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The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage
I Olafsson1, L Thorsteinsson, O Jensson
1Department of Clinical Chemistry, Reykjavlk Hospital, Iceland.
Insights
Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic brain hemorrhage disorder caused by a cystatin C gene mutation. This leads to amyloid buildup in brain arteries, resulting in strokes in young adults.
Area of Science:
- Neurology
- Genetics
- Molecular Biology
Background:
- Hereditary cystatin C amyloid angiopathy (HCCAA), or Icelandic type, is a fatal brain hemorrhage disorder.
- It follows an autosomal dominant inheritance pattern, affecting normotensive young adults.
- The condition stems from mutations in the cystatin C gene.
Purpose of the Study:
- To review the clinical features, family studies, pathology, biochemistry, and molecular genetics of HCCAA.
- To provide an updated understanding of the molecular underpinnings of HCCAA.
- To consolidate current knowledge on this rare neurological disorder.
Main Methods:
- Review of existing literature on HCCAA.
- Analysis of genetic mutations and their impact on cystatin C protein.
- Examination of amyloid deposition and arterial pathology in affected individuals.
Main Results:
- A specific mutation (A to T substitution at codon 68) alters cystatin C, causing leucine to be replaced by glutamine.
- This variant protein exhibits increased aggregation propensity.
- Amyloid deposits form in cerebral artery walls, leading to arterial damage and strokes.
Conclusions:
- The cystatin C gene mutation is the primary cause of HCCAA.
- Amyloid deposition due to the variant protein is central to the disease pathology.
- Understanding the molecular basis is crucial for potential therapeutic strategies.
Abstract:
Knowledge about molecular pathology of hereditary cystatin C amyloid angiopathy (HCCAA), also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type, has increased greatly in the last decade. The disorder has an autosomal dominant mode of inheritance and causes fatal brain hemorrhage in normotensive young adults. It is due to a mutation in the gene encoding the cysteine proteinase inhibitor, cystatin C.A single nucleotide is substituted, A for T, in the codon 68, resulting in glutamine replacing leucine in the protein sequence. This variant protein has an increased tendency to aggregate and forms heavy depositions of amyloid in the walls of the small arteries and arterioles of the brain. The amyloid deposition leads to arterial damage with single or multiple strokes. In the following review the clinical features, family studies, pathology, biochemistry and molecular genetics of HCCAA are addressed.