Dr. Stephanie Guey (Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l’Oeil, Hopital Lariboisière, Paris, France), in her presentation titled “The French COL4A1/COL4A2 Cohort: Phenotypic Spectrum,” examined the data of a cohort of adult and pediatric patients with COL4A1/COL4A2 mutations recruited in France. This data was generated through an academic clinical research program conducted in France from 2010 to 2014, promoted by the public hospital of Arles. The aim of this research program was primarily to determine the role of COL4A1/COL4A2 mutations in intracranial hemorrhages and secondly, to refine the clinical spectrum of these mutations.

The inclusion criteria for adults were: a brain MRI performed before the age of 65 without hypertension, in addition to a vascular anomaly or signs suggestive of collagenopathy, such as tortuous retinal arteries, anterior segment eye malformations, juvenile cataracts, childhood hemiparesis, or intracranial aneurysm. Patients could also be included if they had no history of cerebral hemorrhage but had collagenopathy associated with suggestive signs and a previously identified COL4A1/COL4A2 mutation. Children were recruited if they had a perinatal or postnatal cerebral hemorrhage without an apparent cause or a previously identified COL4A1/COL4A2 mutation.

In total, 41 adults and 17 pediatric patients were included in the research program. All these patients were sequenced for the COL4A1 and COL4A2 genes, resulting in 17 adults and 8 children being identified as mutation carriers and included in the program. Notably, among the adults recruited with early onset criteria and unexplained cerebral hemorrhage, 30% had mutations in COL4A1 or COL4A2. Additionally, familial investigations allowed the inclusion of six additional symptomatic or asymptomatic relatives who were mutation carriers. Thus, 31 individuals, 23 adults, and 8 children, all carrying the pathogenic variant, were recruited for this study.

Most patients had mutations in the COL4A1 gene, many of which were glycine mutations; four had a premature stop codon, and two had mutations in the NC1 domain. Five patients and one relative had mutations in the COL4A2 gene, all of which were glycine mutations. Regarding the neurological manifestations in the cohort, 30% of the 31 included adults had already experienced an intracranial hemorrhage with symptoms at the time of inclusion. Considering that the median age at inclusion for adult patients was 42 years, the age at first cerebral hemorrhage ranged from 29 to 60 years, with a median age of 42 years. Two patients had recurrent cerebral hemorrhages, and one patient had synchronous multifocal cerebral hemorrhage. In all patients, the hemorrhage involved deep regions of the brain, hemispheres, or brainstem. In 19% of cases, the hemorrhage was preceded by intense physical exertion. Additionally, four patients had experienced an ischemic stroke, with a median age at first cerebral ischemia of 33 years. One patient had two episodes of ischemic stroke. About two-thirds of the patients reported headaches, mainly migraines with or without aura. Among the adult patients, 8% had epilepsy, and three reported a history of childhood hemiparesis.

Among the 23 adult patients who had a brain MRI, only two had normal MRIs, in patients aged 31 and 39. Fifteen patients had leukoencephalopathy, six had microhemorrhagic sequelae, and five had microhemorrhages. Among the 19 patients who had an MRI with angiography, six had aneurysms involving the intracranial circulation. Some adult patients had porencephalic cavities that varied in size, with very large cavities in patients with a history of childhood hemiparesis and very small cysts in other patients. These types of anomalies, although subtle, can be a clue for doctors to suspect a diagnosis of collagenopathy.

Regarding the children in the study cohort, eight children were included in this research program, with a median age at inclusion of six years. Among these eight children, one had a history of symptomatic postnatal hemorrhage revealed by epilepsy on the third day of life, which had transformed into a large porencephalic cyst on follow-up MRI performed several months later. Six of the eight children had childhood hemiparesis, three had psychomotor delays, and two were epileptic. All eight children had a brain MRI, and seven of them had a porencephalic cavity, varying in size from very large to a slight ventricular asymmetry, as seen in one child whose anomaly was discovered accidentally during a CT scan after head trauma. Five of the eight had leukoencephalopathy, which was very subtle or extensive, involving the deep gray nuclei and diffuse white matter of the hemispheres. Two had migration anomalies, and among the four children who had a CT scan, three had cerebral calcifications. Four of the children had an MRI with angiography, and none showed aneurysms; all intracranial arteries were normal.

As for extra-neurological manifestations, two adult patients reported a history of early retinal hemorrhage, and three had a history of childhood cataracts diagnosed between the ages of 9 and 13. Two patients had early-onset glaucoma, and other anomalies reported at inclusion were iris malformations and strabismus. Among the 22 adult patients who underwent an ophthalmological exam, this revealed cataracts in five of them, frequent but sometimes subtle microaneurysms, optic disc anomalies such as blurred discs or disc atrophy, and tortuous retinal arteries, an inconsistent but rather specific sign of collagenopathy, observed in only three of the 23 patients. The children did not have systematic ophthalmological exams, but a history of early retinal hemorrhage was reported in one of them on the sixth day of life, childhood cataract in another, iritis in another, and a history of strabismus or amblyopia in all pediatric patients.

Renal manifestations were also present. Renal cysts, hematuria, and proteinuria were observed in a proportion of patients ranging from 10% to 20% of the cohort, and muscle cramps or increased muscle enzymes were observed in two of the 23 patients. In children, a history of hematuria was reported in only one patient.

At the end of her presentation, Dr. Guey concluded by stating that the data presented, combined with those presented by colleagues during the conference, could help better define the spectrum of this rare disease but did not allow genotype-phenotype correlation studies due to the limited number of included patients. So, what could be the next steps? Analyzing the cohort data, what is missing for this pathology are data on the natural history of the disease.

Indeed, Dr. Guey’s ultimate goal is to establish a standardized prospective follow-up for all these patients, with the final aim of sharing these data with collaborators to further increase knowledge of this rare condition.