Hereditary cerebral amyloid angiopathy

Hello. My name is Lou Grangeon and I work as a Neurologist at the Rouen University Hospital in France. My PhD was about genetics in cerebral amyloid angiopathy. Indeed, in this lecture, we are going to talk about hereditary forms of cerebral amyloid angiopathy. I have no conflict of interest in this presentation.

When we speak of cerebral amyloid angiopathy, or CAA, we're actually talking about an extremely heterogeneous entity. In all cases, there is an accumulation of a substance known as amyloid in the vascular wall, but this may be of different types with different peptides accumulating. The most common form is amyloid angiopathy with A-Beta peptide accumulation. But there are other very rare forms, all hereditary with autosomal dominant inheritance, in which other peptides can accumulate. This is the case, for instance, with transthyretin, cystatin C, gelsolin, etc. These angiopathies can present in a variety of ways, with cognitive impairment at the forefront, whether or not there is associated Alzheimer's disease. But the second main presentation is hemorrhagic with recurrent spontaneous lobar hematomas. Other clinical presentations exist, such as inflammatory forms. When we come to the various causes or susceptibility factors, we need to distinguish between acquired forms, meaning iatrogenic forms, which have been described in recent years, and concern early onset very severe forms in patients who several decades earlier had undergone neurosurgery involving grafting of dura mater of cadaveric origin, or growth hormone, mainly of cadaveric origin. Apart from these very rare forms, we speak of non-acquired forms, and we distinguish between the most frequent form of late onset. These are sporadic cases in elderly subjects. We are not looking for a genetic cause with mutation directly responsible for the disease, but rather for risk factors, each of which confers a low to moderate risk of developing the disease. To date, only the APOE genotype is known to be a risk factor for CAA. In cases of early onset, whether familial or sporadic, meaning with only one affected subject in a family, we'll be looking for a genetic cause where a mutation within a gene is directly responsible for the pathology. At present, only autosomal dominant inheritance has been described, and the only gene known to be involved in A-Beta CAA is the APP gene. In the event of accumulation of other peptides, we'll be looking at the TTR gene, which includes transthyretin, or the GSN gene which includes gelsolin for instance.