Stratification of Phenotypes in Childhood-Onset COL4A1/COL4A2-Related Disorders Based on Age of Presentation

Variants in COL4A1 and COL4A2 are associated with a multisystem disorder characterized by prominent neurologic involvement that includes intracranial hemorrhages, white matter injury, neurodevelopmental impairment, and epilepsy. The phenotypic spectrum, however, is broad, and disease subgroups have not been robustly identified. The objective of this study was to distinguish pediatric subgroups based on age at symptom onset.

This was a retrospective cohort study of pediatric patients with variants in COL4A1 or COL4A2 seen at a single center between January 2008 and October 2024. Patients were included if they had likely pathogenic/pathogenic variants or variants of uncertain significance with consistent clinical phenotype and were followed for ≥6 months. Medical records, laboratory data, and neuroimaging were reviewed. Patients were stratified by age at symptom onset into perinatal, early childhood, and late childhood onset (up to 28 days, up to 4 years, and up to 18 years, respectively).

Of the 44 patients meeting inclusion criteria, 33 had variants in COL4A1, 10 in COL4A2, and 1 in both. Neurologic features, such as global developmental delay, cerebral palsy, and epilepsy, were common in perinatal and early childhood cases. In COL4A1-related disease, such neurologic features were present in 14/17 and 8/9 cases, respectively. These features similarly occurred in all patients with perinatal (n = 3) and early childhood (n = 6) onset of COL4A2-related disease. Conversely, these manifestations were less common in late childhood presentations of either disorder (n = 6 total), occurring in 33% of patients. Extracentral nervous system manifestations, particularly ocular abnormalities and renal disease, were predominantly seen in COL4A1-related disease. Neuroimaging in perinatal and early childhood presentations frequently demonstrated periventricular hemorrhagic infarction (20/26 and 6/9 of COL4A1 and COL4A2 patients). Isolated leukoencephalopathy was universally present in late childhood onset patients.

The pediatric phenotype of COL4A1/2-related disorder varies by age at disease onset. Perinatal and early childhood presentations (≤4 years) have a prominent neurologic phenotype with severe developmental delays, cerebral palsy, and epilepsy, correlating on imaging with sequelae from brain injury during prenatal brain development. Late childhood presentations (>4 years) have a milder phenotype, typically with isolated leukoencephalopathy on imaging.