The presentations by Dr. Anna Pichiecchio (Neuroradiology, IRCCS Fondazione Istituto Neurologico C. Mondino, Pavia and University of Pavia, Italy) and Dr. Cecilia Parazzini (Pediatric Radiology and Neuroradiology, Ospedale dei Bambini V. Buzzi, Milan, Italy) titled “Neuroimaging Aspects: From Prenatal to Adulthood” explored diagnostic approaches, particularly in terms of predicting diagnoses through radiological imaging. They addressed the main aspects highlighted by neuroimaging in patients with COL4A1 mutation-associated pathologies, and whether radiological images can raise suspicion of COL4A1-related conditions and guide diagnostic pathways.

Dr. Anna Pichiecchio described in her presentation the principal cerebral manifestations observed in COL4A1 mutation-related pathologies.

Collagen type 4 is crucial for forming the basement membrane, a structure found in many tissues, particularly in vascular endothelium. A mutation in genes responsible for producing collagen type 4 leads to reduced production of normal collagen and the formation of pathological collagen, compromising the functional and structural integrity of the basement membrane.

This mutation is often hereditary, primarily through autosomal dominant inheritance, though de novo mutations can also occur. The clinical phenotype associated with this mutation is highly variable, with varying degrees of severity and frequent multiorgan involvement. One of the main consequences of the COL4A1 gene mutation is small vessel disease involving arterioles, venules, and capillaries, causing microangiopathy.

Cerebral manifestations are diverse and include intraparenchymal haemorrhages (both supratentorial and infratentorial), venous periventricular infarcts caused by involvement of medullary veins, and cortical developmental anomalies such as schizencephaly and polymicrogyria. In neonates, these alterations can cause multifocal lesions involving both infratentorial and supratentorial areas, with deposits of hemosiderin indicative of prior haemorrhages and evolution towards porencephaly (cavity formation within the brain).

The disease can manifest at any point in life, from prenatal to adulthood, with a particularly high incidence during the fetal and neonatal periods. The presence of periventricular venous infarcts in periventricular white matter due to medullary vein thrombosis is a typical but nonspecific feature, as it can also be caused by other conditions such as viral infections.

The evolution of the disease in neonates often leads to permanent lesions, visible as ventricular dilatations and loss of brain substance. In some cases, ocular abnormalities such as posterior lenticonus, microphthalmia, and optic nerve hypoplasia can provide additional diagnostic clues.

Histopathological aspects of the fetal brain show hemosiderin deposits, calcifications, and thrombi in periventricular veins. Additionally, placental abnormalities such as fibrotic and irregular villi can contribute to fetal vascular malperfusion, playing a role in the development of cerebral lesions.

For neuroradiologists, it is important to consider COL4A1 mutation when observing intraparenchymal haemorrhages, porencephaly, or ischemic changes, especially in full-term or preterm neonates. The differential diagnosis of pediatric stroke, cerebral calcifications, and ocular anomalies may include COL4A1 mutation. However, exploring aneurysms in pediatric patients through magnetic resonance imaging remains a relatively unexplored and not clearly defined field in current guidelines.

In conclusion, COL4A1 gene mutation leads to various clinical manifestations, primarily linked to cerebral microangiopathy. Early and accurate identification of this mutation is crucial for patient management and treatment, considering phenotypic variability and multiorgan involvement.

Dr. Cecilia Parazzini, in her presentation, discussed how collagenopathy exhibits significant phenotypic variability and requires specific expertise for accurate diagnosis through imaging, with various findings and patterns differing based on age and brain development stage, influencing both diagnosis and therapeutic pathways.

Collagenopathy presents significant phenotypic and radiological variability. It is important to note that the evolving brain of a child, from fetal stage to 3 years old, behaves differently from that of an adult due to myelination of white matter, which is rich in lipids. This myelination, starting in the neonatal period, continues until 3 years old, necessitating specific expertise of pediatric neuroradiologists to properly conduct exams using different protocols according to age.

A key point in the fetal period is around 24-26 weeks of gestation, during which insult can cause malformations if it occurs earlier, or white matter damage if it occurs later. In adults, lesions with hyperintense components in T2 sequences can often be associated with bilateral multifocal strokes, enlarged ventricles, and reduced thalamic and basal ganglia volume. The outcome of haemorrhage, typically highlighted by porencephaly, is a cavitated lesion surrounded by damaged brain tissue communicating with the ventricles.

Another type of damage is white matter alteration resembling periventricular leukomalacia, which also involves internal capsules and basal ganglia. This condition is often due to congestion of deep medullary veins, suggesting incomplete vascular maturation that favours damage.

If damage occurs early, the picture is predominantly malformation, with alterations communicating with ventricles and liquor spaces. A particular case highlighted schizencephaly in an adult and two polymicrogyria, likely due to interference with pial cortical membrane causing alteration in neuronal cortical distribution.

Calcifications, visible as hyperdensity in CT scans, are accumulations of calcium phosphate and hydroxyapatite and can be better delineated with advanced MRI sequences like gradient echo and susceptibility imaging. These techniques help distinguish between calcifications and haemoglobin degradation products. Calcifications are generally asymmetric and present in periventricular and deep white matter, as well as in basal ganglia, and their pattern aids neuroradiologists in differential diagnoses.

The radiological evolution of the pathology is generally stable over time, but a particular case showed adequate myelination for age at 2 years with subsequent appearance of hyperintense signal alteration in T2 and a likely hemosiderin susceptibility focus, which reduced over time. This suggests that de novo mutations can influence clinical presentation and its evolution.

In adults, imaging shows aspects similar to pediatric cases, with predominantly hemorrhagic strokes, symmetric small vessel disease in periventricular regions, lacunar cavitations, perivascular spaces, and cerebral aneurysms. These vascular anomalies, often asymptomatic, can be analyzed with intracranial MR angiography or CT angiography.

Calcifications in adults are less frequent than in children but can still be present in basal ganglia. Literature shows that the pattern of leukoencephalopathy and distribution of calcifications, together with accurate clinical examination, allow differential diagnoses that include COL4A1-type collagenopathy.

Finally, genetic expression pathologies involving the retinal and systemic systems may present a similar picture of microangiopathy with calcifications, but with inflammatory pseudotumoral lesions not seen in COL4A1 pathology.

In response to the initial question of whether neuroimaging aspects can lead to the diagnosis of COL4A1-related disorders, these two presentations indicate that COL4A1 gene mutation compromises the integrity of the basement membrane and leads to a variety of clinical manifestations, primarily linked to cerebral microangiopathy and multiorgan involvement, making early and accurate diagnosis essential for optimal management. However, the importance of an experienced neuroradiologist is crucial to perform appropriate techniques and raise accurate diagnostic suspicion, not only for specific diagnoses but also for differential diagnoses.