Hadjigeorgiou_Layout 1 28/10/2009 09:56 Page 44
Genetic Susceptibility to Primary Intracerebral Haemorrhage
and Georgios M Hadjigeorgiou
1. Laboratory of Neurogenetics, Department of Neurology, University of Thessaly, University Hospital of Larissa;
2. Institute of Biomedical Research and Technology, CERETETH, Larissa; 3. Department of Neurosurgery, University of Thessaly, University Hospital of Larissa
Primary intracerebral haemorrhage (PICH) originates from the spontaneous rupture of cerebral arteries as a result of chronic degenerative
alterations. Although the aetiology of PICH has not been fully elucidated, it may be the result of an interaction between genetic and
environmental risk factors. Several genetic association studies have been conducted in patients with PICH with both positive and negative
results. Most of them investigated the role of mutations in genes affecting the lipid metabolism, the coagulation processes, the
inflammation and the regulation of blood pressure. In this article we briefly discuss the majority of these studies reporting the susceptibility
genes that have been implicated in PICH.
Primary intracranial haemorrhage (PICH), genetics, association studies, polymorphism
Disclosure: The authors have no conflicts of interest to declare.
Received: 3 October 2008 Accepted: 23 February 2009
Correspondence: Georgios M Hadjigeorgiou, Laboratory of Neurogenetics, Department of Neurology, School of Medicine, University of Thessaly, Greece. E: firstname.lastname@example.org
Primary intracerebral haemorrhage (PICH) originates from the reported in a member of a Volga-German family with Alzheimer’s
spontaneous rupture of small arteries as a result of chronic disease and a mutation in the presenilin-2 gene.
Recently, a novel
degenerative changes due to chronic hypertension or amyloid mutation in presenilin-1 gene was also associated with early-onset
Although environmental factors are important, there is dementia of Alzheimer type and lobar PICH.
However, most familial
accumulating evidence that genetic elements also contribute to the cases of CAA and PICH are caused by mutations in the amyloid
pathogenesis of PICH.
In an epidemiological study, familial clustering precursor protein. Of note, these mutations are located in the Aβ
of PICH was noticed, especially when involving deep brain structures, segment of the amyloid precursor protein, whereas mutations in the
indicating genetic predisposition to cerebral haemorrhage.
Increased flanking regions cause Alzheimer’s disease or ischaemic stroke. PICH
incidence of intracerebral haemorrhage in specific animal models also has been documented in Flemish,
provided additional evidence for the existence of susceptibility genes.
CAA families. Recently, duplication of the amyloid precursor
The importance of genetic factors was unequivocally demonstrated protein gene was reported to be the cause of familial CAA presenting
with the identification of causative mutations in monogenic cases of with dementia and PICH.
familial intracerebral haemorrhage. Furthermore, several association
studies have suggested the presence of susceptibility genes that Type IV Collagen a1 Chain
predispose to PICH (see Table 1). In this article we briefly discuss Type IV collagen a1 chain (COL4A1) is an integral component of the
the current state of knowledge regarding the known major and basement membrane in the brain vasculature and other tissues. A few
susceptibility genes that have been implicated in PICH. families and a sporadic case with PICH and mutations in COL4A1 have
been reported so far.
Mutations in COL4A1 seem to compromise
Familial Cases vascular wall integrity and blood supply, leading to small-vessel diseases
Familial Cerebral Amyloid Angiopathy including PICH, microbleeds, lacunar strokes or leukoaraiosis.
Cerebral amyloid angiopathy (CAA) is caused by the deposition of Electron microscopy of the vascular wall in patients with COL4A1
amyloid in the small and medium-sized cortical and leptomeningeal mutations reveals structural defects of the basement membrane such
arteries leading to intracerebral haemorrhage, ischaemic infarction or as interruptions, variable thickening and inconsistent density.
dementia. Amyloid is caused by the aggregation of β-amyloid peptide
(Aβ) and other proteins, promoting vasculopathic changes such as Cerebral Autosomal-dominant Arteriopathy with
fibrinoid necrosis and microaneurysms. Aβ peptide is formed by the Subcortical Infarcts and Leucoencephalopathy
proteolytic fragmentation of amyloid precursor protein. Amyloid Cerebral autosomal-dominant arteriopathy with subcortical infarcts
formation has also been reported in familial cases of CAA caused by and leucoencephalopathy (CADASIL) is a monogenic disorder
mutations in the cystatin C gene,
the transthyretin gene
or the BRI caused by a variety of mutations in the Notch3 gene, which
The clinical presentation of these familial cases includes is responsible for cell signalling and vascular development.
dementia, vascular cognitive decline and PICH. PICH has also been clinical manifestations of this disorder include migraines, transient
44 © TOUCH BRIEFINGS 2009