NORD gratefully acknowledges Osamu Onodera, MD, PhD, Professor of Department of Molecular Neuroscience, Resource Branch for Brain Disease, Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Japan, for assistance in the preparation of this report.
CARASIL is an extremely rare genetic disorder that is characterized by damage to the small blood vessels in the brain. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or leukoaraiosis (changes in deep white matter in the brain, which are observed on MRI or CT). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs, and pseudobulbar palsy. Pseudobulbar palsy is a group of neurologic symptoms including difficult chewing, swallowing and speech. Eventually, gait disturbance and dementia may result. About a third of patients have stroke-like episodes. The age of onset is between 20 to 50 years old. CARASIL is an acronym that stands for:
(C)erebral - relating to the brain or the cerebellum, which is part of the brain that controls balance and muscular coordination.
(A)utosomal (R)ecessive - a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder.
(A)rteriopathy - disease of the small arteries (blood vessels that carry blood away from the heart).
(S)ubcortical - relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory).
(I)nfarcts - tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal.
(L)eukoencephalopathy - destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous system.
The cerebral symptoms of CARASIL are caused by damage to cerebral small blood vessels. The specific symptoms and severity of the disorder can vary greatly among affected individuals. Onset of the disorder is usually in early adulthood, but may range from the early 20s to the mid-40s. CARASIL is often rapidly progressive.
Damage to the small blood vessels of the brain and reduce or cut off blood flow to the brain (stroke). Reduced blood flow to the brain can cause damage to brain tissue, which may cause a variety of different symptoms. Symptoms that may occur in individuals with CARASIL include increasing muscle tone, slurred speech, stiff movements of the legs (spasticity), gait disturbances, loss of bladder control (urinary incontinence), and impairment of swallowing due to the bilateral problem in pyramidal tract (pseudobulbar palsy). Most affected individuals experience progressive brain damage, especially to the white matter, which is the portion of the brain that contains myelinated nerve fibers. Eventually the disorder causes cognitive impairment, which may include memory problems, difficulties making decisions or solving problems, speech difficulties, deficits in attention span and general loss of interest (apathy). Continued cognitive decline ultimately results in dementia. Dementia is defined as the progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.
Additional important symptoms that have been associated with CARASIL include sparse hair (alopecia) and degenerative change of the spinal column (spondylosis). Spondylosis begins between 10 to 30 years and causes back pain and a herniated disc in the cervical and the lumbar region. Although alopecia occurs in most cases and develops before the onset of neurological symptoms, some cases without alopecia have been reported.
CARASIL is caused by mutations of the HTRA1 gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Investigators have determined that the HTRA1 gene is located on the long arm (q) of chromosome 10 (10q25.3-q26.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 25q25.3-q26.2” refers to bands 25.3-26.2 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
A subtype of CARASIL, or a condition similar to CARASIL, may follow autosomal dominant inheritance. Affected individuals have only one HTRA1 gene mutation and this mutation decreases the function of the normal HTRA1 gene inherited from the other parent. This condition might be more common than the classic type of CARASIL that follows autosomal recessive inheritance.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. In some individuals, the disorder is due to spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
CARASIL is an extremely rare disorder that has been mainly described in the Japanese medical literature, but also reported in Chinese and Caucasian populations. Gender disparity has not been determined. The exact incidence of CARASIL is unknown. Some researchers believe that CARASIL often goes undiagnosed or misdiagnosed, making it difficult to determine the true frequency of this condition in the general population.
CARASIL should be suspected in individuals with early-onset leukoaraiosis, alopecia in the teens or the twenties, and acute lumbago with spondylosis. However, it has been proofed that the alopecia has not been observed in several cases and spondylosis is common in elderly. A diagnosis of CARASIL is made based upon identification of these characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of tests including specialized imaging techniques. Imaging techniques may include magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. An MRI can identify characteristic changes, such as bilateral lesion in the anterior temporal regions, in the external capsules and in the pontocerebellar tract in the brains of individuals with CARASIL.
A diagnosis of CARASIL can be confirmed through molecular genetic testing, which identifies characteristic mutations of the HTRA1 gene.
There is no specific therapy for CARASIL. Treatment is directed toward the specific symptoms that are apparent in each individual. Supportive care including emotional support, practical assistance and genetic counseling may be of benefit for affected individuals and their families.
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