Dr. Anna Bersano (Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy), in her presentation titled “Overview of clinical and neurological features of COL4A1/A2 adult patients,” examined in detail the symptoms and signs of the disease in adults.

This pathology presents extremely heterogeneous symptoms, encompassing both neurological and non-neurological signs. The neurological phenotype is particularly varied, ranging from asymptomatic cases in patients with porencephaly, possibly due to perinatal hemorrhages or small vessel disease, to more complex clinical symptoms like those of cerebrovascular diseases, including ischemic stroke, transient ischemic attacks (TIA), and cerebral hemorrhages. Other symptoms include epilepsy, cognitive disorders, and migraines. The clinical phenotype, not only the neuroradiological one, can overlap with other monogenic genetic diseases that affect small vessel disease. An interesting aspect is that symptoms can also vary among members of the same family, all carriers of the same mutation.

A study published by Markus’s group in 2010 reviewed 52 mutation carriers from 13 families, including one sporadic case. In these patients, a history of stroke was present in about 17% of cases. The authors, in addition to listing neurological and non-neurological symptoms, compared them with other monogenic forms responsible for small vessel disease, which can overlap with the COL4A1/A2 syndrome. It emerged that the age of onset in COL4A1 syndrome is younger compared to, for example, CADASIL. Lacunar infarcts are more frequent in CADASIL compared to COL4A1/A2 syndrome, where subcortical hemorrhages are more common. Cognitive impairment is less represented, likely due to the scarcity of data in the literature. Another distinctive feature of the syndrome is the family history of infantile hemiparesis and the presence of systemic symptoms such as renal impairment, nephropathy with proteinuria and renal insufficiency, Raynaud’s syndrome, supraventricular arrhythmias or mitral valve prolapse, and ocular anomalies like tortuosity of retinal arterioles and congenital cataracts.

From a cerebrovascular perspective, small vessel disease mainly manifests with lacunar-type strokes and deep intracerebral hemorrhages involving the white matter, basal ganglia, or brainstem. These hemorrhages are often associated with trauma or intense physical activity, although it is unclear whether the trauma is a cause or a frequent coincidence. An epileptic phenotype has also been described, with focal and generalized tonic-clonic seizures appearing around the age of 15. Studies have shown that nearly 75% of patients have epilepsy, often associated with porencephalic lesions or small vessel disease.

Another related syndrome is HANAC syndrome, characterized by angiopathy with nephropathy, aneurysms, and cramps, associated with specific mutations in the COL4A1 genes. Patients with HANAC generally do not present with infantile hemiparesis or porencephaly and have a lower risk of haemorrhages.

Making a differential diagnosis with other monogenic diseases is essential. The COL4A1/A2 syndrome should be considered in cases of cerebral haemorrhages or small vessel diseases, especially in the presence of a significant family history. Every intracranial aneurysm associated with small vessel disease should undergo genetic screening for COL4A1/A2. Unfortunately, the therapeutic management and follow-up of patients are still based on clinical experience rather than established evidence, due to the lack of specific studies. Based on experience, recommendations include avoiding intense physical activity and anticoagulants and considering cesarean delivery to reduce the risk of perinatal haemorrhages. Dr. Bersano concluded her presentation by emphasizing the need for networking and systematic studies to better understand the natural history of the disease and improve patient management.