Introduction

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) are both extremely rare hereditary genetic disorders, belonging to the cerebral small vessel disease family.² These types of disorders affect arterioles and capillaries in the brain, leading to neurological defects. Simply put, CARASIL and CADASIL are cerebral, autosomal dominant (in the case of CADASIL) and recessive (in the case of CARASIL) diseases which affect the small arteries and arterioles. This occurs within the subcortical region of the brain, responsible for higher functioning, leading to infarcts or tissue loss in the brain caused by a lack of oxygen to the brain when blood flow in arterioles is blocked. Deprivation of these tissues of oxygen can lead to the degradation of the myelin sheath, which insulates and protects the axons and nerves of the central nervous system.⁴ Thus, patients affected by CADASIL or CARASIL often present with symptoms including muscle spasticity, strokes and speech disorders or slurred speech. Dementia and changes in gait can also develop. While CADASIL and CARASIL share similar features in terms of what tissues or regions of the body they affect, their symptoms, and classification, they are markedly different in their diagnosis, clinical presentation, treatments, and origin. Accurate differentiation between the two disorders is essential for proper clinical management and genetic counselling, as well as guiding effective research into targeted therapies. Here, we look into what exactly CARASIL and CADASIL are, how they differ, and what distinctions clinicians, radiologists, and geneticists should recognise when diagnosing suspected patients.

Differences in genetics and inheritance 

As seen from the acronyms, CARASIL and CADASIL differ only by the terms recessive vs dominant, indicating their mode of inheritance. The dominantly inherited CADASIL is caused by mutations in the NOTCH3 gene, which encodes a receptor expressed in the smooth muscle cells that line arteries and arterioles². Mutations in this gene lead to the progressive degeneration of such smooth muscle cells and fibrosis of arterioles in cerebral white matter. Due to its autosomal dominant manner of inheritance, a single copy of the mutated gene is sufficient to cause disease. CARASIL, on the other hand, is recessively inherited, making it much more rare than CADADSIL as both alleles must be affected in order for the disease to manifest. Mutations in the HTRA1 gene can result in lower concentrations of HTRA1, which acts as a repressor of TGF-β signalling.¹ This can lead to the alteration of the structure of small blood vessels in the brain, which increases the susceptibility to stroke and, similar to CADASIL, results in arteriopathy and white matter degeneration. The autosomal dominant nature of CADASIL implies a strong family history of affected patients, whilst CARASIL likely arises sporadically or in families with known consanguinity.

Epidemiology and demographics

Once CADASIL and CARASIL genetic defects were established and specialists became aware of these disorders, the number of both reported and diagnosed cases increased rapidly. CADASIL is the most common hereditary vascular dementia, with 2 to 5 per 100,000 individuals being affected. It has been reported across all ethnicities from the Far West to the East, although its prevalence may be varied due to misdiagnosis or underdiagnosis⁶. On the other hand, CARASIL is extremely rare, with under 100 cases being reported worldwide, and most cases being predominantly described in East Asian populations. The reason for this prevalence pattern in CARASIL remains unclear.⁷ 

In terms of their age of onset, CADASIL typically presents between the ages of 30 and 50, with the mean age of onset of ischemic strokes being approximately 46 years. The clinical course of CADASIL is variable even among individuals with the same mutation. The pace of deterioration may vary widely, and in some cases, life expectancy may be reduced by approximately 10-20 years. Individuals with CARASIL, however, may experience symptoms such as spondylosis and alopecia beginning in their teens. Neurological abnormalities may further present from ages 20 to 40, with symptoms worsening over time. Thus, CARASIL overall has a lower age of onset and often a short prognosis, with most patients living only 10 years past system onset. 

