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 spectrometry-based 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.