Introduction

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a genetic disorder that deteriorates the brain and spinal cord, thereby producing abnormalities in the nervous system. Approximately 50 cases of CARASIL have been reported in the literature.¹ The clinical manifestations of CARASIL, microscopic histopathological findings, and macroscopic histological analysis as a result of genetic mutations in the HTRA1 (high-temperature requirement serine peptidase A1) gene at the level of the brain and spinal cord have been illustrated in multiple research works.¹

Pathogenesis of CARASIL at a molecular level

How does CARASIL occur?

It is caused by the homozygous or heterozygous missense mutations in the HTRA1 gene, which is present on chromosome 10 (10q26).² This gene is translated into the HTRA1 enzyme, which regulates the transforming growth factor-beta (TGF-β) pathway, crucial in different cell functions like angiogenesis, scar healing, immune system regulation, apoptosis, bone growth, and tissue integrity.²

How is the HTRA1 protein involved in CARASIL?

Primarily, the HTRA1 protein negatively regulates TGF-β receptors, such as TβRII and TβRIII, which are present on the cell surface. The balance between HTRA1 and TβRII or TβRIII is crucial for the normal physiology of cells. If there is any disruption in levels of TGF-β receptors and HTRA1 protein, cellular pathogenesis and subsequent disease may occur. For example, when the HTRA1 gene undergoes a missense mutation, it will not degrade cell surface TGF-β receptors. As a result, there will be a greater concentration of such receptors and activation of TβRII and TβRIII receptors will increase, leading to an uncontrolled downstream signalling mechanism of the cell.³

Normal physiological function of TGF-β

Usually, TGF-β is typically stored in the extracellular matrix (ECM) in an inactive form, bound to latent TGF-β binding proteins (LTBPs). To exert its biological effects, TGF-β must first be activated and released from the ECM in response to specific stimuli. This includes:⁴

• Mechanical forces for conformational changes within the ECM of the cell, which can be done by integrins
• Reactive oxygen species (ROX) or pH value less than 7.0
• Proteolytic cleavage of large latency-associated peptide (LAP) through matrix metalloproteinases (MMP-2, MMP-9) or plasmin

After the activation, TGF-β will bind to receptors like TβRII and TβRIII and initiate signal transduction pathways, like the canonical one and the non-SMAD (Suppressor of Mothers against Decapentaplegic).⁴ These downstream signals will lead to nuclear translocation and resultant transcription of multiple genes, like:^5,6,7

• Alpha-smooth muscle actin (ACTA2) for motility
• Fibronectin (FN1) and collagens for ECM
• Activator protein-1 (AP-1 family) members, such as JUN, JUNB, FOSL1
• Regulators of epithelial-mesenchymal transition (EMT)—ZEB1, SNAI1, and MYC, for cellular proliferation and modulation
• Growth factor receptors, such as GFBR1 and TGFBR2
• SMAD ubiquitination regulatory factors—SMURF1 and SMURF2—for the survival of cells, tumorigenesis, and protein degradation
• Activin Membrane-Bound Inhibitor—BAMBI and transforming growth factor interacting factor 1 (TGIF1) act as negative regulators of TGF-β

Role of TGF-β in CARASIL disease

A mutation in the HTRA1 gene will cause more TGF-β receptors to stay on the cell surface, which leads to the overactivation of the receptors by the ligand TGF-β.³ As a result, there will be enhanced transcription processes of multiple genes responsible for cellular actions within the brain and spinal cord regions, leading to abnormal cell growth, vessel wall thickening, bone disorders like osteoporosis, unusual fractures, and secondary issues like nerve injury leading to hearing and vision loss.^5,6,7

Which nervous system disorders are produced as a result of CARASIL?

How does it disturb the brain region?

Mutations in the HTRA1 gene cause overactivation of the TGF-β pathway, causing transcription of more pro-apoptotic genes like Bax, caspase-3, or p21 and consequent apoptosis of small smooth muscle cells within cerebral arteries. Also, collagen and fibronectin ECM proteins are produced excessively through SMAD-mediated transcription and translation processes, which cause fibrosis and arteriosclerosis, thereby producing arteriopathy in the brain. 

How does arteriopathy damage the brain?

