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40 years!
Last updated:
7/31/2023
Years published: 2010, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Osamu Onodera, MD, PhD and Shoichiro Ando, MD, PhD, 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.
Classic CARASIL is a 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 changes in deep white matter in the brain (leukoaraiosis), 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 that includes difficulty with 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 abnorma.
(L)eukoencephalopathy – destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous system
Other characteristics of classic CARASIL include early sparse hair (alopecia) and degenerative changes in the spine (spondylolisthesis). Spondylolisthesis begins between 10 and 30 years, causing back pain and herniated discs in the cervical and lumbar areas. However, patients without these symptoms have also been reported.
Recently, certain changes (pathogenic variants or mutations) in the HTRA1 gene have been shown to cause cerebral small vessel disease (CSVD) even in people with only one gene variant (heterozygotes) and this is called HTRA1-related cerebral small vessel disease (or CARASIL 2). These patients have neurologic symptoms and small vessel disease similar to CARASIL, but the onset is often later, and symptoms such as alopecia and spondylolisthesis are not present.
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 problems with swallowing 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.
Individuals with only one pathogenic variant (mutation) in the HTRA1 gene can have neurological symptoms and small vessel damage similar to those of CARASIL. However, the onset tends to be later and symptoms such as alopecia and spondylosis are usually not present.
CARASIL is caused by changes (pathogenic variants or mutations) of the HTRA1 gene. CARASIL is inherited as an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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.
However, with variants in HTRA1, depending on the type, even carriers may exhibit symptoms. Symptoms in carriers are usually milder than in patients with classic CARASIL. When this is the case, the condition may follow autosomal dominant 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.
Classic CARASIL is extremely rare and is more common in Asians but has also been reported in Caucasian populations. Equal numbers of males and females are affected.
The incidence of classic CARASIL is unknown.
A rare HTRA1 gene variant (in the protease domain) has been reported in the UK biobank in 1 in 450 individuals. It is difficult to determine the frequency of HTRA1-related cerebral small vessel disease in the general population, but disease related to HTRA1 gene variants may be more common than initially thought.
CARASIL should be suspected in individuals with early onset changes in deep white matter in the brain (leukoaraiosis), alopecia in the teens or the twenties and acute lower back pain (lumbago) with spondylosis. However, some patients do not have these symptoms. Diagnosis of CARASIL is based on these characteristic symptoms, a detailed history, thorough clinical evaluation and a variety of tests, including special imaging techniques. Imaging may include magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to produce cross-sectional images of specific organs and body tissues, including the brain MRI can identify characteristic changes in the brain of CARASIL patients with CADASIL, including bilateral lesions in the anterior temporal regions, external capsule, and spinocerebellar tract CARASIL patients may have a characteristic change in the brainstem called the Ark sign.
The diagnosis of CARASIL can be confirmed by molecular genetic testing that identifies variants in the HTRA1 gene.
Treatment
There is no specific therapy for CARASIL. Treatment is directed toward the specific symptoms that are apparent in each individual.
Patients with one HTRA1 gene variant have an increased risk for cerebrovascular disease and should be treated appropriately.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Uemura M, Hatano Y, Nozaki H, Ando S, et al. High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease. Uemura J Neurol Neurosurg Psychiatry. 2022 Oct 19:jnnp-2022-329917.
Kato T, Manabe RI, Igarashi H, et al. Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model. J Clin Invest. 2021 Nov 15;131(22):e140555.
Uemura M, Nozaki H, Kato T, et al. HTRA1-related cerebral small vessel disease: a review of the literature. Front Neurol. 2020 Jul 3;11:545.
Cho BPH, Harshfield EL, Al-Thani M, et al. Association of vascular risk factors and genetic factors with penetrance of variants causing monogenic stroke. JAMA Neurol. 2022 Dec 1;79(12):1303-1311.
Malik R, Beaufort N, Frerich S, et al. Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Dichgans M. Brain. 2021 Oct 22;144(9):2670-2682.
Nozaki H, Kato T, Nihonmatsu M, et al. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology 2016, 24;86(21):1964-74.Nozaki H, Sekine Y, Fukutake T, et al. Characteristic features and progression of abnormalities on MRI for CARASIL. Neurology 2015;85:459-463.
Verdura E, Herve D, Scharrer E, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015;138:2347-2358.
Nozaki H, Nishizawa M, Onodera O. Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. Stroke 2014;45:3447-3453.
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.
Arima K, Yanagawa S, Ito N, Ikeda S. Cerebral arterial pathology of CADASIL and CARASIL (Maeda syndrome). Neuropathology. 2003;23:327-334.
Fukutake T, Hirayama K. Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension. Eur Neurol. 1995;35:69-79.
INTERNET
Onodera O, Nozaki H, Fukutake T. HTRA1 Disorder. 2010 Apr 27 [Updated 2019 Nov 7]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK32533/ Accessed July 26, 2023.
McKusick VA. CARASIL. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:600142. Updated 08/31/2022. Available from: https://omim.org/entry/600142 Accessed July 26, 2023.
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