Dr. Simona Orcesi, from the Pediatric Neuropsychiatry Operational Unit at the IRCCS C. Mondino Neurological Institute, Pavia, and the University of Pavia, Italy, in her presentation titled “The Phenotypic Spectrum of COL4A1/A2-related Disorders: a Focus on Pediatric Age”, provided an overview of the disease, its origins, and the protein affected by this condition, and then focused her attention on the clinical conditions that emerge in children and infants.

COL4A1/A2-related disorders are diseases linked to mutations in Type 4 Collagen, which is an essential component of the vascular basement membranes, particularly in small and medium-sized vessels. This type of collagen primarily consists of two chains, Alpha 1 and Alpha 2, which assemble into a three-dimensional structure. The correct arrangement of this structure is critical for the stability of the vessel walls. Genetic mutations in the COL4A1 and COL4A2 genes, located on chromosome 13, can disrupt this structure, making the collagen more fragile and disorganized, leading to pathological effects on the vascular system.

Moreover, these alterations can compromise not just the structure, but also the protective and regulatory functions of the basement membrane, making the vessels more susceptible to fragility and at risk of ischemic and hemorrhagic events. The pathology associated with these mutations was initially identified in animal models, specifically in a strain of mice studied by Dr. Gould, which showed a predisposition to porencephaly, a condition characterized by the formation of a brain scar resulting in substance loss. Subsequent observations in humans have shown that mutations in the COL4A1 gene increase susceptibility to severe brain conditions from birth or the perinatal period, as well as to various adult-onset manifestations, all due to increased fragility of the cerebral vessels, known as small vessel disease.

These findings have led to the identification of a broad spectrum of multisystemic diseases termed COL4A1-related diseases. The differences between the mutations in the COL4A1 and COL4A2 genes are still under investigation, but it is known that the former is more frequent and often associated with more severe and early clinical manifestations. The transmission modes of these mutations can be autosomal dominant, where a single copy of the mutated gene inherited from one parent is sufficient to cause the disease, with a 50% chance of passing it. They can also occur de novo, not inherited but appearing for the first time in an individual due to environmental factors or DNA replication errors, with no family history of the disorder. Some rare cases show an autosomal recessive transmission mode, requiring mutations in both alleles to manifest the pathology, where different probabilities apply depending on whether one or both parents are carriers or affected.

Dr. Orcesi’s speech shifts its focus to the clinical conditions that emerge in children and infants. The heterogeneity of clinical manifestations and the variable severity of outcomes underscore the importance of a meticulous diagnostic approach and early intervention, especially in pediatric cases, to prevent or mitigate severe complications that can affect various organs and systems, including the brain, eyes, muscles, heart, and kidneys. This complex pathological landscape requires the integration of various medical disciplines for optimal and personalized patient management.

Early diagnosis and genetic counseling are crucial in vascular diseases with a genetic basis, such as those associated with mutations in Type 4 Collagen, because many clinical manifestations could be mistakenly attributed to environmental causes. These conditions exhibit considerable variability in both clinical presentation and severity, influenced by a combination of genetic factors, environmental interactions, and individual susceptibility.

A critical aspect is the age at which the damage occurs. During the first months and years of life, the brain undergoes critical developmental phases such as cell proliferation, neuronal migration, and myelination. Damage occurring during these initial phases can lead to significant malformations, while damage later on can cause injuries in already formed structures, altering the observed clinical picture. For example, mutations in Type 4 Collagen can cause a variety of brain abnormalities, from severe malformations like anencephaly to milder conditions such as alterations in white matter.

These conditions can be particularly insidious in children, where vascular fragility may manifest as ischemic or hemorrhagic events that mimic the typical conditions of premature infants, but without prematurity as a cause. Additionally, it has been noted that these pathologies can lead to neurological complications such as epilepsy, microcephaly, cerebral palsy, and developmental delays, often complicated by a central visual deficit due to damage in the cerebral visual pathways.

Treatment remains a challenge, with the management of epileptic symptoms potentially including pharmacological interventions and, in some resistant cases, surgical procedures. However, research is still limited and therapeutic approaches need further optimization. The presence of cerebral calcifications in children, rarely observed in other conditions, signals the possible genetic origin of their condition, underscoring the importance of a thorough genetic evaluation even in the face of seemingly isolated neurological symptoms.

In the context of pathologies related to Type 4 Collagen, the eye emerges as a significantly vulnerable organ, rich in this collagen and subject to various complications. Disorders such as anomalies of the anterior chamber, early-onset congenital cataracts, and other ocular diseases may suggest a genetic basis, particularly mutations in the COL4A1 and COL4A2 genes. A distinctive feature of these pathologies is the coexistence of both peripheral visual deficits, directly linked to the eye anomaly, and central deficits, due to brain lesions affecting the visual pathways. This duality of visual problems greatly complicates rehabilitation, requiring a multifocal approach that considers visual acuity, the ability to track moving objects, and spatial understanding.

To address these challenges, the neuro-ophthalmology center at the Mondino Institute, in collaboration with the Mariani Foundation, has developed informational materials to help families navigate the complexities of raising children with such visual deficits. These initiatives are essential for improving the quality of life of young patients, facilitating better understanding and management of their conditions. https://www.fondazione-mariani.org/pubblicazione/not-just-eyes-for-growing-up/

Additionally, other systemic complications linked to the presence of Type 4 Collagen include renal disorders, as highlighted by the HANAC syndrome, which associates nephrological problems with muscular dysfunctions, often indicated by fluctuating increases in muscle enzymes and cramps. Early diagnosis, facilitated by technologies such as next-generation sequencing (NGS), is crucial for recognizing these complex pathologies and intervening effectively.

In conclusion, Dr. Orcesi’s presentation emphasizes that detailed medical history, both of the patient and their relatives, is crucial for identifying the hereditary nature of the condition and for correctly guiding therapeutic strategies, which currently focus on symptomatic management. Prevention through lifestyle changes and, in some cases, adapting obstetric practices, such as opting for cesarean delivery, becomes essential to reduce the risk of severe complications. Ultimately, the speech highlights the importance of a multidisciplinary and informed approach to managing these complex pathologies, considering their genetic nature and the diversity of clinical manifestations.

Pierangela Totta, Phd