Overview
Embarking on an exploration of CARASIL, a rare genetic condition impacting brain wellness, let's delve into its intricacies. CARASIL (cerebral autosomal recessive arteriopathy w/subcortical infarcts and leukoencephalopathy) is a genetic disorder that adversely affects small blood vessels in the brain. It is marked by progressive damage to these vessels, resulting in various neurological symptoms and impairments. Typically emerging in early adulthood, between the ages of 20 and 50, CARASIL exhibits a slight male predominance. It can lead to strokes even in the absence of heart risk factors, with symptoms stemming from damaged vessels affecting movement, speech, and thinking.
The acronym CARASIL encapsulates its defining characteristics:
- (C)cerebral pertains to the brain and balance.
- (A)autosomal (R)recessive signifies both parents passing on an abnormal gene
- (R)recessive means both parents pass on an abnormal gene.
- (A)arteriopathy denotes small artery disease.
- (S)subcortical affects deep brain areas.
- (I)infarcts refer to brain tissue loss due to blocked blood flow.
- (L)leukoencephalopathy harms nerve fibres’ protection.
Classic CARASIL is accompanied by hair loss and spine issues, while CARASIL 2, linked to HTRA1 gene changes, presents with similar problems, though symptoms may appear later and differ.1
Understanding the family of small vessel diseases linked to CARASIL
CARASIL represents the second type of Cerebral small-vessel disease (SVD), affecting tiny blood vessels in the brain and causing strokes and memory loss.2 The first type known is CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy). Both CARASIL and CADASIL are genetic blood vessel disorders passed down in families. Another related disorder is CARASAL (Cathepsin A-related Arteriopathy with Strokes and Leukoencephalopathy - Autosomal Dominant), which leads to strokes, hard-to-treat high blood pressure, and hearing loss in the middle-frequency range.3
CADASIL is autosomal dominant, requiring one affected gene from one parent for the disorder, while CARASIL is autosomal recessive, needing two affected genes (one from each parent). CARASAL is autosomal dominant with distinct symptoms like resistant hypertension and brainstem problems. The genetic causes are on different chromosomes.3
Causes of CARASIL
The HTRA1 (high-temperature requirement A serine peptidase 1) disorder shows different levels of symptoms. Some individuals may have few or no problems, while others experience severe CARASIL symptoms. Classic CARASIL results from gene issues from both parents, leading to early brain changes and issues like trouble walking. For those with a milder form, known as HTRA1-CSVD (HTRA1 – cerebral small vessel disease), symptoms usually begin with slow problems in walking after 40, followed by mood changes and thinking problems. Genetic testing can reveal changes in the HTRA1 gene. Some individuals have very few or no problems, while others have more severe CARASIL symptoms. People with one problematic HTRA1 gene might have mild brain issues seen on brain scans or mild-to-okay brain symptoms. "Classic CARASIL" is the name for the stronger symptoms caused by gene issues from both parents, while "HTRA1 cerebral small vessel disease" is a milder form from one problematic gene.4
Classic CARASIL means early brain changes appear on brain scans and cause issues like trouble walking. It starts around 20 to 40 years old. Almost half might have stroke-like events before 40. Changes in mood, trouble with speech and thinking, and hair loss happen between 20 to 50 years old. The condition slowly gets worse after these symptoms begin. Early baldness and strong pain in the lower back before 30 are expected.
For people with milder HTRA1-CSVD (HTRA1 – cerebral small vessel disease), the first symptom is usually slow problems with walking after 40. This might be followed by mood changes and thinking problems. Many might have a stroke-like event after 40. Only a few with HTRA1-CSVD have spine issues and hair loss.4
Signs and symptoms of CARASIL
CARASIL damages tiny blood vessels in the brain, causing different symptoms. Symptoms vary among people and can start in early adulthood (20s to 40s).
Symptoms include:
- Muscle stiffness
- Speech problems
- Walking difficulty
- Memory loss.
- Brain damage happens, especially in the white matter part, leading to cognitive problems and dementia.
- Other signs are early hair loss and spine issues causing back pain.
The milder form affects people with one problematic gene but starts later and lacks certain symptoms. People with the problematic HTRA1 gene might have brain and blood vessel issues like CARASIL, but it usually starts later and doesn't cause hair loss or spine problems.
