Familial porencephaly is part of a group of conditions called the COL4A1-related disorders. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. In familial porencephaly, fluid-filled cysts develop in the brain (porencephaly) during fetal development or soon after birth. These cysts typically occur in only one side of the brain and vary in size. The cysts are thought to be the result of bleeding within the brain (hemorrhagic stroke). People with this condition also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI).

During infancy, people with familial porencephaly typically have paralysis affecting one side of the body (infantile hemiplegia). Affected individuals may also have recurrent seizures (epilepsy), migraine headaches, speech problems, intellectual disability, and uncontrolled muscle tensing (dystonia). Some people are severely affected, and others may have no symptoms related to the brain cysts.

Mutations in the COL4A1 gene cause familial porencephaly. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Type IV collagen molecules attach to each other to form complex protein networks. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature).

The COL4A1 gene mutations that cause familial porencephaly result in the production of a protein that disrupts the structure of type IV collagen. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Basement membranes without normal type IV collagen are unstable, leading to weakening of the tissues that they surround. In people with familial porencephaly, the vasculature in the brain weakens, which can lead to blood vessel breakage and hemorrhagic stroke. Bleeding within the brain is followed by the formation of fluid-filled cysts characteristic of this condition. It is thought that the pressure and stress on the head during birth contributes to vessel breakage in people with this condition; however in some individuals, bleeding in the brain can occur before birth.

Normal Function

The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many tissues throughout the body. Specifically, this gene makes the alpha1(IV) chain of type IV collagen. This chain combines with another alpha1 chain and a different type of alpha (IV) chain called alpha2 to make a complete type IV collagen alpha1-1-2 molecule. Type IV collagen molecules attach to each other to form complex protein networks. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Type IV collagen alpha1-1-2 networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). The type IV collagen network helps the basement membranes interact with nearby cells, playing a role in cell movement (migration), cell growth and division (proliferation), cell maturation (differentiation), and the survival of cells.

Health Conditions Related to Genetic Changes

COL4A1-related brain small-vessel disease

Mutations in the COL4A1 gene have been found to cause COL4A1-related brain small-vessel disease. This condition is part of a group of conditions called COL4A1-related disorders that have overlapping signs and symptoms involving fragile blood vessels. COL4A1-related brain small-vessel disease is characterized by stroke and eye abnormalities. Most of the identified COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease change one of the protein building blocks (amino acids) used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly, which causes the tissues they support to weaken. Blood vessels throughout the body become fragile, leading to the signs and symptoms of COL4A1-related brain small-vessel disease.

It is unclear how mutations in the COL4A1 gene can lead to different disorders. It is likely that mutations in different regions of this gene play a role in the development of the various signs and symptoms of the COL4A1-related disorders. Other genetic changes as well as environmental factors may also contribute to the features of the different COL4A1-related disorders.

Familial porencephaly

Mutations in the COL4A1 gene have been found to cause familial porencephaly, another member of the group of vascular conditions called COL4A1-related disorders. Familial porencephaly is characterized by early stroke and brain cysts. Most of the identified COL4A1 gene mutations that cause familial porencephaly change one of the amino acids used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly, which causes the tissues they support to weaken. Blood vessels in the brain become fragile, leading to the signs and symptoms of familial porencephaly.

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome

Mutations in the COL4A1 gene have been found to cause hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome, a third member of the group of conditions called COL4A1-related disorders. HANAC syndrome is characterized by weakened blood vessels in the brain and throughout the body, kidney disease, muscle cramps, and eye abnormalities. Most of the identified COL4A1 gene mutations that cause HANAC syndrome change one of the amino acids used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly. As a result, the tissues they support weaken, particularly in the eyes and kidneys. Fragile blood vessels and weakened basement membranes lead to the signs and symptoms of HANAC syndrome.

Other Names for This Gene

• arresten
• CO4A1_HUMAN
• COL4A1 NC1 domain
• collagen alpha-1(IV) chain
• collagen alpha-1(IV) chain preproprotein
• collagen IV, alpha-1 polypeptide
• collagen of basement membrane, alpha-1 chain
• collagen type IV alpha 1
• collagen, type IV, alpha 1

Genomic Location

Familial porencephaly is a rare condition, although the exact prevalence is unknown. At least eight affected families have been described in the scientific literature.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.