👤 Helmut G Rennke

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m Show less

Amyloidosis is caused by extracellular deposition of proteins in an insoluble manner within tissues. In hereditary forms of amyloidosis, transthyretin, fibrinogen A-α, lysozyme, gelsolin, apolipoprotein A-I, and A-II accumulate in the tissue plaques. Here we describe a 52-year-old man with no family history of renal disease who presented with increased urinary frequency, gradual loss of renal function but no significant proteinuria. Renal biopsy found large amounts of amyloid restricted to the medulla with no involvement of glomeruli or vessels. Immunohistochemical analysis for transthyretin or serum amyloid A and tests for an underlying monoclonal gammopathy were negative. Although initially suspected to be amyloid light chain amyloidosis, laser microdissection and mass spectrometry showed that the amyloid was composed of large amounts of apolipoprotein A-IV. This was based on mass spectrometry studies that showed 100, 96, and 73 spectra in three microdissected samples that matched to apolipoprotein A-IV with 100% probability. DNA analyses detected three sequence variants representing common polymorphisms of the apolipoprotein A-IV gene. Thus, in this case, apolipoprotein A-IV deposition and renal involvement appear to be restricted to the medulla. A high degree of suspicion is required for the diagnosis of apolipoprotein A-IV amyloidosis as it may be missed if a renal biopsy consists only of cortex. Show less