Diagnostic methods and differential diagnosis
- CARASIL should be suspected in individuals with Gradual dementia, Mood changes (apathy, irritability), and Progressive spastic gait.3
- Finding out if someone has CARASIL involves looking at their symptoms and brain images from MRI (magnetic resonance imaging) scans. Changes in the brain of patients with CADASIL mustn’t be misdiagnosed as CARASIL. Images from CADASIL often show small, damaged areas in certain brain parts. These images also show issues in the white matter, which is deep inside the brain.4
- Even though they're inherited differently, the symptoms of CADASIL and CARASIL are very much alike, but in CADASIL, strokes usually happen later in life (around age 45), while migraines with visual disturbances tend to occur about 10 years earlier.
- Molecular genetic testing methods use different approaches to test for genes that are involved. Some of the methods are gene-targeted testing and comprehensive genomic testing.
- To be sure, genetic tests can check for changes in the HTRA1 gene, but doctors need to be careful because other illnesses can seem like CARASIL. These include problems like brain inflammation, certain diseases that affect the white matter, and other conditions with similar brain changes. It's important to tell these apart to make sure the right treatment is given.4
Management and prognosis
Currently, there's no cure for CARASIL, but symptoms can be managed to improve the quality of life. Tools like canes or wheelchairs may be used to prevent falls, and medications can alleviate muscle stiffness and behavioural changes. Hair loss can be managed with hairpieces or wigs. Lifestyle changes, including avoiding excessive salt and smoking, are recommended. While CARASIL typically lasts around 10 years, some individuals may live with it for 20 to 30 years. Seeking help for both the person with CARASIL and their family is essential to cope with the challenges it presents.4
Epidemiology and genetic counselling
CARASIL is extremely rare, with confirmed cases mostly reported in Japan and a few in Spain and China. Genetic counsellors play a crucial role in advising families with known gene problems, explaining the condition's potential transmission to children and providing essential information.4
FAQs
What are the other names for CARASIL?
- Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
- Nemoto disease
- Maeda syndrome
- CADASIL2 (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2).4
How common is CARASIL?
Currently, over 50 people with symptoms from HTRA1 mutations have been documented, with most cases found in Japan and China. The parents of those with CARASIL often show no signs of the condition.4
Are there diseases with similar symptoms as CARASIL?
Yes, disorders like Binswanger’s disease, multiple sclerosis (MS), CADASIL, MELAS, Fabry disease, and certain leukodystrophies share symptoms with CARASIL. Comparing these disorders aids in distinguishing them.
- Binswanger’s disease is a brain disorder caused by clogged blood vessels. It leads to memory loss, trouble thinking, walking difficulties, and urinary issues. Symptoms can get worse suddenly due to strokes and gradually worsen over time.
- Multiple sclerosis (MS) is a long-lasting nervous system disorder. It damages the protective covering of nerves in the brain and spinal cord. MS can cause various symptoms that vary in intensity and location. People with MS can have attacks, get worse over time, or stabilize.
Some rare genetic disorders also have symptoms like CARASIL. These include CADASIL, MELAS, Fabry disease, and certain leukodystrophies. These disorders affect the brain, spinal cord, and nerves.
Can CARASIL be inherited?
Yes, CARASIL is a rare hereditary form of cerebral small-vessel disease (SVD).2
Summary
CARASIL, a rare genetic disorder affecting brain blood vessels, presents with diverse symptoms and challenges. With no current cure, management focuses on improving the individual’s quality of life. Although extremely rare, it’s crucial to distinguish CARASIL from similar conditions for accurate diagnosis and treatment. Genetic counselling is valuable for families with known gene problems, offering insights into potential transmissions and essential information. The disorder remains an area of ongoing medical research to enhance understanding and develop effective treatments.
References
- CARASIL-Symptoms,Causes, Treatment | NORD. Available from: https://rarediseases.org/rare-diseases/carasil/. Accessed 12 Dec. 2023.
- Ohta K, Ozawa T, Fujinaka H, Goto K, Nakajima T. Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1. Intern Med. 2020 May 15;59(10):1309–13. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303461/.
- Badachi S, John SK, Sekhar M, Mathew T. CARASIL; The Backache, Baldness, Brain Attack Syndrome: The Indian Scenario. Ann Indian Acad Neurol. 2020;23(4):559–61. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657304/.
- Onodera O, Nozaki H, Fukutake T. HTRA1 Disorder. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Aug 31]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK32533/.