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Copyright 2010, 2013
NORD is very grateful to 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 beginning ages between 20 and 30 year. Pseudobulbar palsy is a group of neurologic symptoms including difficult chewing, swallowing and speech. Eventually, cognitive impairment and dementia may result. About half of cases have a stroke-like episode. The age of onset is 20 to 50 years old. CARASIL is an acronym that stands for:
(C)erebral - relating to the brain or the cerebellum, which the 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 cerebellum 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, even among members of the same family. Onset of the disorder is usually in early adulthood, but may range from the teen-aged years 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, involuntary muscle spasms that result in slow, 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). In most cases, 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 patchy areas of the hair loss (alopecia) and degenerative inflammation of the spinal column (spondylosis). Spondylosis begins between 10 to 30 years and causes back pain and a herniated disc in 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 the same abnormal gene for the same trait from each parent. If an individual receives 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
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.
Some cases of CARASIL have had parents who were related by blood (consanguineous). 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.
CARASIL is an extremely rare disorder that has bee mainly described in the Japanese medical literature, but also reported in Caucasian population. More males have been reported with the disorder than females. The exact incidence of CARASIL is unknown. Some researchers believe that cases of CARASIL often goes undiagnosed or misdiagnosed, making it difficult to determine the disorders true frequency in the general population.
Symptoms of the following disorders can be similar to those of CARASIL. Comparisons may be useful for a differential diagnosis.
Binswanger's disease is a progressive neurological disorder characterized by atherosclerotic blood vessels supplying the white-matter and deep structures of the brain (basal ganglia and thalamus). Most patients experience progressive memory loss and deterioration of intellectual abilities (dementia), urinary urgency or incontinence, and an abnormally slow, shuffling, unsteady pattern of walking, usually over a 5-10 year period. Due to their vascular etiology, the symptoms and physical findings associated with Binswanger's disease may suddenly worsen due to stroke, stabilize and then improve for a brief time, but the patient’s overall condition continues to progress as the blood vessels become increasingly obstructed. (For more information on this disorder, choose "Bingswanger’s disease" as your search term in the Rare Disease Database.)
Multiple sclerosis is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal chord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly at multiple sites and vary in intensity. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches affects the nerve’s ability to transmit information (neurotransmission) and causes a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves, (axons), in addition to the myelin sheaths, are affected by the neuroimmunologic attacks. Damage to the nerve cells may be irreversible. As a result, clinicians recommend early intervention with one of the disease-modifying agents (see below). (For more information on this disorder, choose "multiple sclerosis" as your search term in the Rare Disease Database.)
A variety of rare genetic disorders may have symptoms similar to those found in CARASIL. These disorders include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukodystrophy (CADASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and some of the leukodystrophies, which are a rare group of progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
CARASIL should be suspected in individuals with early-onset leukoaraiosis, alopecia in the teens, and 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 in the brains of individuals with CARASIL. However, such changes are not unique to CARASIL and can occur with other disorders.
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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Nishimoto Y, Shibata M, et al. A novel mutation in the HTRA1 gene causes CARASIL without alopecia. Neurology. 2011 Apr 12;76(15):1353-5
Mendioroz M, Fernández-Cadenas I, et al. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology. 2010 Nov 30;75(22):2033-5.
Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009;360:1729-1739.
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Report last updated: 2013/02/20 00:00:00 GMT+0