Disorder

CLINICAL CHARACTERISTICS

disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (erebral utosomal ecessive rteriopathy with ubcortical nfarcts and eukoencephalopathy) phenotype. Those who have a heterozygous pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and " cerebral small vessel disease" (-CSVD) refers to the milder phenotype associated with a heterozygous pathogenic variant. Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic. The most frequent initial symptom in individuals with -CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with -CSVD.

DIAGNOSIS/TESTING: The diagnosis of disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in on molecular genetic testing.

MANAGEMENT

Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds; physical therapy, walking aids, and home adaptations for those with gait disturbance; consideration of medication (baclofen or tizanidine) for spasticity; wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families. Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their caregivers. : Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis.

GENETIC COUNSELING

disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner. disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner. . At conception, each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for disorder. . Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent. Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for disorder are possible.