Inspired by a recent patient
Shaheen Durrani-Kolarik, Kandamurugu Manickam and Bernadette Chen. COL4A1 Mutation in a Neonate with Intrauterine Stroke and Anterior Segment Dysgenesis. Pediatric Neurology in press.
COL4A1 , located on chromosome 13q34, encodes the alpha 1 chain of type IV collagen that is a component of basal membranes. It is expressed mainly in the brain, muscles, kidneys and eyes. COL4A1 mutations can vary in presentation, from asymptomatic carriers to severe devastating disease secondary to the effects on small vessels, including porencephaly, intracerebral hemorrhage, infantile hemiparesis in neonates and children, intracerebral hemorrhage, intracranial aneurysms and retinal arteriolar tortuosities in adults. Given its limited description in the medical literature, diagnosis of this mutation can be overlooked. This is important, as identification of this mutation in affected individuals has implications for perinatal management and genetic counseling with availability of prenatal testing to determine inheritance in additional family members. In addition, making this diagnosis may help tailor appropriate screening tests for organs typically involved with COL4A1 mutations. In this case report, we describe a term infant with an extensive intrauterine stroke and anterior segment dysgenesis with a de novo mutation in COL4A1 .
Non-contrast Brain MRI with coronal fast spin echo (FSE) T2-weighted (a) and sagittal T1-weighted (b) imaging demonstrating bilateral hemorrhagic MCA infarction with severe cystic encephalomalacia/absent parenchyma with mass effect on brainstem. Bilateral cerebellar hemisphere infarction with severe cystic encephalomalacia also demonstrated.
From the article:
At present, no diagnostic criteria have been established for COL4A1 -related disorders. There is a wide spectrum of clinical symptoms that variably include brain, ocular, renal, and muscle involvement, as well as reports of Raynaud phenomenon and supraventricular arrhythmia. Brain involvement can include infantile hemiplegia, migraines with or without aura, seizures, dementia, intellectual disability, intracerebral hemorrhage presenting at various ages, including antenatal and recurrent episodes, and ischemic stroke. Neuroimaging demonstrates the features of brain small-vessel disease such as porencephaly characterized by a fluid-filled cavity in the brain; leukoencephalopathy, usually bilateral and symmetric, located mainly in the supratentorial posterior periventricular areas; cerebral microhemorrhages; lacunar infarcts; deep intracerebral hemorrhages; dilated perivascular spaces; and single or multiple intracranial aneurysms. On ophthalmologic examination, a multitude of findings have variably been described including bilateral tortuosity of the second- and third-order arteries, hemorrhagic spots, and Axenfeld-Reiger anomaly with microcornea, congenital or juvenile cataract, increased intraocular pressure, iris hypoplasia, retinal detachment and optic nerve excavation. Renal involvement includes hematuria and renal cysts. Muscle cramps have been reported involving a variety of muscles with associated persistent elevation of serum creatine kinase concentrations.
The inheritance of COL4A1 mutation is autosomal dominant with near 100% penetrance with expression varying in age of onset and severity of clinical symptoms, even within the same family. Therefore, if a parent of the proband is affected, the risk to the siblings is 50%. There may also be de novo mutations or low-level parental mosaicism; however, the proportion of these cases in the population remains unknown.
In our patient and as others have shown, the clinical onset of small vessel disease in the brain as a result of COL4A1 mutations can occur as early as the antenatal period. In neonatology and pediatrics, patients diagnosed with stroke, both in utero and postnatal, often do not have an etiology identified. Therefore, a detailed family history as well as ophthalmologic exam may be warranted to determine other small-vessel organ involvement, as COL4A1 mutations may be grossly underestimated in this patient population. Despite not having a family history of small-vessel disease with the associated clinical spectrum of COL4A1 mutations, this mutation needs to be recognized by practitioners and be considered on the list of differential diagnoses in patients with no known etiology for an in utero or postnatal stroke. In one case series, three of the four neonates with extensive prenatal porencephaly had no known family history and were found to have sporadic COL4A1 mutations.
The implications for making a diagnosis of COL4A1 mutation in a patient such as the one presented herein are considerable. Prenatal testing can be performed by chorionic villus sampling or by amniocentesis if one of the parents is known to carry the mutation. Preimplantation genetic diagnosis may also be an option for these families. In animal studies of mice with the COL4A1 mutation, it was demonstrated that none of the surgically delivered mutant pups had severe cerebral hemorrhage as was observed in the heterozygous mutant pups that were born naturally. Therefore, preventive measures could be taken in cases of known familial COL4A1 mutation, specifically cesarean delivery.