Hereditary renal amyloidosis associated with variant lysozyme in a large English family

Background. Two kindreds with hereditary systemic amyloidosis caused by the first two mutations to be described in the human lysozyme gene were discov ered recently and study of the variant lysozyme has been powerfully informa tive about mechanisms of amyloid fibrillogenesis. However, the clinical man ifestations in these families, additional members of which have lately been identified, have not previously been reported in detail. Methods. The proband presented with proteinuria aged 50 and a family histor y of amyloidosis, and underwent renal, biopsy, whole-body serum amyloid P c omponent (SAP) scintigraphy, and sequencing of the lysozyme gene. Her famil y history and the phenotype of hereditary lysozyme amyloidosis were thoroug hly documented and compared with the presentation and natural history of al l other known patients with this condition. Results. The proband belonged to an extended English family other members o f which were known to have hereditary lysozyme amyloidosis. Those with amyl oid in previous generations presented with renal involvement, frequently de veloped complications due to gastrointestinal amyloid, and died before age 60. All amyloid deposits were composed of lysozyme and complete concordance was established between amyloid and heterozygosity for a point mutation in the lysozyme gene, encoding the previously reported Asp67His substitution in the mature protein. Conclusion. The phenotype, reported for the first time in this extended kin dred, contrasts with that of an apparently unrelated family carrying the sa me mutation who presented with spontaneous hepatic haemorrhage and rupture, and with the manifestations in a family with the lysozyme Ile56Thr variant who presented with dermal petechiae before proceeding to fatal visceral am yloidosis. A remarkably wide spectrum of disease can be caused by the same amyloid fibril protein, although renal involvement predominates in all case s except those dying of hepatic rupture.