Characterization of Heterozygous Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE

Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene () cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of mutations in a Taiwanese cohort with SVD.

METHODS

Mutational analyses of were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a mutation. The influence of these mutations on HTRA1 protease activities was characterized.

RESULTS

Seven novel heterozygous mutations in were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia.

CONCLUSIONS

Heterozygous mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of -related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of and highlight the pathogenic role of heterozygous mutations in SVD.