BACKGROUND: Two kindreds with hereditary systemic amyloidosis caused by the first two mutations to be described in the human lysozyme gene were discovered recently and study of the variant lysozyme has been powerfully informative about mechanisms of amyloid fibrillogenesis. However, the clinical manifestations 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 history of amyloidosis, and underwent renal biopsy, whole-body serum amyloid P component (SAP) scintigraphy, and sequencing of the lysozyme gene. Her family history and the phenotype of hereditary lysozyme amyloidosis were thoroughly documented and compared with the presentation and natural history of all other known patients with this condition. RESULTS: The proband belonged to an extended English family other members of which were known to have hereditary lysozyme amyloidosis. Those with amyloid in previous generations presented with renal involvement, frequently developed 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 kindred, contrasts with that of an apparently unrelated family carrying the same 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 amyloidosis. A remarkably wide spectrum of disease can be caused by the same amyloid fibril protein, although renal involvement predominates in all cases except those dying of hepatic rupture.
BACKGROUND: Two kindreds with hereditary systemic amyloidosis caused by the first two mutations to be described in the humanlysozyme gene were discovered recently and study of the variant lysozyme has been powerfully informative about mechanisms of amyloid fibrillogenesis. However, the clinical manifestations 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 history of amyloidosis, and underwent renal biopsy, whole-body serum amyloid P component (SAP) scintigraphy, and sequencing of the lysozyme gene. Her family history and the phenotype of hereditary lysozymeamyloidosis were thoroughly documented and compared with the presentation and natural history of all other known patients with this condition. RESULTS: The proband belonged to an extended English family other members of which were known to have hereditary lysozymeamyloidosis. Those with amyloid in previous generations presented with renal involvement, frequently developed 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 kindred, contrasts with that of an apparently unrelated family carrying the same mutation who presented with spontaneous hepatic haemorrhage and rupture, and with the manifestations in a family with the lysozymeIle56Thr variant who presented with dermal petechiae before proceeding to fatal visceral amyloidosis. A remarkably wide spectrum of disease can be caused by the same amyloid fibril protein, although renal involvement predominates in all cases except those dying of hepatic rupture.
Authors: Samih H Nasr; Surendra Dasari; John R Mills; Jason D Theis; Michael T Zimmermann; Rafael Fonseca; Julie A Vrana; Steven J Lester; Brooke M McLaughlin; Robert Gillespie; W Edward Highsmith; John J Lee; Angela Dispenzieri; Paul J Kurtin Journal: J Am Soc Nephrol Date: 2017-01-03 Impact factor: 10.121
Authors: Minkoo Ahn; Erwin De Genst; Gabriele S Kaminski Schierle; Miklos Erdelyi; Clemens F Kaminski; Christopher M Dobson; Janet R Kumita Journal: PLoS One Date: 2012-11-16 Impact factor: 3.240
Authors: Janet R Kumita; Linda Helmfors; Jocy Williams; Leila M Luheshi; Linda Menzer; Mireille Dumoulin; David A Lomas; Damian C Crowther; Christopher M Dobson; Ann-Christin Brorsson Journal: FASEB J Date: 2011-09-29 Impact factor: 5.191