Pathogenesis and clinical presentation

As mentioned, CADASIL is caused by a defective NOTCH3 gene, which can lead to significant morphological changes. Some of these include vascular alterations, where stenosis of affected arteries is often seen, as well as thickening and fibrosis of arterioles. Patients with CADASIL also present a breached blood-brain barrier and various alterations in myelinated tissues.² In contrast, CARASIL, caused by a faulty HTRA1 gene, leads to a reduced amount of the protein that is encoded by this gene, which usually suppresses TGF-β activity (a growth factor involved in many signalling pathways). Reduced HTRA1 levels lead to an increase in TGF-β activity, resulting in the tunica media of affected arterioles.¹ These pathological conditions result in markedly distinct differences in patients affected by CADASIL vs CARASIL. In CADASIL, these include migraines, which are often a hallmark early symptom, accompanied by seizures, psychiatric disturbances such as mood disorders, but no systemic manifestations outside of the nervous system. In CARASIL, these include limb spasticity, slurred speech, patchy hair loss and spondyloarthropathy (inflammation of the spine) and dysarthria, otherwise known as a speech sound disorder. Overlap in symptoms between the two diseases includes neurological symptoms such as forgetfulness or dementia, mood changes and confusion.

Diagnostic approach 

For both CARASIL and CADASIL, diagnosis of these conditions begins with a physical examination and review of the patient’s medical history and symptoms. Positive diagnosis can only be confirmed by genetic testing to make sure that the specific mutations characteristic of each disease are present within the affected genome. Magnetic resonance imaging (MRI) can also be used to help medical professionals look for areas of the brain which resemble stroke conditions and help determine if neurological deterioration has occurred. This can be identified by white matter lesions, which are usually concentrated around the basal ganglia, peri-ventricular white matter and the pons within the brain. So far, both CADASIL and CARASIL use similar imaging tests and approaches to scan for symptoms. Interestingly, as mentioned, the number of cases of CARASIL is far fewer than CADASIL, and it is suspected that one of the reasons for this is due to its similarities with other neurological disorders. 

Management and treatment 

Neither CADASIL nor CARASIL have specific available treatments, with drugs being mainly used to target symptoms similar to those that affect patients without either of these diseases. Antiplatelet agents such as aspirin or clopidogrel can be used for CADASIL patients to help prevent strokes and control high blood pressure. L-arginine has also been proposed as a potential therapy for CADASIL. For CARASIL, most often, a combination of supportive care and medications to prevent the occurrence of stroke is taken, alongside medications which can be used to treat specific symptoms of the disease, such as baclofen, which may be used to treat limb spasticity. 

FAQ’s

Are vascular risk factors relevant in CADASIL and CARASIL?

Both diseases are genetic and caused by mutations in different genes that lead to disease pathogenesis, but risk factors such as hypertension, smoking and hyperlipidemia may accelerate disease progression, particularly in CADASIL. Risk factor control is thus still recommended.

What are the key considerations for prognosis and long-term care?

Typically, CADASIL has a more variable course, with some patients living into late adulthood with mild symptoms, while others may present with early disability. CARASIL, on the other hand, shows rapid progression, with severe motor and cognitive deterioration by mid-adulthood. Long-term care planning and support are essential for both. 

How early should family members be screened?

In families with CADASIL, predictive genetic testing is possible but should be preceded by genetic counselling. CARASIL is rarer and is typically seen in consanguineous families, so siblings of affected individuals should be offered testing if appropriate.

Are there treatments that modify disease progression?

Unfortunately, no disease-modifying therapies exist for either condition. Treatment is supportive and symptomatic, focusing on preventing more severe symptoms such as stroke and limb spasticity through pharmaceutical drugs and rehabilitation, respectively. 

Summary

CARASIL and CADASIL are both rare hereditary cerebral small vessel diseases that affect the brain's arterioles, leading to strokes, cognitive decline, and neurological symptoms. However, they differ significantly in their genetics, clinical features, and progression:

• CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an autosomal dominant, caused by mutations in the NOTCH3 gene and typically presents between the ages of 30–50. It is more common, with global prevalence, and often features migraines, psychiatric symptoms, and no systemic signs
• CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is autosomal recessive, linked to HTRA1 mutations, and presents earlier (often in teens or 20s) with systemic symptoms like hair loss, spine inflammation (spondylosis), and more rapid neurological decline. It is much rarer and mainly reported in East Asian populations

Diagnosis relies on genetic testing and MRI imaging of white matter lesions. No disease-specific treatments exist; management is symptomatic, focusing on stroke prevention, spasticity control, and supportive care. Understanding their differences is critical for accurate diagnosis, prognosis, and genetic counselling.