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

Abstract

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.

HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature

“…After reviewing the literature, mutations identified among patients with HTRA1related CSVD were summarized. Reports of a total of 82 patients with HTRA1-related CSVD in 31 articles were identified (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Twenty-eight of those patients were CARASIL, and the other 54 were heterozygous HTRA1-related CSVD symptomatic carriers.…”

“…We further reviewed the literature for patients with a clinical history of migraine, lumbago/spondylosis deformans, and alopecia of younger onset. Alopecia of younger onset was defined as the age at onset of alopecia in individuals aged ≤40 years, according to the Japanese diagnostic criteria of CARASIL 5 . Family history was defined as the positive history of cognitive impairment, stroke, or leukoencephalopathy.…”

“…At present, more than 50 symptomatic carriers of HTRA1 mutations have been reported (6)(7)(8)(9)(10). However, most parents of CARASIL patients are asymptomatic (1,3,5,(11)(12)(13)(14)(15)(16)(17). It thus remains unclear why certain mutations cause CSVD in HTRA1 carriers.…”

“…On brain magnetic resonance imaging (MRI), severe leukoencephalopathy with multiple lacunar infarctions (LIs), microbleeds (MBs), and brain atrophy are common. Although CARASIL patients were initially reported in Japan, after identification of HTRA1 as a causative gene, more than 25 CARASIL patients were subsequently identified in other countries, including China, Italy, India, and the United States ( 2 – 5 ).…”

Modeling blood–brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms

“…In addition, aging BECs "suffer" metabolic damage manifested as reduced expression of glucose transporter 1, increased pinocytotic vesicles and decreased mitochondria [13,193]. Similarly, the inherited form of cerebral small vessel diseases, CADASIL and CARASIL, have white matter lesions, frequent lacunar infarcts and enlarged perivascular spaces with persistent leakage of BBB [19,20]. The BBB hyperpermeability is associated with pericyte dysfunction that destabilizes the barrier and consequently causes development of an inflammatory response and enhances BBB injury [19].…”