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Familial amyloid polyneuropathy, Iowa type(AMYLD3)

MedGen UID:
1635231
Concept ID:
C4551500
Disease or Syndrome
Synonyms: AMYLD3; Amyloid polyneuropathy-nephropathy, Iowa type; AMYLOIDOSIS, HEREDITARY SYSTEMIC 3; AMYLOIDOSIS, IOWA TYPE; AMYLOIDOSIS, TYPE III; AMYLOIDOSIS, TYPE IV; AMYLOIDOSIS, VAN ALLEN TYPE; Familial amyloid polyneuropathy type III
SNOMED CT: Familial amyloid polyneuropathy type III (9133005); Van Allen type amyloid polyneuropathy (9133005); Iowa type amyloid polyneuropathy (9133005); Familial amyloid polyneuropathy, Iowa type (9133005); Iowa type amyloidosis (9133005); van Allen type amyloidosis (9133005)
 
Gene (location): APOA1 (11q23.3)
 
Monarch Initiative: MONDO:0971008
OMIM®: 620657

Definition

Hereditary amyloidosis is an autosomal dominant disorder in which amyloid deposition occurs in various tissues. Hereditary systemic amyloidosis-3 (AMYLD3) is characterized by a wide clinical spectrum including amyloid neuropathy, nephropathy, hepatopathy, and cardiomyopathy. Amyloid deposition can also occur in skin, larynx (resulting in hoarseness), and testis (resulting in infertility) (summary by Hamidi Asl et al., 1999, Lachmann et al., 2002). For a discussion of genetic heterogeneity of hereditary systemic amyloidosis, see AMYLD1 (105210). [from OMIM]

Clinical features

From HPO
Infertility disorder
MedGen UID:
43876
Concept ID:
C0021359
Finding
Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Microscopic hematuria
MedGen UID:
65997
Concept ID:
C0239937
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Renal amyloidosis
MedGen UID:
120633
Concept ID:
C0268382
Disease or Syndrome
A form of amyloidosis that affects the kidney. On hematoxylin and eosin stain, amyloid is identified as extracellular amorphous material that is lightly eosinophilic. These deposits often stain weakly for periodic acid Schiff (PAS), demonstrate a blue-to-gray hue on the trichrome stain and are typically negative on the Jones methenamine silver (JMS) stain. These tinctorial properties contrast with the histologic appearance of collagen, a major component of basement membranes, mesangial matrix and areas of sclerosis, which demonstrates strong positivity for PAS and JMS (See Figure 1 of PMID:25852856).
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Dilatation of the cerebral artery
MedGen UID:
1386760
Concept ID:
C4476540
Anatomical Abnormality
The presence of a localized dilatation or ballooning of a cerebral artery.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Hepatic amyloidosis
MedGen UID:
75642
Concept ID:
C0267839
Disease or Syndrome
A form of amyloidosis that affects the liver.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
Amyloidosis
MedGen UID:
272
Concept ID:
C0002726
Disease or Syndrome
The presence of amyloid deposition in one or more tissues. Amyloidosis may be defined as the extracellular deposition of amyloid in one or more sites of the body.
Decreased HDL cholesterol concentration
MedGen UID:
57731
Concept ID:
C0151691
Finding
An decreased concentration of high-density lipoprotein cholesterol in the blood.
Conjunctival amyloidosis
MedGen UID:
75676
Concept ID:
C0268402
Disease or Syndrome
A form of amyloidosis that affects the conjunctiva.
Cardiac amyloidosis
MedGen UID:
488730
Concept ID:
C0268407
Disease or Syndrome
Extracellular deposition in cardiac tissue of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue. Viewed with electron microscopy, the amyloid deposits are seen to be composed of a beta-sheet fibrillar material. These nonbranching fibrils have a diameter of 7.5 to 10 nm and are the result of protein misfolding.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Generalized amyloid deposition
MedGen UID:
354872
Concept ID:
C1862968
Finding
A diffuse form of amyloidosis.
Decreased circulating apolipoprotein A-I concentration
MedGen UID:
1634454
Concept ID:
C4703545
Finding
Concentration of apolipoprotein A-I below the lower limit of normal. Apolipoprotein A-I is the major protein component of high density lipoprotein (HDL) in plasma. Defects in this gene are associated with HDL deficiencies, including Tangier disease.
Cutaneous amyloidosis
MedGen UID:
1830283
Concept ID:
C5779562
Disease or Syndrome
The presence of amyloid deposition in the superficial dermis.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Acanthosis nigricans
MedGen UID:
54
Concept ID:
C0000889
Disease or Syndrome
A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.

