TY - JOUR
T1 - Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I
AU - Rowczenio, Dorota
AU - Dogan, Ahmet
AU - Theis, Jason D.
AU - Vrana, Julie A.
AU - Lachmann, Helen J.
AU - Wechalekar, Ashutosh D.
AU - Gilbertson, Janet A.
AU - Hunt, Toby
AU - Gibbs, Simon D.J.
AU - Sattianayagam, Prayman T.
AU - Pinney, Jenny H.
AU - Hawkins, Philip N.
AU - Gillmore, Julian D.
N1 - Funding Information:
Supported by the UK Department of Health.
PY - 2011/10
Y1 - 2011/10
N2 - 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. Laser microdissection and tandem mass spectrometrybased proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.
AB - 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. Laser microdissection and tandem mass spectrometrybased proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.
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U2 - 10.1016/j.ajpath.2011.06.024
DO - 10.1016/j.ajpath.2011.06.024
M3 - Article
C2 - 21820994
AN - SCOPUS:80053283839
SN - 0002-9440
VL - 179
SP - 1978
EP - 1987
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -