Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis

Abstract

Mutations in the fibrinogen A␣-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A␣-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0 -12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

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

“…The absence of a family history is apparently unusual in apoAI amyloidosis and might suggest a de novo mutation; however, variable penetrance is well recognized in other types of hereditary systemic amyloidosis. 34 We have not been able to obtain DNA from the parents of the three relevant patients to investigate this in more detail. Patient 5 presented a diagnostic challenge.…”

Transthyretin Amyloidosis and the Kidney

“…In contrast to other types of hereditary nephropathic amyloidosis, in ATTR this approach was not attempted (51).…”

Hereditary lysozyme amyloidosis – phenotypic heterogeneity and the role of solid organ transplantation

“…Interestingly, liver function tests were barely deranged and remained relatively stable during follow-up, which contrasts AL amyloidosis, in which patients with similar SAP scintigraphic appearances have markedly deranged liver biochemistry and may develop hepatic decompensation [19]. Both this and the finding that median time from presentation with renal dysfunction to ESRD in this cohort was 11.0 years indicate that the natural history of ALys is markedly slower than AL and other types of hereditary amyloidosis [15,20]. The mechanism by which amyloid accumulation in native organs appears to abate in ALys once patients have accumulated a large total body amyloid burden remains unclear.…”

“…ALys is the most clinically heterogeneous condition in this group and may mimic the more common AL amyloidosis associated with plasma cell dyscrasias [13]. ALys is very penetrant, however, and a family history of amyloidosis is usually present in marked contrast to other forms of hereditary systemic amyloidosis [14,15].…”