Clinical characteristics: The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract.
Diagnosis/testing: Diagnosis is based on clinical findings and molecular genetic testing of COL4A1.
Management: Treatment of manifestations: Supportive care tailored to the individual’s specific medical needs and including practical help and emotional support for affected individuals and their families. Hypertension should be treated to reduce the overall risk of stroke.
Prevention of primary and secondary complications: Avoiding head trauma and anticoagulant exposure may decrease the risk for intracerebral hemorrhage.
Surveillance: Depends on the severity and type of symptoms.
Agents/circumstances to avoid: Smoking and hypertension because these factors increase the risk for stroke; sustained head pressure or physical activities that may cause head trauma; anticoagulant use.
Genetic counseling: COL4A1-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. The proportion of cases caused by a de novo pathogenic variant is estimated to be at least 27%. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.
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