The Expanding Phenotypic Spectrum of COL4A1- and COL4A2-Related Disorders: A Systematic Review

To characterize the phenotypic spectrum of COL4A1- and COL4A2-related disorders across the lifespan, providing a descriptive evidence base to complement recently published consensus recommendations.

Using the PubMed database and applying predefined inclusion and exclusion criteria, we identified and included 99 articles in this study. For each patient reported in these 99 studies, the available data were collected regarding sex, age at diagnosis and at last follow-up, genetic findings, pre- and perinatal history, presenting symptoms and multisystem manifestations developed over time (categorized by organ system), laboratory data, imaging and neuroimaging findings, acute focal neurological events and any identified potential associated triggers, medication use and related adverse events, death and any known associated causes, and family history.

We included 367 patients. Neurological symptoms were seen in 78.5% of the reported patients. Acute neurological deficits were reported in 16.9% of cases, with some experiencing recurrent events. Brain magnetic resonance imaging was mostly pathological, with leukoencephalopathy and porencephaly as the most common findings, also in cases of isolated non-neurological signs; lesion progression was reported in 62.3% of cases. Ocular involvement was reported in 71.3%, renal in 15.5%, muscular in 17.8%, and cardiovascular in 7.9%.

The disorder presents with a broad phenotypic spectrum with neurological and ocular issues as the most common manifestations; brain magnetic resonance imaging is pathological in most cases, even without clinical neurological signs. It should be acknowledged that this patient population is possibly biased toward the more severe phenotypes, as only limited data have been published on mildly symptomatic or asymptomatic individuals. A multicenter study with shared follow-up protocols is needed to further understand the disease.