Abstract TMP94: Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy

Abstract

Introduction: Recently, various causative genes have been identified in adult-onset white matter disorders. Some of these genes cause cerebral small vessel disease (CSVD). However, the frequency of genetic CSVD is unknown in the group of adult-onset white matter disorders (leukoencephalopathy). The purpose of this study is to clarify the frequency of genetic CSVD in adult-onset leukoencephalopathy patients and to examine their clinical features. Methods: One hundred patients in the Japanese cohort were included. All patients had neurological symptoms/signs and white matter lesions of grade 3/III classified by Fazekas grade on magnetic resonance imaging. Initially, genetic tests for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), high-temperature requirement A serine peptidase 1 (HTRA1)- related CSVD and retinovasculopathy with cerebral leukoencephalopathy (RVCL) were performed by Sanger method. For the remaining samples, we preformed whole exome sequencing. Patients were divided into groups according to the age at onset of neurological signs/symptoms and family history. Results: In 40 of 100 patients with leukoencephalopathy, we identified genetic mutations that cause CSVD: twenty-five patients with CADASIL,10 patients with HTRA1 -related CSVD, 3 patients with pseudoxanthoma elasticum (PXE), 1 patient with RVCL, and 1 patient with a mutation in COL4A1 . More than 85% patients have mutations in NOTCH3 or HTRA1 . In addition, we identified 3 patients with vanishing white matter disease, and 1 patient with X-linked adrenoleukodystrophy. The hereditary CSVDs other than CADASIL or HTRA1 -related CSVD were identified in the groups of age at onset ≤ 40 years-old irrespective of family history or age at onset ≤ 55 years-old with family history. Conclusions: The frequencies of genetic CSVDs were quite high among patients with leukoencephalopathy with neurological signs/symptoms. Although the genetic tests for CADASIL and HTRA1- related CSVD are sufficient for the most patients, we should consider the other genetic diseases especially for the patients with younger age onset of neurological signs/symptoms or positive family history.