Primary intracerebral haemorrhage (PICH) originates from the spontaneous rupture of small arteries as a result of chronic degenerative changes due to chronic hypertension or amyloid angiopathy.¹ Although environmental factors are important, there is accumulating evidence that genetic elements also contribute to the pathogenesis of PICH.^2,3 In an epidemiological study, familial clustering of PICH was noticed, especially when involving deep brain structures, indicating genetic predisposition to cerebral haemorrhage.⁴ Increased incidence of intracerebral haemorrhage in specific animal models also provided additional evidence for the existence of susceptibility genes.⁵ The importance of genetic factors was unequivocally demonstrated with the identification of causative mutations in monogenic cases of familial intracerebral haemorrhage. Furthermore, several association studies have suggested the presence of susceptibility genes that predispose to PICH (see Table 1). In t his article we briefly discuss the current state of knowledge regarding the known major and susceptibility genes that have been implicated in PICH.


Familial Cases

Familial Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy (CAA) is caused by the deposition of amyloid in the small and medium-sized cortical and leptomeningeal arteries leading to intracerebral haemorrhage, ischaemic infarction or dementia. Amyloid is caused by the aggregation of β-amyloid peptide (Aβ) and other proteins, promoting vasculopathic changes such as fibrinoid necrosis and microaneurysms. Aβ peptide is formed by the proteolytic fragmentation of amyloid precursor protein. Amyloid formation has also been reported in familial cases of CAA caused by mutations in the cystatin C gene,^6,7 the transthyretin gene8–12 or the BRI gene.^13,14 The clinical presentation of these familial cases includes dementia, vascular cognitive decline and PICH. PICH has also been reported in a member of a Volga-German family with Alzheimer’s disease and a mutation in the presenilin-2 gene.¹⁵ Recently, a novel mutation in presenilin-1 gene was lso associated with early-onset dementia of Alzheimer type and lobar PICH.¹⁶ However, most familial cases of CAA and PICH are caused by mutations in the amyloid precursor protein. Of note, these mutations are located in the Aβ segment of the amyloid precursor protein, whereas mutations in the flanking regions cause Alzheimer’s disease or ischaemic stroke. PICH has been documented in Flemish,¹⁷ Dutch,¹⁸ Arctic,¹⁹ Iowan²⁰ and Italian²¹ CAA families. Recently, duplication of the amyloid precursor protein gene was reported to be the cause of familial CAA presenting with dementia and PICH.^22,23

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