Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy

Dominant negative or haploinsufficient mutations in the collagen genes COL4A1 and COL4A2 are characterized by arterial basement membrane thickening resulting in a multisystem microangiopathy targeting the CNS but also potentially affecting the ocular, renal, cardiac, and muscular systems. Within the brain, such changes predispose affected individuals to recurrent ischemic and/or hemorrhagic strokes beginning during early fetal development but extending into the postnatal period and even into adulthood.1 Mutations affecting glycine residues of the Gly-Xaa-Yaw (typically representing glycine-proline-4-trans-hydroxyproline in vertebrates) repeat domains that typify collagens usually manifest in an autosomal dominant (AD) fashion. However, recent work suggests that tissue-specific mutation effects may also occur, with mutations leading to gain of function effects in some tissues and loss of function effects in others.2 Stroke-related complications may be insidious and clinically silent. Neuroimaging phenotypes of COL4A-associated disease include chronic white matter disease, porencephaly/hydranencephaly, encephalomalacia, cerebral calcifications, schizencephaly and hydrocephalus and corresponding clinical diagnoses of cerebral palsy, intellectual disability, cortical visual impairment, and epilepsy.3

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