A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review.

Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas.

Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene.

Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation.

Conclusion: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-β1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included.