Pathogenic variant of the COL4A1 gene simulating congenital infection with central nervous system involvement

*Correspondence: [e-mail].

Abstract

Case Presentation: A late preterm female patient with no gestational or perinatal complications is admitted for investigation of congenital STORCH-Z infection. She presented periventricular calcifications on cerebral ultrasound and abnormal ocular findings suggestive of chorioretinitis. An extensive investigation for CMV, toxoplasmosis, rubella and herpes resulted negative. The ophthalmologic evaluation identified bilateral retinal detachment not consistent with congenital infection. A brain MRI showed areas of encephalomalacia due to previous ischemic events in the basal ganglia, periventricular white matter and cerebellum, in addition to signs of recent hemorrhage in the lentiform nuclei and the presence of polymicrogyria. At 1 month old, she presented tonic seizures and an abnormal EEG. Later, she developed motor delay, spasms and displayed an EEG with hypsarrhythmia, when treatment for West Syndrome was instituted. After complete genome analysis the patient was diagnosed with a genetic disorder related to COL4A1 [c.4927A>C p.(Lys1643Gln)]. Currently, she has refractory epilepsy and severe neurodevelopmental delay.

Discussion: The COL4A1 gene decodes the alpha-1 subunit of collagen IV, which forms the basement membrane of vascular, epithelial and smooth muscle structures. The aberrant formation of this protein results in vessel wall fragility and greater susceptibility to hemorrhages in the central nervous system, in addition to ocular, renal and cardiac alterations. The COL4A1 gene mutation is associated with a spectrum of neurologic phenotypes, from asymptomatic carriers to more severe clinical scenarios such as the reported case presenting intraparenchymal hemorrhages from intrauterine life, severe delay in neuropsychomotor development, cognitive impairment and drug-resistant epilepsy. The clinical features are associated with structural abnormalities in neuroimaging, such as porencephalic cysts, periventricular leukoencephalomalacia, periventricular calcifications, cortical alterations (schizencephaly, cortical dysplasias and polymicrogyria) and posterior fossa abnormalities. These findings are often attributed to perinatal hypoxic-ischemic insults or associated with congenital infections.

Final Comments: In newborns with neurological impairment and abnormalities suggestive of congenital infection and/or perinatal insult with an inconsistent history and negative investigation, a genetic disorder should be raised as a differential diagnosis.

Publication History

Article published online:
12 May 2025