Endothelial cells within brain capillaries are attached to each other through occludin and claudins, which prevents the leakage of noxious chemicals into brain tissue. But in the case of TGF-β overactivation, expression of matrix metalloproteinases-2 and 9 (MMP-2, MMP-9) is enhanced, which makes blood vessels leaky and allows immune cells and toxins to cross the blood-brain barrier (BBB) and enter brain tissues. This arteriopathy activates microglial-mediated inflammation and destruction of white matter, leading to brain shrinkage.^5,6,7,8,9

• Leukoencephalopathy—white matter damaging
• Tissue loss in the ventricles of the cerebrum—atrophy
• Lacunar infarcts in basal ganglia and thalamic regions reduce blood flow, reducing oxygen levels to tissues
• Microbleeding in the lobes of the cerebrum, brainstem, and cerebellum

Spine disorders in CARASIL

Fibrosis and apoptosis through MMPs in joints, ligaments, and intervertebral discs lead to the following abnormalities in the spine:^5,6,7,8

• Degenerative changes in the lumbar region and bony spurs around vertebrae, i.e., spondylosis deformans
• Stenosis of the spinal cord: osteophytes in the lumbar and cervical spine cause the narrowing of the neural foramina
• Disc hernia: deterioration of discs

The interplay between pathophysiology and clinical symptoms of CARASIL

When a disease occurs in an organism, clinical symptoms appear on the body. Certified professionals term them as clinical manifestations. This is how the pathogenesis and clinical manifestations of CARASIL in organisms are related to each other.^5,6,7,8

Neurological manifestations

Brain disorders resulting from the damaged white matter tracts (like the corticospinal tract), cerebellar connections, and sensory-motor integration pathways are associated with the following clinical symptoms:^5,6,7,8

• Walking problems like losing balance, unsteadiness, and uncontrolled spasticity
• White matter lesions are associated with memory problems like dementia, cognitive incapacity, and memory deficits
• Insufficient oxygen supply to the brain causes a stroke

Skeletal problems

• Pain in the lower back from disc degeneration, pressure on the nearby nerves, joint stiffness, weakness, numbness, tingling, and thinning of intervertebral discs¹⁰

Dermatological issues

• Damages to hair follicles may lead to hair loss, or alopecia¹⁰

Histopathological findings of CARASIL

A plethora of histological abnormalities have been identified macroscopically, like intense hardening of arteries and cerebral infarcts. Microscopic examination reveals a granular appearance in the white matter and an absence of amyloid substances in the basal ganglia. It also showed intense arteriopathy in the brain and spinal cord regions.¹⁰

Radiographic images

These are comprised of computerised tomography (CT) scans and magnetic resonance imaging (MRI). Both types of techniques detect morphological changes and functional loss of the brain, spinal cord, and musculoskeletal regions.¹⁰

MRI illustrates minor and finer details like scars, bleeding, and inflammation of the whole nervous system and musculoskeletal system. In contrast, a CT scan shows major morphological changes in them.¹⁰

CT scan results in CARASIL

This test would reveal an abnormal, patchy, diffuse appearance of white matter. There would be dark areas in the periventricular regions of the white matter of the brain. Enlarged appearance of ventricles and axonal degeneration in the cerebrospinal tract are typically reported in CT scan images. Kyphosis—bending of the spine—is found in computerised tomography.¹⁰

MRI of CARASIL patients

This usually shows small bleeding areas in the basal ganglia, cerebrum, and thalamic regions. Spondylosis is found in MRI results.¹⁰

FAQs

How is CARASIL different from CADASIL?

There is a genetic difference between CADASIL and CARASIL. If a mutation occurs in the HTRA1 gene, which is present on chromosome 10, then this is CARASIL, whereas a genetic mutation in NOTCH3 on chromosome 19 leads to CADASIL. Generally, microscopic and macroscopic features are somewhat similar in both genetic illnesses.¹¹

Is there any pharmacological treatment for CARASIL?

There is no exact pharmacotherapy. However, prescribed medications can be used to manage symptoms.¹⁰ For example, spasticity is treated with muscle relaxants like baclofen, and cognitive deficit is controlled through donepezil. Aspirin is administered for infarct-like symptoms.¹⁰

Are brain disorders hereditary?

Yes, they are. Hereditary conditions involve the genetic transmission of traits from ancestors to offspring and are embedded within family lineage. In the case of CARASIL, for instance, specific genetic mutations lead to the overactivation of the TGF-β signalling pathway. This results in the transcription of genes and the production of proteins that drive disease progression.^5,6,7,8

Summary

CARASIL is a rare genetic disease caused by mutations in the HTRA1 gene. This malfunction leads to an increased number of TGF-β receptors on the plasma membrane of cells. Overactivation of the TGF-β pathway leads to more gene transcription responsible for the proliferation of cells and overstimulation of microglial cells. The resulting inflammation, fibrosis, intense thickening of blood vessels, and narrowing of cerebral arteries lead to oxygen deprivation to the particular organs. This causes infarcts, white matter lesions, and multiple motor disorders. This illustrates how CARASIL contributes to progressive damage in the brain and spinal cord.