Background: Mutations in the CACNA1A gene have been associated phenotypically with Familial Hemiplegic Migraine Type 1, Episodic Ataxia Type 2, Idiopathic Generalized Epilepsy, and Developmental and Epileptic Encephalopathy 42. Only six cases have linked ischemic strokes to mutations in the CACNA1A gene. Summary of Cases: We describe two unrelated patients who were found to have different mutations of the CACNA1A gene, one being a novel mutation, as shown by whole exome sequencing. One presented with seizures at birth and the other with seizures at 17 months old, both eventually exhibiting intractable epilepsy, ischemic stroke, and developmental delays. Results: Whole exome sequencing demonstrated de novo pathogenic mutations in the CACNA1A gene, which both caused similar phenotypes in unrelated patients. Conclusion: Pediatric patients who present with ischemic stroke and a history of seizures should be evaluated for CACNA1A mutations, as prompt recognition can help providers facilitate appropriate medical management.
Background: Homozygous mutations and deletions of the microcephalin gene (MCPH1; OMIM *607117) have been identified as a cause of autosomal recessive primary microcephaly and intellectual disability (MIM #251200). Previous studies in families of Asian descent suggest that the severity of the phenotype may vary based on the extent of the genomic alteration. We report chromosome microarray (CMA) findings and the first described family study of a patient with primary microcephaly in a consanguineous Hispanic family. Case presentation: The proband, a boy born at full-term to consanguineous parents from Mexico, presented at 35 months of age with microcephaly, abnormal brain MRI findings, underdeveloped right lung, almond-shaped eyes, epicanthal folds, bilateral esotropia, low hairline, large ears, smooth philtrum, thin upper lip, and developmental delay. MRI of the brain showed a small dermoid or lipoma (without mass effect) within the interpeduncular cistern and prominent arachnoid granulation. The underdeveloped right lung was managed with long-acting inhaled corticosteroids. Otherwise the proband did not have any other significant medical history. The proband had 2 older brothers, ages 14 and 16, from the same consanguineous parents. The 14-year-old brother had a phenotype similar to that of the proband, while both parents and the oldest brother did not have the same phenotypic findings as the proband. The SNP-based CMA analysis of the proband detected a homozygous 250-kb microdeletion at 8p23.2p23.1, extending from 6,061,169 to 6,310,738 bp [hg19]. This genomic alteration encompasses the first 8 exons of MCPH1. Follow-up studies detected the same homozygous deletion in the affected brother, segregating with microcephaly and intellectual disability. Regions of homozygosity (ROHs) were also observed in the affected brother. Since ROHs are associated with an increased risk for recessive disorders, presence of ROH may also contribute to the phenotype of the affected brothers. The parents were both hemizygous for the deletion. Conclusion: Here we report a homozygous deletion of multiple exons of the MCPH1 gene that was associated with primary microcephaly and intellectual disability in a Hispanic family. In the context of previous studies, our results support the idea that deletions involving multiple exons cause a more severe phenotype than point mutations.
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