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Other TitlesHereditary central nervous system amyloid angiopathy
CitationLæknablaðið 1988, 74(1):9-16
AbstractHereditary central nervous system amyloid angiopathy occurring in Icelanders is the first human disease known to cause deposition of fragments of the alkaline microprotein cystatin C ( & -trace), forming amyloid fibrils in the walls of the brain arteries, leading to single or multiple strokes with fatal cerebral hemorrhages in most cases. Extensive pedigree studies based on ascertainment of 126 affected members in eight families who are originated in the same geographic area of Iceland, indicate that the autosomal dominant gene causing amyloid angiopathy has been transmitted over at least two centuries. Over 80% of those who have died from this disorder were less than 40 years. Carrier state is compatible with reaching old age. Of Icelanders, who died 1958-1968 from stroke at the age of 35 years or less, 18 individuals or 17% died from brain hemorrhage due to this amyloid angiopathy. The disorder is characterised by abnormally low value of cystatin C in the cerebrospinal fluid or one third of the average value found in comparable normal adults. This is the lowest value of cystatin C ever found in the CSF of man. In vivo diagnosis of this disease is now possible for the first time by simple estimation of cystatin C in the CSF, also in asymptomatic affected members. Recently only one amino acid difference (Glu for Leu) was found in the composition of a tryptic peptide corresponding to position 55-70 cystatin C (y-trace) numbering. It is conceivable therefore that a mutation has occurred leading to the production of an unusual cystatin C (y-trace) that is abnormally degraded, bound and/or precipitated. Restriction fragment length polymorphism analysis is under way to establish whether a defect in the cystatin C gene gauses the disease (28, 29). Cystatin C has recently been established as a major cysteine proteinase inhibitor by its strong homologies (up to 43%) with all sequenced human and animal cysteine proteinase inhibitors and by direct determinations of its strong inhibition of the human lysosomal cysteine proteinases cathepsin B, H and L. A hereditary CNS amyloid angiopathy has also been described in several families in Holland (W. Luyendijk and Bots, 1980; Wattendorff et al, 1982). Recently estimation of cystatin C (y-trace) was made in the CSF and plasma of six members of Dutch families, including four who had symptoms of cerebral hemorrhage. The CSF values of cystatin C in the Dutch patients were within normal range. Autopsy specimens were obtained from the brain of three Dutch patients who had died from cerebral hemorrhage due to hereditary cerebral amyloid angiopathy. Immunohistochemical investigation of the brain tissue sections showed moderated and weak immunoreactivity in two cases and a doubtful reaction in the third. Recent findings indicate that the amyloid material involved in the Dutch type of hereditary cerebral amyloid angiopathy is not cystatin C derived but related to (3-protein of Alzheimer disease an Down's syndrome (30). - This review is based on a lecture held in memory of Þórður Þórðarson M.D. who died 10.03.85. He and his wife Louise translated Dr. Árni Árnason's thesis from Icelandic to German, see ref. 2.
Árni Árnason læknir varði ritgerð sína um heilaslag og arfgengi fyrir doktorsnafnbót 1935 (1, 2). Fyrsta lýsingin á meingerð þessa arfgenga heilaæðasjúkdóms var eftir breska lækna og birtist í Lancet 1946 (3). Í ritgerð íslenskra lækna í tímaritinu Brain 1972 er frá því skýrt, að æðameinið eigi rót að rekja til myndunar mýlildis (amyloidosis) og upphleðslu þess í heilaæðaveggjunum (4). Rannsóknir á sjúkdómnum frá 1976-1982 beindust einkum að tilraunum til að skýra efnafræðilegt eðli mýlildisins. Til að leysa það mál var stofnað til samvinnu við erlenda vísindamenn. Sú samvinna bar árangur 1982 og kemur fram í tímaritsgreinum 1982 (5) og 1983 (6, 7). Aðferð til að greina sjúkdóminn með mælingu á latefninu »gamma trace« (cystatin C) í mænuvökva var fundin (8). Stofnað var til erlendrar samvinnu um ýmsa fleiri þætti þessara rannsókna (9, 10). Helstu samstarfsmenn um rannsóknir á arfgengu æðamýlildi með heilablæðingu árin 1982-1987 hafa verið þessir: Ólafur Jensson, Alfreð Árnason, Leifur Þorsteinsson, Ingibjörg Pétursdóttir, Ástríður Pálsdóttir, Blóðbankinn, Landspítalinn; Gunnar Guðmundsson, taugalækningadeild, Landspítalinn; Hannes Blöndal, Rannsóknastofa Háskólans í meinalfræði v/Barónsstíg, Líffærafræðideild Læknadeildar Háskóla islands; Bias Franione, New York University, Medical Center; Anders Grubb, Helge Löfberg, Magnus Abrahamsson, Ísleífur Ólafsson, Almánna sjukhuset, Malmö, Lunds Universitet; Mark Pepys, Hammersmith Hospital, London; Willem Luyendijk, Háskólasjúkrahúsinu, Leiden. Eins og fram kemur í heimildaskrá hafa frá 1980 alls um 30 sérfræðingar innlendir og erlendir látið að sér kveða með rannsóknastörfum og ritgerðum um ýmsa þætti sjúkdómsins.
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