Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CARASIL, is an inherited condition that causes stroke and other impairments.

Abnormalities affecting the brain and other parts of the nervous system become apparent in an affected person's twenties or thirties. Often, muscle stiffness (spasticity) in the legs and problems with walking are the first signs of the disorder. About half of affected individuals have a stroke or similar episode before age 40. As the disease progresses, most people with CARASIL also develop mood and personality changes, a decline in thinking ability (dementia), memory loss, and worsening problems with movement.

Other characteristic features of CARASIL include premature hair loss (alopecia) and attacks of low back pain. The hair loss often begins during adolescence and is limited to the scalp. Back pain, which develops in early to mid-adulthood, results from the breakdown (degeneration) of the discs that separate the bones of the spine (vertebrae) from one another.

The signs and symptoms of CARASIL worsen slowly with time. Over the course of several years, affected individuals become less able to control their emotions and communicate with others. They increasingly require help with personal care and other activities of daily living; after a few years, they become unable to care for themselves. Most affected individuals die within a decade after signs and symptoms first appear, although few people with the disease have survived for 20 to 30 years.

CARASIL is caused by mutations in the HTRA1 gene. This gene provides instructions for making an enzyme that is found in many of the body's organs and tissues. One of the major functions of the HTRA1 enzyme is to regulate signaling by proteins in the transforming growth factor-beta (TGF-β) family. TGF-β signaling is essential for many critical cell functions. It also plays an important role in the formation of new blood vessels (angiogenesis).

In people with CARASIL, mutations in the HTRA1 gene prevent the effective regulation of TGF-β signaling. Researchers suspect that abnormally increased TGF-β signaling alters the structure of small blood vessels, particularly in the brain. These blood vessel abnormalities (described as arteriopathy) greatly increase the risk of stroke and lead to the death of nerve cells (neurons) in many areas of the brain. Dysregulation of TGF-β signaling may also underlie the hair loss and back pain seen in people with CARASIL, although the relationship between abnormal TGF-β signaling and these features is less clear.

Normal Function

The HTRA1 gene provides instructions for making a protein that is found in many of the body's organs and tissues. This protein is a type of enzyme called a serine protease, which has an active center that cuts (cleaves) other proteins into smaller pieces. The HTRA1 enzyme helps break down many other kinds of proteins in the space surrounding cells (the extracellular matrix).

The HTRA1 enzyme also attaches (binds) to proteins in the transforming growth factor-beta (TGF-β) family and slows down (inhibits) their ability to send chemical signals. TGF-β proteins normally help control many critical cell functions, including the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). TGF-β signaling also plays an important role in the formation of new blood vessels (angiogenesis).

Researchers have proposed several additional functions for the HTRA1 enzyme. It may play a role in the stabilization of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (cytoskeleton). Additionally, the HTRA1 enzyme may be involved in depositing minerals, such as calcium and phosphorus, in developing bone (mineralization). Studies have also suggested that the HTRA1 enzyme acts as a tumor suppressor, a protein that helps prevent the development of cancerous tumors by keeping cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

At least four mutations in the HTRA1 gene have been found to cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CARASIL. This condition is characterized by a highly increased risk of stroke, deterioration of cognitive function (dementia), premature hair loss (alopecia), and attacks of low back pain. These signs and symptoms usually become apparent in early to mid-adulthood.

The HTRA1 gene mutations responsible for CARASIL reduce or eliminate the function of the HTRA1 enzyme. As a result, the enzyme is not available to inhibit signaling by TGF-β proteins. Researchers suspect that abnormally increased TGF-β signaling alters the structure of small blood vessels, particularly in the brain. These blood vessel abnormalities increase the risk of stroke and lead to the death of nerve cells (neurons) in many areas of the brain. Dysregulation of TGF-β signaling may also underlie the hair loss and back pain seen in people with CARASIL, although the relationship between abnormal TGF-β signaling and these features is less clear.

Age-related macular degeneration

The HTRA1 gene is located on the long (q) arm of chromosome 10 in a region known as 10q26. This region has been strongly associated with the risk of developing age-related macular degeneration, a common cause of vision loss in older adults. Researchers have identified several variations (polymorphisms) in the HTRA1 gene that may explain the association between the 10q26 region and age-related macular degeneration. One of the variants, known as rs11200638, is found in an area of the gene called the promoter region, which starts the production of the HTRA1 enzyme.

It is unclear how a polymorphism in the HTRA1 gene might be related to age-related macular degeneration. In the 10q26 region, the HTRA1 gene is located next to a gene called ARMS2; changes in this gene have also been studied as a risk factor for the disease. Because the two genes are so close together, it is difficult to tell whether changes in one gene or the other, or possibly changes in both genes, account for the increased disease risk. Age-related macular degeneration is a complex condition that likely results from a combination of multiple genetic and environmental factors.

Cancers

The HTRA1 gene is less active (downregulated) in some cancerous tumors than in normal cells. Studies have found this gene downregulation in several forms of cancer, including ovarian cancer, cancer that occurs in the lining of the uterus (endometrial cancer), a form of skin cancer called melanoma, and a form of liver cancer called hepatocellular carcinoma. Having reduced amounts of the HTRA1 enzyme may be related to tumor progression, the risk that cancer will spread (metastasize) to other parts of the body, and resistance to treatment with chemotherapy. However, the mechanism by which downregulation of the HTRA1 gene influences cancer development and growth is unknown.

Other Names for This Gene

• ARMD7
• HtrA
• HTRA1_HUMAN
• IGFBP5-protease
• L56
• ORF480
• protease, serine, 11 (IGF binding)
• PRSS11
• serine protease HTRA1

Genomic Location

As its name suggests, this condition is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

CARASIL appears to be a rare condition. It has been identified in about 50 people, primarily in Japan and China.