COL4A1 and COL4A2 what the literature tells us
Dr. Eleonora Bonaventura (Neurology, “Vittore Buzzi” Children’s Hospital, Milan) presented a study titled “COL4A1 and COL4A2 – what the literature tells us,” which reviewed 96 scientific articles on patients with mutations in the COL4A1 and/or COL4A2 genes. This study analyzed 306 patients, considering details of their pre-and perinatal history, phenotypic and neuroradiological characteristics, medication use, and genetic information, including family medical histories. The symptoms in these patients, who were equally distributed by gender, primarily manifested during childhood, especially within the first year of life, while a minority developed symptoms in adulthood. In 22 cases, clinical data were unavailable, and in 12 cases, a voluntary termination of pregnancy was reported following a prenatal diagnosis.
Genetic Information in the Study
From a genetic standpoint, 87% of the patients exhibit a variant in the COL4A1 gene, and 11% in the COL4A2 gene, while a large duplication on chromosome 13 was reported in five cases from one family. In 70% of the cases, the variants are inherited, whereas 17% are de novo mutations, meaning they are not genetically transmitted.
Pre- and Perinatal History in the Study
The prenatal history reveals fetal issues in 20% of the patients, with pathological findings on ultrasound or fetal MRI, such as ventriculomegaly, intraventricular hemorrhages, cortical malformations, porencephaly, and hemorrhagic infarcts.
The type of delivery is known for only 20% of the patients, but it is noted that in 21 of the 56 cases with available data, an elective cesarean section was performed. However, this does not exclude the manifestation of neurological symptoms, suggesting that a cesarean section does not guarantee the prevention of such symptoms. The gestational age at birth is known for only 30% of the patients.
In some patients, premature birth is a relevant factor to consider, as the clinical and neuroradiological characteristics may mimic COL4A1/A2 disorder. If a full-term baby presents with periventricular leukomalacia, a possible sign of prematurity, this may indicate a genetic disorder that needs investigation. Prematurity, however, should not exclude the possibility of a more complex disorder. Even in cases of prematurity, if a baby presents with periventricular leukomalacia, further investigation is warranted. Therefore, it is crucial to gather an accurate history, both familial and individual, considering all organs and systems that could be involved.
3% of the patients reported a history of respiratory distress at birth requiring intensive care, highlighting the importance of not limiting the interpretation of the clinical and neuroradiological findings to just the history of birth distress. Additionally, perinatal problems such as hyperbilirubinemia and hemolytic anemia have been reported.
Hemolytic anemia could be caused by an alteration of the endothelial basement membrane in the bone marrow, especially during the perinatal period, due to the increased susceptibility of fetal hemoglobin.
Phenotypic and Neuroradiological Characteristics in the Study
About 45% of the patients exhibited neurological symptoms at onset, highlighting the clinical complexity of these disorders and the importance of comprehensive, multidisciplinary evaluation. In addition to neurological symptoms, some patients presented ocular signs such as congenital cataracts. More than 50% of the patients showed motor problems, mainly hemiplegia and tetraplegia (in contrast to the spastic diplegia reported in cerebral palsy), often associated with intellectual disability and epilepsy.
54% of the patients experienced acute neurological episodes, more frequently in adults, such as major hemorrhages, ischemic strokes, and acute venous thrombosis, leading to further neuroradiological and clinical progression. Some patients had recurrences of these events, and there are potential triggering factors such as anticoagulant therapy, trauma, or high-intensity sports activities.
Neuroradiological analyses predominantly revealed leukoencephalopathy, porencephaly, and cortical malformations. Brain calcifications were found in 15% of the patients, and CT scans can be useful for diagnosing these calcifications. 50% of the patients had ocular involvement, mainly congenital cataracts and retinal abnormalities.
Other extra-neurological signs included renal, muscular, and cardiovascular problems, sometimes occurring in isolation. Even in the absence of neurological symptoms, MRI often showed abnormalities, confirming its importance in the diagnosis and monitoring of patients with COL4A1/A2 disorders.
Medication Data in the Study
Families often ask which medications are safe for patients with COL4A1/A2 variants, but literature data are limited, available for only 57 patients, covering a wide range of administered drugs (antiepileptics, benzodiazepines, antiplatelets, anticoagulants, antihemorrhagics, corticosteroids, chemotherapeutics, anesthetics, antihypertensives, statins, muscle relaxants). Most did not report adverse events, even with drugs that can alter coagulation profiles (but not anticoagulants!), such as valproate or antiplatelet drugs. However, in 3 out of 4 patients who took anticoagulants, adverse events such as death, major hemorrhages with hematuria, and acral necrosis were reported. In 2020, useful recommendations for managing these patients were published, although there are no definitive guidelines.
Specific Case and Importance of Diagnosis
Dr. Bonaventura’s presentation concluded with the description of a specific case. During a pre-admission for scoliosis correction surgery, she saw a 15-year-old patient diagnosed with cerebral palsy following prematurity at 31 weeks. She did not have access to complete medical history documentation, but it was noted that the patient had experienced intraventricular hemorrhage and multicystic leukomalacia at birth. Subsequently, a second hemorrhagic episode was recorded during the first month of life with coagulation studies yielding no significant findings, followed by surgery for congenital cataracts in early childhood. These details led her to consider the possibility that the diagnosis of cerebral palsy might be more complex.
The family history of congenital cataracts in the father raised further questions about the nature of the disorder, suggesting the possibility of a condition associated with COL4A1 and COL4A2 mutations. Reflecting on this diagnosis is important because it would have implications for the intraoperative and postoperative management of the patient, with the possible advice to avoid anticoagulants and the need to minimize stress during the procedure.
