4 research outputs found
Genetic Causes of Cerebrovascular Disorders in Childhood
__Abstract__
Cerebrovascular disorders in childhood comprise ischemic stroke and hemorrhagic stroke. This thesis comprises a escription of genetic causes of childhood cerebrovascular disorders. Two examples of genetic causes of ischemic stroke, comprising a case of ACTA2 mutation and a review of the neurological findings in incontinentia pigmenti. In addition, genetic causes of childhood hemorrhagic stroke, mainly in the perinatal period, are provided. These comprise descriptions of special phenotypes linked to COL4A1 mutations, i.e. hydranencephaly, anterior segment disorders and a case of putative autosomal recessive inheritance of a COL4A1 mutation. The identification of COL4A2 mutations as a novel cause of porencephaly and small vessel disease is described. In addition, USP18 mutations were identified as novel causes of severe pseudo-TORCH syndrome with cerebral hemorrhage and early demise
COL4A2 mutation associated with familial porencephaly and small-vessel disease
Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV
Defining the phenotypical spectrum associated with variants in TUBB2A
BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic