title: A novel NOTCH3 frameshift deletion and mitochondrial abnormalities in a patient with CADASIL.
abstract: BACKGROUND
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which leads to strokes and dementia, is caused by single missense mutations or, in a few cases, small deletions in the NOTCH3 gene. These mutations result in a gain or a loss of 1 (or, rarely, 3) cysteine residue in 1 of 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of NOTCH3.
  
  
  OBJECTIVE
  To describe a patient with a novel NOTCH3 mutation in whom clinical and laboratory findings of mitochondrial abnormalities were associated with a diagnosis of CADASIL. Patient A patient with a history of migraines, repeated transient ischemic attacks, and generalized fatigue underwent muscle biopsy, brain magnetic resonance spectroscopic imaging, and screening of mitochondrial DNA and NOTCH3.
  
  
  RESULTS
  Molecular genetic analysis showed a NOTCH3 mutation (the first documented frameshift deletion in a patient with CADASIL) in exon 4. Although the screening of mitochondrial DNA did not show mitochondrial mutations, findings from muscle biopsy and brain magnetic resonance spectroscopic imaging showed signs of mitochondrial impairment (ultrastructural mitochondrial abnormalities and increased parenchymal brain lactate, respectively).
  
  
  CONCLUSIONS
  A patient with CADASIL and a 5-base pair deletion leading to a frameshift mutation showed clinical and laboratory evidence of mitochondrial dysfunction. This adds to the previously reported hypothesis of a pathogenetic role of NOTCH3 or, less specifically, a microvascular pathologic effect on mitochondrial energy metabolism.
authors.affiliation: Unit of Neurology and Neurometabolic Diseases, Department of Neurological and Behavioral Sciences, University of Siena, Italy. dotti@unisi.it
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dotti
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.forename: Silvia
authors.initials: S
authors.lastname: Bianchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.forename: Carla
authors.initials: C
authors.lastname: Battisti
authors.forename: Elena
authors.initials: E
authors.lastname: Cardaioli
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
mesh_terms: D001483:Base Sequence; D015161:Dementia, Multi-Infarct / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000235:genetics*; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch