ReviewCerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): From Discovery to Gene Identification
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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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): A challenging diagnosis and a rare multiple sclerosis mimic
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Neurovascular Syndromes
2022, Neurosurgery Clinics of North AmericaCitation Excerpt :Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive disorder affecting cerebral small vessels that results from mutation in HTRA1. CARASIL is characterized as a “ischemic, non-hypertensive, small vessel cerebrovascular disease.”80 The clinical presentation is similar to CADASIL, with cerebrovascular ischemia that typically has earlier onset in comparison, as well as presence of gait disturbance, low back pain, lower extremity muscular spasticity, and alopecia80,81
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