Term Hierarchy

Professional guidelines

PubMed

Stern LK, Patel J
Methodist Debakey Cardiovasc J 2022;18(2):59-72. Epub 2022 Mar 14 doi: 10.14797/mdcvj.1050. PMID: 35414852Free PMC Article
Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G
J Neurol 2021 Jun;268(6):2109-2122. Epub 2020 Jan 6 doi: 10.1007/s00415-019-09688-0. PMID: 31907599Free PMC Article
Maurer MS, Bokhari S, Damy T, Dorbala S, Drachman BM, Fontana M, Grogan M, Kristen AV, Lousada I, Nativi-Nicolau J, Cristina Quarta C, Rapezzi C, Ruberg FL, Witteles R, Merlini G
Circ Heart Fail 2019 Sep;12(9):e006075. Epub 2019 Sep 4 doi: 10.1161/CIRCHEARTFAILURE.119.006075. PMID: 31480867Free PMC Article

Recent clinical studies

Etiology

Coelho T, Marques W Jr, Dasgupta NR, Chao CC, Parman Y, França MC Jr, Guo YC, Wixner J, Ro LS, Calandra CR, Kowacs PA, Berk JL, Obici L, Barroso FA, Weiler M, Conceição I, Jung SW, Buchele G, Brambatti M, Chen J, Hughes SG, Schneider E, Viney NJ, Masri A, Gertz MR, Ando Y, Gillmore JD, Khella S, Dyck PJB, Waddington Cruz M; NEURO-TTRansform Investigators
JAMA 2023 Oct 17;330(15):1448-1458. doi: 10.1001/jama.2023.18688. PMID: 37768671Free PMC Article
Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D
Neurol Sci 2022 Dec;43(Suppl 2):595-604. Epub 2020 Nov 14 doi: 10.1007/s10072-020-04889-2. PMID: 33188616Free PMC Article
Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, Gospodinova M, Obici L, Rapezzi C, Garcia-Pavia P
JACC Heart Fail 2019 Aug;7(8):709-716. Epub 2019 Jul 10 doi: 10.1016/j.jchf.2019.04.010. PMID: 31302046
Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, Lane T, Gilbertson JA, Rowczenio D, Petrie A, Hawkins PN
Eur Heart J 2018 Aug 7;39(30):2799-2806. doi: 10.1093/eurheartj/ehx589. PMID: 29048471
Planté-Bordeneuve V, Said G
Lancet Neurol 2011 Dec;10(12):1086-97. doi: 10.1016/S1474-4422(11)70246-0. PMID: 22094129

Diagnosis

Brito D, Albrecht FC, de Arenaza DP, Bart N, Better N, Carvajal-Juarez I, Conceição I, Damy T, Dorbala S, Fidalgo JC, Garcia-Pavia P, Ge J, Gillmore JD, Grzybowski J, Obici L, Piñero D, Rapezzi C, Ueda M, Pinto FJ
Glob Heart 2023;18(1):59. Epub 2023 Oct 26 doi: 10.5334/gh.1262. PMID: 37901600Free PMC Article
Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D
Neurol Sci 2022 Dec;43(Suppl 2):595-604. Epub 2020 Nov 14 doi: 10.1007/s10072-020-04889-2. PMID: 33188616Free PMC Article
Garcia-Pavia P, Domínguez F, Gonzalez-Lopez E
Med Clin (Barc) 2021 Feb 12;156(3):126-134. Epub 2020 Oct 31 doi: 10.1016/j.medcli.2020.06.064. PMID: 33138983
Donnelly JP, Hanna M
Cleve Clin J Med 2017 Dec;84(12 Suppl 3):12-26. doi: 10.3949/ccjm.84.s3.02. PMID: 29257735
Planté-Bordeneuve V, Said G
Lancet Neurol 2011 Dec;10(12):1086-97. doi: 10.1016/S1474-4422(11)70246-0. PMID: 22094129

Therapy

Coelho T, Marques W Jr, Dasgupta NR, Chao CC, Parman Y, França MC Jr, Guo YC, Wixner J, Ro LS, Calandra CR, Kowacs PA, Berk JL, Obici L, Barroso FA, Weiler M, Conceição I, Jung SW, Buchele G, Brambatti M, Chen J, Hughes SG, Schneider E, Viney NJ, Masri A, Gertz MR, Ando Y, Gillmore JD, Khella S, Dyck PJB, Waddington Cruz M; NEURO-TTRansform Investigators
JAMA 2023 Oct 17;330(15):1448-1458. doi: 10.1001/jama.2023.18688. PMID: 37768671Free PMC Article
Kaur D, Tiwana H, Stino A, Sandroni P
Muscle Nerve 2021 Jan;63(1):10-21. Epub 2020 Sep 14 doi: 10.1002/mus.27048. PMID: 32926436
Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, Gospodinova M, Obici L, Rapezzi C, Garcia-Pavia P
JACC Heart Fail 2019 Aug;7(8):709-716. Epub 2019 Jul 10 doi: 10.1016/j.jchf.2019.04.010. PMID: 31302046
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators
N Engl J Med 2018 Sep 13;379(11):1007-1016. Epub 2018 Aug 27 doi: 10.1056/NEJMoa1805689. PMID: 30145929
Cullis PR, Hope MJ
Mol Ther 2017 Jul 5;25(7):1467-1475. Epub 2017 Apr 13 doi: 10.1016/j.ymthe.2017.03.013. PMID: 28412170Free PMC Article

