What is CARASIL?

Cerebral Small Vessel Disease (SVDs)
Cause and symptoms
HTRA1 Gene
Epidemiology
Diagnosis and treatment
References 
Further reading

CARASIL, or cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy is a rare genetic disorder following the autosomal recessive inheritance pattern. Maeda et al. in Japan were the first to describe CARASIL in 1976. CARASIL directly affects the cerebral small blood vessels and is caused by mutations in the HTRA1 gene.

Symptoms of CARASIL commonly appear in people between the ages of 20 and 30. Recurrent lacunar strokes or progressive decline of motor abilities, cognitive dysfunction, alopecia (premature baldness), and lumbago are the hallmarks of CARASIL. There is no specific treatment or cure for this condition; however, there are techniques to manage the symptoms.

​​​​​​​Image Credit: Rost9/Shutterstock.com

Cerebral Small Vessel Disease (SVDs)

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are two Mendelian variants of cerebral small vessel disease (SVD).

The acronyms merely denote a variation in inheritance mode—dominant vs. recessive. On the other hand, their gene abnormalities, clinical images, imaging results, and diseases differ to such an extent that clinicians are alerted. Radiologists and pathologists should be able to discriminate between these two SVD entities, with definitive diagnosis emerging from molecular genetic tests at the very latest.

CADASIL is autosomal dominantly inherited. Only a few cases with clear de novo mutations have been reported. NOTCH3 is the faulty gene on 19p13.1–13.2. Migraine with aura, ischemia episodes, cognitive decline and dementia, and psychiatric signs are the four cardinal manifestations. CADASIL is the most prevalent genetic vascular dementia, affecting people of all ethnic groups from the Far West to the Far East.

CARASAL (cathepsin A–related arteriopathy with strokes and leukoencephalopathy) is another SVD form. CARASAL is now a rare condition with little impact on neurologists' daily diagnostic work. More research on the frequency of CTSA mutations is needed to determine the prevalence of this illness.

Cause and symptoms

Mutations in the HTRA1 gene cause CARASIL. This gene codes for an enzyme found in various organs and tissues throughout the body.

Leukoencephalopathy, lumbago, and baldness are the three most common clinical manifestations of CARASIL.

To make a clinical diagnosis of CARASIL, recurrent ischemic strokes or progressive worsening in neurological functions, premature baldness, and backache owing to spondylosis deformans/disk herniation are required.

Premature baldness normally appears in the second decade, whereas clinical signs appear in the third to fourth decade. CARASIL causes white matter lesions that range from mild to severe. During the early stages of CARASIL, involvement of the external capsule with frontal dominating white matter lesions is common.

Early adulthood (20-30 years) onset of non-hypertensive cerebral small vessel disease (CSVD) (23 percent develop stroke before the age of 40 years), rapidly progressive disability in cognitive and motor domains, behavioral and mood changes such as easy irritability and apathy, in association with extra-neurological manifestations such as premature alopecia and spondylosis, are all distinctive features of the disease.

The disease proceeds slowly over five to 20 years after the onset of neurological symptoms. Diffuse leukoencephalopathy and numerous subcortical infarcts are visible on brain neuroimaging.

HTRA1 Gene

The HTRA1 enzyme regulates signaling by proteins in the transforming growth factor-beta (TGF-) family, which is one of its main functions. TGF signaling is required for a variety of cell functions. It's also necessary to develop new blood vessels (angiogenesis). Mutations in the HTRA1 gene hinder proper TGF-signaling regulation in persons with CARASIL.

The anatomy of small blood arteries, particularly in the brain, is thought to be altered by abnormally high TGF signaling, according to researchers. Arteriopathy is a term used to describe blood vessel abnormalities that raise the risk of stroke and contribute to the death of nerve cells (neurons) in numerous parts of the brain.

TGF signaling dysregulation may also contribute to hair loss and back discomfort in patients with CARASIL, though the link between aberrant TGF signaling and these symptoms is less obvious.

Epidemiology

CARASIL is a relatively rare disease. Only about 50 cases have been documented until recently, with the majority coming from Japan. Three cases have been reported from China, a couple from India, and one case each from Spain, Romania, and Turkey.

Diagnosis and treatment

Diffuse lesions in MRI and the clinical picture of premature baldness, low back pain, and neurological symptoms should alert the doctor, especially in Far Eastern nations, to explore CARASIL as a feasible, if rare, option. Of course, similar patients among relatives showing a genetic disease are a crucial lead.

The scarcity of CARASIL outside of Asia, of course, further complicates the challenge in those countries. As a result, an immediate molecular genetic study is required, with the demonstration of a pathogenic mutation in HTRA1 providing a definitive diagnosis. As previously stated, a skin biopsy is not an auxiliary approach, although it can aid in the differentiation between CARASIL and CADASIL.

There is currently no effective treatment for CARASIL, although there are ways to control the symptoms. The treatment includes non-CARASIL-related ischemic stroke prevention, genetic counseling, supportive care, and dementia drugs. The therapeutic roles of antithrombotic and anticoagulant medicines are largely unknown. Further investigations are required.

CARASIL's indications and symptoms progressively increase over time. Affected individuals lose their ability to control their emotions and communicate with others over several years.

They become increasingly reliant on others for personal care and other everyday activities, and after a few years, they cannot care for themselves. Although some persons with the condition have survived for 20 to 30 years, most of those affected die within a decade of the onset of signs and symptoms.

References

• Badachi, S., John, S. K., Sekhar, M., & Mathew, T. (2020). CARASIL; The Backache, Baldness, Brain Attack Syndrome: The Indian Scenario. Annals of Indian Academy of Neurology, 23(4), 559–561. https://doi.org/10.4103/aian.AIAN_31_20
• Nozaki, H., Kato, T., Nihonmatsu, M., Saito, Y., Mizuta, I., Noda, T., Koike, R., Miyazaki, K., Kaito, M., Ito, S., Makino, M., Koyama, A., Shiga, A., Uemura, M., Sekine, Y., Murakami, A., Moritani, S., Hara, K., Yokoseki, A., Kuwano, R., … Onodera, O. (2016). Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology, 86(21), 1964–1974. https://doi.org/10.1212/WNL.0000000000002694
• Haffner, C., & Vinters, H. V. (2016). CADASIL, CARASIL, CARASAL: The linguistic subtleties of cerebral small vessel disease. Neurology, 87(17), 1752–1753. https://doi.org/10.1212/WNL.0000000000003271
• Nozaki, H., Sekine, Y., Fukutake, T., Nishimoto, Y., Shimoe, Y., Shirata, A., Yanagawa, S., Hirayama, M., Tamura, M., Nishizawa, M., & Onodera, O. (2015). Characteristic features and progression of abnormalities on MRI for CARASIL. Neurology, 85(5), 459–463. https://doi.org/10.1212/WNL.0000000000001803
• Tikka, S., Baumann, M., Siitonen, M., Pasanen, P., Pöyhönen, M., Myllykangas, L., Viitanen, M., Fukutake, T., Cognat, E., Joutel, A., & Kalimo, H. (2014). CADASIL and CARASIL. Brain pathology (Zurich, Switzerland), 24(5), 525–544. https://doi.org/10.1111/bpa.12181
• Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. [Online] Medline plus. Available at: https://medlineplus.gov/genetics/condition/cerebral-autosomal-recessive-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy/
• Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/10424/cerebral-autosomal-recessive-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy

Further reading

• What is Charcot–Marie–Tooth Disease (CMT)?
• What is a Rare Disease?
• What is Buerger’s Disease?