Abstract / Summary
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), also known as HTRA1-related cerebral small vessel disease, is a rare hereditary arteriopathy caused by biallelic pathogenic variants in the HTRA1 gene. Because of overlapping clinical and radiological features, CARASIL may be misdiagnosed as multiple sclerosis (MS), leading to delayed diagnosis and unnecessary exposure to immunomodulatory therapies. We report two Iranian siblings with genetically confirmed CARASIL who presented with early-onset leukoencephalopathy, premature alopecia, and recurrent low back pain. The male sibling presented with acute right-sided hemiparesis. Brain magnetic resonance imaging (MRI) demonstrated symmetrical periventricular and deep white matter hyperintensities together with the characteristic middle cerebellar peduncle “arc sign.” His sister experienced recurrent episodes of hemiparesis, progressive cognitive and mood impairment, and MRI findings consistent with CARASIL. She had previously been misdiagnosed with multiple sclerosis and treated accordingly. Whole-exome sequencing identified a homozygous HTRA1 frameshift variant (NM_002775.5:c.406_409dup; p.Arg137Glnfs*33), confirming the diagnosis in both siblings. These cases highlight CARASIL as an important diagnostic mimic of multiple sclerosis. Early recognition of characteristic clinical features—including premature alopecia and recurrent lumbago—together with distinctive neuroimaging findings such as symmetrical deep white matter involvement, relative sparing of subcortical U-fibers, anterior temporal lobe and external capsule involvement, cerebral microbleeds, and the middle cerebellar peduncle “arc sign” may facilitate timely diagnosis. Although no disease-modifying therapy is currently available for CARASIL, early diagnosis can prevent inappropriate MS-directed treatment, enable appropriate supportive management, and facilitate genetic counselling for affected families.