, M., Hawkins, P. N., Pepys, M. B. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 468: 93-97, 2010. [PubMed: 20962779] [Full Text: https://doi.org/10.1038/nature09494]
Davison, A. M. The United Kingdom Medical Research Council's glomerulonephritis registry. Contrib. Nephrol. 48: 24-35, 1985. [PubMed: 3912110]
Hamidi Asl, L., Liepnieks, J. J., Uemichi, T., Rebibou, J.-M., Justrabo, E., Droz, D., Mousson, C., Chalopin, J.-M., Benson, M. D., Delpech, M., Grateau, G. Renal amyloidosis with a frame shift mutation in fibrinogen A(alpha)-chain gene producing a novel amyloid protein. Blood 90: 4799-4805, 1997. [PubMed: 9389696]
Lachmann, H. J., Booth, D. R., Booth, S. E., Bybee, A., Gilbertson, J. A., Gillmore, J. D., Pepys, M. B., Hawkins, P. N. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New Eng. J. Med. 346: 1786-1791, 2002. [PubMed: 12050338] [Full Text: https://doi.org/10.1056/NEJMoa013354]
Libbey, C. A., Talbert, M. L. A 43-year-old woman with hepatic failure after renal transplantation because of amyloidosis. New Eng. J. Med. 317: 1520-1531, 1987. [PubMed: 3317049] [Full Text: https://doi.org/10.1056/NEJM198712103172407]
Maxwell, E. S., Kimbell, I. Familial amyloidosis with case reports. Med. Bull. Vet. Admin. 12: 365-369, 1936.
McKusick, V. A. Personal Communication. Baltimore, Md. 1974.
Mornaghi, R., Rubinstein, P., Franklin, E. C. Studies of the pathogenesis of a familial form of renal amyloidosis. Trans. Assoc. Am. Phys. 94: 211-216, 1981. [PubMed: 7344220]
Mornaghi, R., Rubinstein, P., Franklin, E. C. Familial renal amyloidosis: case reports and genetic studies. Am. J. Med. 73: 609-614, 1982. [PubMed: 7124780] [Full Text: https://doi.org/10.1016/0002-9343(82)90342-4]
Muchtar, E., Dispenzieri, A., Magen, H., Grogan, M., Mauermann, M., McPhail, E. D., Kurtin, P. J., Leung, N., Buadi, F. K., Dingli, D., Kumar, S. K., Gertz, M. A. Systemic amyloidosis from A (AA) to T (ATTR): a review. J. Intern. Med. 289: 268-292, 2021. [PubMed: 32929754] [Full Text: https://doi.org/10.1111/joim.13169]
Ostertag, B. Demonstration einer eigenartigen familiaeren Paramyloidose. Zbl. Path. 56: 253-254, 1932.
Ostertag, B. Familiaere Amyloid-erkrankung. Z. Menschl. Vererb. Konstitutionsl. 30: 105-115, 1950.
Pepys, M. B., Hawkins, P. N., Booth, D. R., Vigushin, D. M., Tennent, G. A., Soutar, A. K., Totty, N., Nguyen, O., Blake, C. C. F., Terry, C. J., Feest, T. G., Zalin, A. M., Hsuan, J. J. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature 362: 553-557, 1993. [PubMed: 8464497] [Full Text: https://doi.org/10.1038/362553a0]
Uemichi, T., Liepnieks, J. J., Benson, M. D. Fibrinogen Indianapolis: a fibrinogen A-alpha chain associated with hereditary amyloidosis. (Abstract) Clin. Res. 41: 133 only, 1993.
Uemichi, T., Liepnieks, J. J., Benson, M. D. Hereditary renal amyloidosis with a novel variant fibrinogen. J. Clin. Invest. 93: 731-736, 1994. [PubMed: 8113408] [Full Text: https://doi.org/10.1172/JCI117027]
Uemichi, T., Liepnieks, J. J., Yamada, T., Gertz, M. A., Bang, N., Benson, M. D. A frame shift mutation in the fibrinogen A-alpha chain gene in a kindred with renal amyloidosis. Blood 87: 4197-4203, 1996. [PubMed: 8639778]
Valleix, S., Gillmore, J. D., Bridoux, F., Mangione, P. P., Dogan, A., Nedelec, B., Boimard, M., Touchard, G., Goujon, J.-M., Lacombe, C., Lozeron, P., Adams, D., and 14 others. Hereditary systemic amyloidosis due to asp76asn variant beta-2-microglobulin. New Eng. J. Med. 366: 2276-2283, 2012. [PubMed: 22693999] [Full Text: https://doi.org/10.1056/NEJMoa1201356]
Weiss, S. W., Page, D. L. Amyloid nephropathy of Ostertag with special reference to renal glomerular giant cells. Am. J. Path. 72: 447-460, 1973. [PubMed: 4728894]
Weiss, S. W., Page, D. L. Amyloid nephropathy of Ostertag: report of a kindred. Birth Defects Orig. Art. Ser. X(4): 67-68, 1974. [PubMed: 4470911]