Jolanta Dorszewska1, Marta Kowalska1, Tomasz Grzegorski2,3, Dorota Dziewulska4,5, Katarzyna Karmelita-Katulska6, Anna-Maria Barciszewska7, Michał Prendecki1, Wojciech Gorczyński2, Wojciech Kozubski2. 1. Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland. 2. Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland. 3. Department of Clinical Neuroimmunology, Poznan University of Medical Sciences, Poznan, Poland. 4. Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. 5. Department of Neurology, Medical University of Warsaw, Poland. 6. Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, Poznan, Poland. 7. Department and Clinic of Neurosurgery and Neurotraumatology, Poznan University of Medical Sciences, Poznan, Poland.
Abstract
INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3 Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. MATERIAL AND METHODS: The study included twelve subjects from one family. The NOTCH3 mutation, APOE and MTHFR polymorphisms were determined by high-resolution melting analyses (HRMA) and Sanger sequencing. Neuroimaging included CT and MRI. Ultrastructural examination of skin-muscle biopsy material of the proband was performed. RESULTS: The NOTCH3 Y189C mutation was present in a 36-year-old woman and her two sisters (aged 40 and 27) from 6 siblings. The MA was found in all of them, and started or became more severe after childbirth. The numerous T2/FLAIR hyperintense lesions were shown in the brain MRI. The deposition of granular osmiophilic material in the wall of small vessels of the proband observed in histopathological analysis confirmed the high degree of CADASIL severity. CONCLUSIONS: Patients with the Y189C mutation of NOTCH3 from the same family display a similar phenotype of CADASIL.
INTRODUCTION:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. MATERIAL AND METHODS: The study included twelve subjects from one family. The NOTCH3 mutation, APOE and MTHFR polymorphisms were determined by high-resolution melting analyses (HRMA) and Sanger sequencing. Neuroimaging included CT and MRI. Ultrastructural examination of skin-muscle biopsy material of the proband was performed. RESULTS: The NOTCH3Y189C mutation was present in a 36-year-old woman and her two sisters (aged 40 and 27) from 6 siblings. The MA was found in all of them, and started or became more severe after childbirth. The numerous T2/FLAIR hyperintense lesions were shown in the brain MRI. The deposition of granular osmiophilic material in the wall of small vessels of the proband observed in histopathological analysis confirmed the high degree of CADASIL severity. CONCLUSIONS:Patients with the Y189C mutation of NOTCH3 from the same family display a similar phenotype of CADASIL.