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A novel NOTCH3 frameshift deletion and mitochondrial abnormalities in a patient with CADASIL
Maria Teresa Dotti1, Nicola De Stefano, Silvia Bianchi
1Unit of Neurology and Neurometabolic Diseases, Department of Neurological and Behavioral Sciences, University of Siena, Italy. dotti@unisi.it
Insights
A novel NOTCH3 gene mutation causing CADASIL was identified in a patient with mitochondrial dysfunction. This finding suggests a link between NOTCH3 gene mutations, microvascular disease, and impaired mitochondrial energy metabolism.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic stroke disorder.
- It is typically caused by NOTCH3 gene mutations affecting cysteine residues.
- CADASIL leads to strokes and dementia.
Observation:
- A patient with migraines, transient ischemic attacks, and fatigue was studied.
- The patient presented with clinical and laboratory evidence of mitochondrial abnormalities.
- Investigations included muscle biopsy, brain MRI, and genetic screening.
Findings:
- A novel frameshift deletion in the NOTCH3 gene (exon 4) was identified, the first documented in CADASIL.
- Muscle biopsy revealed ultrastructural mitochondrial abnormalities.
- Brain MRI showed increased parenchymal brain lactate, indicating mitochondrial impairment.
Implications:
- This case links a novel NOTCH3 mutation to CADASIL and mitochondrial dysfunction.
- It supports the hypothesis that NOTCH3 gene mutations or microvascular pathology impact mitochondrial energy metabolism.
- Further research into this pathway may reveal new therapeutic targets for CADASIL.
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.
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