The Genetic Landscape of Ischemic Stroke in Children - Current Knowledge and Future Perspectives.

Stroke in childhood has multiple etiologies, which are mostly distinct from those in adults. Genetic discoveries over the last decade pointed to monogenic disorders as a rare but significant cause of ischemic stroke in children and young adults, including small vessel and arterial ischemic stroke. These discoveries contributed to the understanding that stroke in children may be a sign of an underlying genetic disease. The identification of these diseases requires a detailed medical and family history collection, a careful clinical evaluation for the detection of systemic symptoms and signs, and neuroimaging assessment. Establishing an accurate etiological diagnosis and understanding the genetic risk factors for stroke are essential steps to decipher the underlying mechanisms, optimize the design of tailored prevention strategies, and facilitate the identification of novel therapeutic targets in some cases. Despite the increasing recognition of monogenic causes of stroke, genetic disorders remain understudied and therefore under-recognized in children with stroke. Increased awareness among healthcare providers is essential to facilitate accurate diagnosis in a timely manner. In this review, we provide a summary of the main single-gene disorders which may present as ischemic stroke in childhood and describe their clinical manifestations. We provide a set of practical suggestions for the diagnostic work up of these uncommon causes of stroke, based upon the stroke subtype and imaging characteristics that may suggest a monogenic diagnosis of ischemic stroke in children. Current hurdles in the genetic analyses of children with ischemic stroke as well as future prospectives are discussed.

Three Pediatric Siblings With CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a congenital small vessel disease of the brain due to NOTCH3 gene mutations. Although adult-onset CADASIL is well documented, more cases are being described within the pediatric population. We describe three siblings with NOTCH3 mutations with various symptomatic presentations of early-onset CADASIL and one sibling with concurrent moyamoya syndrome. METHODS: Review of electronic medical records of identified patients. RESULTS: A 19-year-old male who has experienced behavioral dysregulation, hallucinations, and memory loss along with a hyperintense signal abnormality in his temporal lobe; his 15-year-old sister who has the mildest presentation in terms of normal imaging results but experiences severe headaches, anxiety, and depression; and the youngest sibling, a 13-year-old with first reported case of a NOTCH3 mutation associated with moyamoya syndrome and a TREX1 gene mutation of uncertain clinical significance. She had multiple strokes before age five years. CONCLUSION: Our set of siblings share many similarities with other reported pediatric cases of CADASIL, all with NOTCH3 gene mutations and with early-onset symptoms that range from abnormalities in the cognitive/behavioral/psychiatric field to neurological deficits, migraines, and strokes. Gene testing and imaging studies in symptomatic children with a family history suggestive of CADASIL might aid in early diagnosis, even though there is no effective therapy. We believe that the correlation of clinical presentations and gene mutations together with increased research into the molecular mechanisms underlying CADASIL (and related arteriopathies such as moyamoya syndrome) are critical to the eventual development of targeted therapies.