COL4A1/COL4A2-related disorders
General description
COL4A1 and COL4A2 genes encode the alpha-1 and alpha-2 chains of type IV collagen, which are fundamental components of basement membranes throughout the body. Type IV collagen forms heterotrimers with a 2:1 stoichiometry (α1α1α2), creating triple-helical structures that provide structural integrity to basement membranes in blood vessels, particularly cerebral small vessels.
Clinical manifestations
The central nervous system represents the most commonly affected organ system. Severe presentations include porencephaly, characterized by cystic cerebral cavities communicating with ventricles, typically resulting from perinatal or fetal brain hemorrhages. These severe forms commonly associate with infantile hemiparesis, hydrocephalus, seizures, developmental delays, intellectual disability, and cerebral palsy. Epilepsy emerges as a predominant neurological feature, particularly childhood-onset focal seizures that frequently progress to status epilepticus and demonstrate resistance to antiepileptic medications.
Adult-onset manifestations include intracerebral hemorrhages, both spontaneous and triggered by trauma, anticoagulation, or physical stress. Some patients experience lacunar strokes, migraine headaches, and progressive cognitive decline. Asymptomatic carriers may remain clinically unaffected throughout their lives.
Ophthalmological abnormalities are highly penetrant, with retinal arterial tortuosity being the most consistent finding across patients with COL4A1/COL4A2 mutations. Nephropathy manifests with diverse presentations ranging from microscopic hematuria to renal cysts and functional insufficiency.
References
- Guey, Stéphanie, and Dominique Hervé. "Main features of COL4A1-COL4A2 related cerebral microangiopathies." Cerebral Circulation-Cognition and Behavior 3 (2022): 100140.
- Singh, Ramandeep, et al. "Teaching NeuroImage: Porencephaly and Hemorrhage in Infantile COL4A2-Related Cerebral Microangiopathy." Neurology 103.5 (2024): e209758.
- Vahedi, K., et al. "Clinical and brain MRI follow-up study of a family with COL4A1 mutation." Neurology 69.16 (2007): 1564-1568.
White matter leukoencephalopathy
Periventricular leukoencephalopathy represents one of the most frequent imaging findings, typically appearing as widespread, symmetrical white matter hyperintensities on T2-weighted and FLAIR sequences.
Microbleeds
Cerebral microbleeds frequently appear as small, rounded hypointense lesions on gradient-echo or susceptibility-weighted imaging sequences, primarily distributed in the deep white matter and subcortical regions.
Porencephaly and schizencephaly
Cortical malformations including polymicrogyria, schizencephaly, and subcortical heterotopia frequently accompany porencephalic changes. Schizencephaly typically presents as clefts extending from the cortical surface to the ventricular system, often with surrounding polymicrogyric cortex. These malformations may be unilateral or bilateral and can occur in association with other developmental anomalies.
Porencephalic cysts
Porencephalic cysts appear as fluid-filled cavities within the brain parenchyma that typically communicate with the ventricular system. These cavities most commonly involve deep periventricular regions and result from tissue necrosis following perinatal or fetal brain hemorrhages.
Intracranial aneurysms
Intracranial aneurysms represent another hallmark finding, most commonly affecting the internal carotid arteries, particularly the C4 and C5 segments.