Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.
OBJECTIVE
Hereditary systemic amyloidoses are autosomal dominant, late-onset disorders caused by mutations in the genes for a group of plasma proteins including transthyretin, lysozyme, fibrinogen Aalpha chain, gelsolin, apolipoprotein A-I, and apolipoprotein A-II. We investigated both phenotypic and genotypic aspects of apolipoprotein A-I amyloidosis unexpectedly disclosed by liver biopsy in 13 unrelated individuals with asymptomatic, persistent elevation of alkaline phosphatase and gamma-glutamyltransferase levels.


METHODS
Immunoelectron microscopy was used for in situ characterization of amyloid deposits on liver biopsy specimens. Mutation analysis was performed by sequencing of the apolipoprotein A-I gene in all patients. Wild-type/variant apolipoprotein A-I ratio in plasma high-density lipoproteins was assessed by a peptide mass fingerprinting approach after purification of total apolipoprotein A-I of 2 patients.


RESULTS
Family history was informative in 5 cases. Renal failure developed in 9 cases. Hypogonadism due to testicular involvement was observed. Amyloid fibrils specifically stained with anti-apolipoprotein A-I antibody. A novel (Leu75Pro) heterozygous mutation in the apolipoprotein A-I gene was present in affected individuals but not in controls. Variant apolipoprotein A-I was about 10% of the total protein in high-density lipoproteins.


CONCLUSIONS
The high number of individuals with apparently sporadic disease might reflect widespread occurrence of this mutation in the population and a milder phenotype of this variant compared with other apolipoprotein A-I amyloidogenic mutants. These findings suggest that specific staining for amyloid should be performed on liver biopsy of individuals with asymptomatic chronic elevation of alkaline phosphatase and gamma-glutamyltransferase levels.
Obici
Laura
L
Biotechnology Research Laboratories, IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.
Palladini
Giovanni
G
Giorgetti
Sofia
S
Bellotti
Vittorio
V
Gregorini
Gina
G
Arbustini
Eloisa
E
Verga
Laura
L
Marciano
Sabrina
S
Donadei
Simona
S
Perfetti
Vittorio
V
Calabresi
Laura
L
Bergonzi
Cesare
C
Scolari
Francesco
F
Merlini
Giampaolo
G
D000368:Aged; D000686:Amyloidosis / Q000235:genetics*; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001706:Biopsy; D004247:DNA / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D007930:Leucine; D008099:Liver / Q000473:pathology*; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011392:Proline
D016632:Apolipoprotein A-I; D004247:DNA; D011392:Proline; D007930:Leucine