COL4A1/2-related disease: phenotypic characterisation and proposal for management and prevention of complications

The genes COL4A1 and COL4A2 encode for the chain α1 and α2, respectively, of collagen IV, a constituent of the cellular basal membrane. In recent years, mutations of COL4A1 and COL4A2 have been associated with neurological, ophthalmological, and nephrological alterations. However, COL4A1 and COL4A2-related diseases include a broad spectrum of manifestations that is not yet fully characterised. In this study, we first performed a systematic review of the literature and then developed a questionnaire to investigate the full range of phenotypic manifestations of individual with COL4A1 and COL4A2 mutations. Secondly, we administered the questionnaires and collected information from a group of 28 individuals within 11 distinct families carrying COL4A1 or COL4A2 mutations. Common clinical findingss in such case history were epilepsy, cerebral structural abnormalities, cognitive disability, refraction disorders, and congenital cataracts. Furthermore, we performed ophthalmological and cardiological examinations in asymptomatic individuals carrying COL4A1 or COL4A2 mutations. The ophthalmological screening showed the presence of retinal vascular tortuosity (5 patients), dysgenesis of the anterior segment (2 patients), and cataract (1 patient). The cardiological screening is ongoing, and no results are available yet. The fourth step consisted in the proposal of a protocol for clinical management and prevention of complications based on the results from the questionnaire, the opthalmological and cardiological screening, and the manifestations reported in the literature. The management protocol should include a periodic evaluation of the nervous, cardiac, vascular, ophthalmological, and nephrological systems. This comprehensive approach, based on the analysis of intrafamiliar phenotype variability, aims to early detect the possible complications of COL4A1 or COL4A2-related disease and ultimately improve patients’ quality of life