Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature

Abstract

Rationale:Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form.Patient concerns:We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2.Diagnoses:After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history.Interventions:Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors.Outcomes:Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency.Lessons:Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement

“…In general, only homozygosity or compound heterozygosity for loss-offunction mutations in rate-limiting genes for HDL biogenesis display clinical manifestations, although there are exceptions. 76 Specific clinical features can provide clues to the underlying molecular diagnosis (figure 2).…”

“…Heterozygotes are typically asymptomatic despite low HDL cholesterol concentrations, although some specific ultrarare missense mutations are the second most frequent cause of familial amyloidosis after transthyretin variants. 76 The location of the structural alteration is reported to determine the site of deposition of apolipoprotein A-Iamyloid; those affecting the amino-terminal domain are mainly associated with hepatic and renal amyloidosis, whereas mutations affecting residues 173-178 are mostly responsible for cardiac, laryngeal, and cutaneous amyloidosis. 76,78 Only some amyloidogenic apolipoprotein A-I variants are associated with low HDL cholesterol concentrations; many of these were initially identified by immunohistochemical analysis of amyloid in affected organs, although definitive diagnosis now requires APOA1 gene sequencing.…”

“…76 The location of the structural alteration is reported to determine the site of deposition of apolipoprotein A-Iamyloid; those affecting the amino-terminal domain are mainly associated with hepatic and renal amyloidosis, whereas mutations affecting residues 173-178 are mostly responsible for cardiac, laryngeal, and cutaneous amyloidosis. 76,78 Only some amyloidogenic apolipoprotein A-I variants are associated with low HDL cholesterol concentrations; many of these were initially identified by immunohistochemical analysis of amyloid in affected organs, although definitive diagnosis now requires APOA1 gene sequencing. 7 Homozygous or compound heterozygous apolipoprotein A-I deficiency has been described in less than 20 patients worldwide and is characterised by an almost Review complete deficiency of HDL cholesterol (<0·3 mmol/L or <10 mg/dL) and apolipoprotein A-I (<0·1 g/L) and, in most individuals, premature coronary heart disease.…”

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

“…Since any protein needs to adopt an appropriate conformation in order to perform its function, protein unfolding into the cross-β conformation accompanied by phase transformation into solid fibrils generally abolishes the native function of the protein. Proteins such as lipoproteins, antibodies and IAPP (also called amylin) are not able to perform their homeostatic, immunological, or hormonal functions in their pathological amyloid forms in Apo-AI amyloidosis, lightchain amyloidosis and diabetes, respectively (Hieronymus and Griffin, 2015;Muchtar et al, 2016;Lu et al, 2017). The same applies to Aβ, prion protein (PrP) and α-syn, which are the most studied in the context of neurodegenerative disorders.…”

Amyloidoza nerek

“…Białko to jest stałym, stabilizującym składnikiem każdego typu amyloidu, dlatego obniżenie jego stężenia w surowicy miałoby hamować deponowanie amyloidu w tkankach. Prowadzone są badania kliniczne przeciwciał anty-SAP oraz leku o nazwie CPHPC (R-1--[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid) [1,13,57,61,62].…”