Review
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): From Discovery to Gene Identification

https://doi.org/10.1016/j.jstrokecerebrovasdis.2010.11.008Get rights and content

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified gene, along with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The exact prevalence of CARASIL is currently unknown, and to date approximately 50 patients have been reported, most of them from Japan and two from China. Genetically, no founder haplotype has been identified, and thus the disease is expected to be found more widely. The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-β family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

Section snippets

History

What was possibly the first recorded encounter with a patient with CARASIL (at that time genetically unproven) was reported by Nemoto12 in 1960, when a 30-year-old male was admitted to Tohoku University’s Department of Neuropsychiatry. The patient died 18 months later following frequent seizures after cerebral angiography, and an autopsy was performed. Nemoto12 described the clinical and pathological features of that patient and of two similar brothers of another family at his leading

Epidemiology

The exact prevalence of CARASIL is unknown; to date, approximately 50 patients have been reported, all but two from Japan.19 Recently, two siblings of a Chinese family have been described.7 Genetically, no founder haplotype has yet been identified, and thus CARASIL is expected to be found more widely.8 The age of onset of encephalopathy ranges from 20 to 45 years (mean, 32 years), earlier than in CADASIL (mean, 45 years) and Binswanger’s disease (BD) (50-60 years). Alopecia also develops

Clinical Features

Ischemic stroke or stepwise deterioration of brain functions, progressive dementia, premature baldness/alopecia, and attacks of severe low back pain or spondylosis deformans/disk herniation are the cardinal clinical features of CARASIL.5, 9, 10, 11, 18, 19

Brain Imaging

CT scans showed diffuse homogeneous white matter changes in all examined patients and small foci with softening in approximately 50% of patients, even in early stages of CARASIL. Dilatation of the lateral ventricles and cerebral sulci was noted with varying levels of severity.5 Approximately 25% of patients had small areas of low attenuation in the pontine base, suggesting Wallerian degeneration of the cortico-descending tracts, but not lacunes (Fig 2).5

The most characteristic brain MRI

Pathology

Histopathologically, CARASIL is characterized by intense arteriosclerosis mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition.12, 13, 14, 15, 16, 17, 22, 26, 28, 31, 32 Arteriosclerotic changes are most intense in the cerebral white matter and basal ganglia. Fibrous intimal proliferation, hyaline degeneration of the media, loss of vascular smooth muscle cells, thickening and splitting of the internal elastic lamina, and concentric narrowing of

Genetics and Molecular Pathogenesis

HTRA1 is the only gene known to be associated with CARASIL.20 No other phenotypes with mutations in the HTRA1 gene are known. A single-nucleotide polymorphism at the promoter region of HTRA1 for which homozygosity for the AA genotype increases the risk of wet (neovascular) age-related macular degeneration has been identified as age-related macular degeneration 7.33

Genome-wide linkage analysis of the disease has revealed a link to the 2.4-Mb region on chromosome 10q (10q25.3-q26.2) that contains

Differential Diagnosis

The differential diagnosis of CARASIL includes sporadic SVDs, including BD, primary angiitis of the nervous system, and chronic progressive multiple sclerosis. The clinical characteristics and MRI abnormalities in these conditions may resemble those of CARASIL. The presence of diffuse white matter lesions on MRI extending to the temporal poles or external capsules; the presence of extraneural symptoms, such as acute low back pain and premature baldness; the absence of known vascular risk

Treatment

At present there is no effective treatment for patients with CARASIL. Primary treatments include genetic counseling, supportive care, and medications for treating dementia and secondary prevention of ischemic stroke. The effects of antiplatelet agents and anticoagulants are unclear in these patients, however.

Conclusion

CARASIL is a systemic genetic disease of the cerebral small vessels, spine, and hair follicles. Four causative mutations in the HTRA1 gene have been identified to date. Disinhibition of signaling by TGF-β family members caused by mutant HTRA1 is believed to contribute to the pathogenesis of CARASIL. This condition has never been reported outside Asia, although it is the second most common hereditary cerebral SVD in Japan. Genetically, no founder haplotype has yet been identified, and thus

Acknowledgment

I thank Dr. K. Arima, Japanese National Center of Neurology and Psychiatry and Dr. O. Onodera, Brain Research Institute, Niigata University for their comments on the manuscript.

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