Prognosis

Brito D, Albrecht FC, de Arenaza DP, Bart N, Better N, Carvajal-Juarez I, Conceição I, Damy T, Dorbala S, Fidalgo JC, Garcia-Pavia P, Ge J, Gillmore JD, Grzybowski J, Obici L, Piñero D, Rapezzi C, Ueda M, Pinto FJ
Glob Heart 2023;18(1):59. Epub 2023 Oct 26 doi: 10.5334/gh.1262. PMID: 37901600Free PMC Article
Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, Gospodinova M, Obici L, Rapezzi C, Garcia-Pavia P
JACC Heart Fail 2019 Aug;7(8):709-716. Epub 2019 Jul 10 doi: 10.1016/j.jchf.2019.04.010. PMID: 31302046
Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS
J Am Coll Cardiol 2019 Jun 11;73(22):2872-2891. doi: 10.1016/j.jacc.2019.04.003. PMID: 31171094Free PMC Article
Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN
Circulation 2016 Jun 14;133(24):2404-12. Epub 2016 Apr 22 doi: 10.1161/CIRCULATIONAHA.116.021612. PMID: 27143678
Planté-Bordeneuve V, Said G
Lancet Neurol 2011 Dec;10(12):1086-97. doi: 10.1016/S1474-4422(11)70246-0. PMID: 22094129

Clinical prediction guides

Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, Damy T, Garcia-Pavia P, Taubel J, Solomon SD, Sheikh FH, Tahara N, González-Costello J, Tsujita K, Morbach C, Pozsonyi Z, Petrie MC, Delgado D, Van der Meer P, Jabbour A, Bondue A, Kim D, Azevedo O, Hvitfeldt Poulsen S, Yilmaz A, Jankowska EA, Algalarrondo V, Slugg A, Garg PP, Boyle KL, Yureneva E, Silliman N, Yang L, Chen J, Eraly SA, Vest J, Maurer MS; HELIOS-B Trial Investigators and Collaborators
N Engl J Med 2025 Jan 2;392(1):33-44. Epub 2024 Aug 30 doi: 10.1056/NEJMoa2409134. PMID: 39213194
Coelho T, Marques W Jr, Dasgupta NR, Chao CC, Parman Y, França MC Jr, Guo YC, Wixner J, Ro LS, Calandra CR, Kowacs PA, Berk JL, Obici L, Barroso FA, Weiler M, Conceição I, Jung SW, Buchele G, Brambatti M, Chen J, Hughes SG, Schneider E, Viney NJ, Masri A, Gertz MR, Ando Y, Gillmore JD, Khella S, Dyck PJB, Waddington Cruz M; NEURO-TTRansform Investigators
JAMA 2023 Oct 17;330(15):1448-1458. doi: 10.1001/jama.2023.18688. PMID: 37768671Free PMC Article
Adams D, Tournev IL, Taylor MS, Coelho T, Planté-Bordeneuve V, Berk JL, González-Duarte A, Gillmore JD, Low SC, Sekijima Y, Obici L, Chen C, Badri P, Arum SM, Vest J, Polydefkis M; HELIOS-A Collaborators
Amyloid 2023 Mar;30(1):1-9. Epub 2022 Jul 23 doi: 10.1080/13506129.2022.2091985. PMID: 35875890
Dorbala S, Cuddy S, Falk RH
JACC Cardiovasc Imaging 2020 Jun;13(6):1368-1383. Epub 2019 Oct 11 doi: 10.1016/j.jcmg.2019.07.015. PMID: 31607664Free PMC Article
Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN
Circulation 2016 Jun 14;133(24):2404-12. Epub 2016 Apr 22 doi: 10.1161/CIRCULATIONAHA.116.021612. PMID: 27143678

Recent systematic reviews

Nativi-Nicolau J, Yilmaz A, Dasgupta N, Macey R, Cochrane J, Peatman J, Summers C, Luth J, Zolty R
J Comp Eff Res 2024 Jul;13(7):e230158. Epub 2024 Jun 13 doi: 10.57264/cer-2023-0158. PMID: 38869839Free PMC Article
Antonopoulos AS, Panagiotopoulos I, Kouroutzoglou A, Koutsis G, Toskas P, Lazaros G, Toutouzas K, Tousoulis D, Tsioufis K, Vlachopoulos C
Eur J Heart Fail 2022 Sep;24(9):1677-1696. Epub 2022 Aug 2 doi: 10.1002/ejhf.2589. PMID: 35730461
Magrinelli F, Fabrizi GM, Santoro L, Manganelli F, Zanette G, Cavallaro T, Tamburin S
Cochrane Database Syst Rev 2020 Apr 20;4(4):CD012395. doi: 10.1002/14651858.CD012395.pub2. PMID: 32311072Free PMC Article
Finsterer J, Iglseder S, Wanschitz J, Topakian R, Löscher WN, Grisold W
Acta Neurol Scand 2019 Feb;139(2):92-105. Epub 2018 Oct 23 doi: 10.1111/ane.13035. PMID: 30295933
Schmidt H, Cruz MW, Botteman MF, Carter JA, Chopra A, Stewart M, Hopps M, Fallet S, Amass L
Amyloid 2017 Mar;24(sup1):111-112. doi: 10.1080/13506129.2017.1292903. PMID: 28434339

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