Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis

Lachmann, HJ; Booth, David R.; Booth, SE; Bybee, A; Gilbertson, Janet A.; Gillmore, Julian D.; Pepys, Mark B.; Hawkins, Philip N.

doi:10.1056/nejmoa013354

Cited by 604 publications

(397 citation statements)

References 29 publications

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“…Furthermore, it is important to recognize that the presence of a plasma cell dyscrasia, which occurs in approximately 3% of the population older than 50 years and approximately 5% of those older than 70 years, 29 in a patient with amyloidosis does not prove AL type and may be incidental to their amyloidosis. 30 The deposits in approximately 20% of patients with AL amyloidosis fail to stain with antibodies against and immunoglobulin light chains, presumably reflecting the fact that the fibrils consist of misfolded, variable light chain domains within which certain epitopes may be masked. [31][32][33] Similarly, to confirm the amyloidogenicity of a novel mutation, even within a known amyloid fibril protein gene, one is required to demonstrate the protein composition of the amyloid fibrils.…”

Section: Discussionmentioning

confidence: 99%

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Rowczenio

Doğan

Theis

et al. 2011

The American Journal of Pathology

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The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Amyloidosis is a rare disorder characterized by extracellular deposition of fibrillar protein that results in a progressive disruption of structure and function of affected tissues and organs. Amyloidosis is a remarkably heterogeneous disease; it can be acquired or hereditary and systemic or localized.The most common form of systemic amyloidosis is AL (light chain, previously referred to as "primary"), in which the fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (V L ) domain. The prognosis of systemic AL amyloidosis is generally worse than in other amyloid types, although there is marked heterogeneity in the extent of organ involvement and rate of disease progression. Treatment of AL amyloidosis is with chemotherapy for which there is no role in other amyloid types.Hereditary systemic amyloidosis is a rare autosomal dominant condition caused by deposition of variant proteins as amyloid fibrils. The term "hereditary nonneuropathic systemic amyloidosis" (Online Mendelian Inheritance of Man no. 105200) was coined by Ostertag 1 in 1932 following the discovery of two families with dominantly inherited renal amyloidosis. Mutations in the genes encoding apolipoprotein A-I (apoAI), 2-12 apolipoprotein A-II (apoAII), 13 fibrinogen A␣-chain, 14 -17 and lysozyme 18 have since been identified as the cause of hereditary renal amyloidosis in different kindreds (Online Mendelian Inheritance of Man no. 105200). The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age at onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis. Indeed, certain apoAI variants are associated with neuropathy 19,20 such that the nomenclature, which includes the term "nonneuropathic," is confusing and probably no longer appropriate.Supported by the UK Department of Health.Accepted for publication June 15, 2011.The licensed patent rights to perform protein extraction from paraffinembedded tissue for the mass spectrometry-based amyloid typing test were granted by Expression Patholo...

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Section: Discussionmentioning

confidence: 99%

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Rowczenio

Doğan

Theis

et al. 2011

The American Journal of Pathology

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113

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“…The presence of a monoclonal gammopathy should not be used as the only evidence of AL, because a small fraction of patients with familial (AF), secondary (AA), and senile systemic amyloidosis (SSA) will have an incidental monoclonal gammopathy [35] and evidence of clonal plasma cell dyscrasia associated with amyloidosis of nonimmunoglobulin origin [36]. Accurate classification may include immunohistochemical staining of tissues with appropriate antisera [37].…”

Section: How Is the Amyloidosis Characterized As Al Type?mentioning

confidence: 99%

Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

et al. 2005

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“…1 ApoA-I hereditary amyloidosis (AApoAI, MIM 107680) is a rare disease characterized by progressive deposition of amyloid fibrils mainly constituted by Nterminal polypeptide fragments of this protein. Ten amyloidogenic apoA-I variants have been identified thus far, 2,3 and most of these are private. Amyloid deposits predominantly affect the kidneys, heart, and liver, causing either progressive nephropathy or cardiomyopathy and, rarely, hepatopathy.…”

Section: Background and Aimsmentioning

confidence: 99%

Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families

et al. 2004

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Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis

Cited by 604 publications

References 29 publications

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families

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