Brain AVM- Genetic Influences

Our genome is the cellular software that directs the physical activity of our cells. Our understanding of the role of
genetics in many forms of disease is increasing all the time. Formerly genetic influence on the development
of brain or spinal cord AVM was understood to be present in rare subtypes of these conditions. Evidence
is mounting however that disorders of genes and gene expression play a far greater role than was previously realised.

It was believed that AVMs formed in-utero or in the period immediately after birth in response perhaps to an event which itself precipitated a vessel thrombosis. The resultant chemical message serve to stimulate the development of aberrent vessels in the affected area. In recent years cases have emerged where the AVM clearly developed later in childhood. This tells us that the development of an AVM can be a dynamic process. Most AVMs encountered in clinical practice are isolated lesions but there are uncommon conditions where an aberrent gene programs AVMs and other vascular malformations to develop throughout life.

Hereditary Haemorrhagic Telangectasia (HHT)

Hereditary Haemorrhagic Telangectasia (HHT) is a collective term for a group of conditions characterised by the development of multiple AVMs in various locations including the brain, skin, eyes, mucus membranes and lungs. Telangectasia are small bright red vascular malformations in the skin. It is thought to affect between 0.1-0.2% of the population.

  • HHT-1 is caused by a mutation of the ENG gene. Patients develop AVMs in the lung and in the brain.
  • HHT-2 is caused by a mutation of the ACVRLI gene. AVMs of the brain and lung develop but patients are affected later in life than in HHT-1.
  • HHT-3 is assosciated with more frequent involvment of the liver than types 1 and 2. The exact gene abnormality is not known but thought to be on chromosome 5.
  • HHT/Juvenile Polyposis Syndrome is the result of a mutation of the SMAD4 gene and results in a propensity to develop polyps in the gastrointestinal tract as well as AVMs. Such polyps are not found in HHT types 1-3.


Craniofacial Arteriovenous Metameric Syndrome (CAMS)

is again a collective term for a group of related conditions, some of which have been recognised in isolation for a long time. The human body develops in discrete sections (called metameres). Vascular malformations of the head, neck and brain occur in this condition within the discrete metameres that make up the head and neck. A rare variety of spinal coloumn AVM (juvenile or metameric AVM) likely results from the same process ("SAMS"). This group of conditions may encompass the Sturge-Weber and Wyburn-Mason Syndromes.

  • CAMS1 sees AVMs develop in the region of the nose, the frontal part of the brain and the hypothalamus.
  • CAMS2 is characterised by AVMs of the mid-face, retina, visual pathways within the brain, the thalamus and the occipital lobes.
  • CAMS3 affects the hindmost parts of the brain (pons, cerebellum) and the jaw.

Capillary Malformation- Arteriovenous Malformation Syndrome(CM-AVM)

CM-AVM is a condition first described in 2003. It results from a mutation of he RASA1 gene. RASA1 provides instructions for making a protein called p120-RasGAP. This protein helps regulate a signalling pathway from a cells nucleus to the elements of the cell outside the nucleus. This is the RAS/MAPK signaling pathway and it is involved with several important cell functions. In the CM-AVM syndromes AVMs develop on the face, arms and legs but may also be found in muscle, bone, brain and spinal cord. For some affected only malformations of the capillaries develop. In others both capillary malformations and arteriovenous malformations co-exist.

Usually an individual affected by CM-AVM will have inherited the condition from one affected parent (autosomal dominant inheritence). It is possible, however, for the condition to arise with no previous family history of the disease as a result of a new gene mutation. The condition affects approximately 1:100000 persons of northern european descent.

KRAS Mutations in Non-syndromic AVM

In 2018 Nikolayev and colleagues reported that they had identified somatic mutations of the KRAS gene in sporadic brain AVMs. A somatic mutation is one which occurs only in the tissue affected by the disease and therefore is not passed to the next generation necessarily. KRAS mutations were already well recognised in several cancers e.g. lung, pancreas and colorectal carcoinoma. Again the RAS/MAPK signal pathway is affected. These changes to that pathway seem to affect how the cells in the inner wall of the blood vessel (endothelial cells) develop and move but not how they proliferate. Therefore the growth of AVMs seems to arrest early in life.

There is a great deal yet to be learned about why AVMs develop in tissues and through understanding these processes it is hoped new treatments may emerge.