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Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage
O Jensson1, G Gudmundsson, A Arnason
1Blood Bank, National Hospital, Reykjavik, Iceland.
Insights
Icelandic hereditary CNS amyloid angiopathy is caused by cystatin C amyloid deposits in brain arteries, leading to strokes. Low cerebrospinal fluid cystatin C levels aid diagnosis in affected families.
Area of Science:
- Neurology
- Genetics
- Biochemistry
Background:
- Hereditary CNS amyloid angiopathy is a rare neurological disorder.
- It is characterized by amyloid deposition in cerebral arteries.
- This deposition leads to strokes and has a fatal outcome.
Purpose of the Study:
- To investigate the cause of hereditary CNS amyloid angiopathy in an Icelandic population.
- To identify the specific protein involved in amyloid deposition.
- To establish diagnostic markers for the disease.
Main Methods:
- Histological examination of affected individuals.
- Cerebrospinal fluid analysis for cystatin C levels.
- Amino acid sequence analysis of amyloid fibrils.
Main Results:
- Identified cystatin C amyloid fibrils deposited in brain artery walls.
- Confirmed hereditary CNS amyloid angiopathy in 8 families (127 affected individuals).
- Found abnormally low cystatin C levels in cerebrospinal fluid of affected individuals.
- Determined the amyloid fibril is a variant of cystatin C with a specific amino acid substitution (Gln68Leu).
Conclusions:
- Hereditary CNS amyloid angiopathy in Icelanders is caused by deposition of a cystatin C variant.
- Low cerebrospinal fluid cystatin C is a potential diagnostic biomarker.
- A point mutation likely leads to the production of this amyloidogenic protein.
Abstract:
Hereditary CNS amyloid angiopathy occurring in Icelanders is the first human disorder known to be caused by deposition of cystatin C amyloid fibrils in the walls of the brain arteries leading to single or or multiple strokes with fatal outcome. One or more affected members have been verified by histological examination in 8 families containing 127 affected. These originated from the same geographic area. Abnormally low value of cystatin C found in the cerebrospinal fluid of those affected can be used to support or make diagnosis of this disease, also in asymptomatic relatives. By amino acid sequence analysis the amyloid fibrils in the patients are found to be a variant of cystatin C (gamma-trace), a major cysteine proteinase inhibitor. The variant protein has an amino acid substitution (glutamine for leucine) at position 58 in the amyloid molecule. It is postulated that a point mutation has occurred leading to production of amyloidogenic protein causing the disorder.