Intracerebral hemorrhage and COL4A1 and COL4A2 mutations, from fetal life into adulthood

Cerebral small vessel disease (SVD) is an important cause of stroke, and an increasing number of singlegene disorders causing SVD have recently been identified. Of these, CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is most common; others such as mutations in the HtrA serine protease 1 (HTRA1) gene and the TREX1 gene have also been identified. In this issue of Annals of Neurology, Weng and colleagues investigated the potential role of COL4A1 mutations in patients with sporadic late onset intracerebral hemorrhage (ICH). ICH, accounting for 10 to 15% of all strokes, is associated with the highest rate of mortality, with up to 50% of individuals dying within the first year following their ICH. Mutations in collagen IV gene COL4A1 have recently been reported to underlie a spectrum of cerebrovascular diseases, including ICH. Weng and colleagues were able to find 2 novel putative COL4A1 mutations in 2 of 96 patients diagnosed with sporadic cerebral amyloid angiopathy, or presumed hypertension-related ICH. To test the biosynthetic consequences of these putative mutations, they developed and validated a cell culturebased functional assay using nonpathogenic polymorphisms and previously confirmed disease-causing mutations. They were able to show that COL4A1 proteins containing a known mutation, or the 2 putative mutations identified in this study, impair secretion of COL4A1 and lead to protein accumulation within cells. The findings presented herein raise the possibility that COL4A1 mutations may underlie a significant proportion of new cases of ICH every year in the United States and in other parts of the world, and that therapies aimed at promoting protein folding might be effective in preventing hemorrhagic stroke in some patients. COL4A1 dominant mutations are responsible for a broad range of clinical phenotypes presenting from the fetal period until late adulthood. COL4A1 is expressed in the basement membranes of blood vessels and many organs, and mutations are the cause of a SVD affecting the brain, eyes, muscle, and kidneys. With more cases reported, it is becoming increasingly clear that a wider spectrum of cerebrovascular disease may occur than initially considered. Several case reports have illustrated that onset can occur antenatally, during the second trimester of pregnancy, resulting in severe antenatal destructive changes resembling hydranencephaly, often associated with involvement of the cerebellum. A diagnosis can also be made in the neonatal period, showing porencephaly, present at birth, due to the occurrence of an antenatal parenchymal haemorrhage. Hemiplegia and leukoencephalopathy, sometimes associated with intracranial calcifications, have been reported in children presenting in infancy or early childhood. Finally, a diagnosis can also be made following presentation with adult stroke, SVD, and cerebral aneurysms (Figure). Trauma, exercise, and anticoagulation have been recognized as precipitating factors of intracerebral hemorrhage in affected individuals. It was suggested by Gould et al that vaginal delivery could be a trauma leading to a parenchymal hemorrhage with subsequent porencephaly, and it was recommended that this potential trauma should be avoided in a family where a child is known to be affected by a COL4A1 mutation. Recent case series have, however, shown that affected individuals are more often already developing their hemorrhage many weeks before their delivery. It is not yet known how often a parenchymal hemorrhage in a preterm infant occurs in the context of a COL4A1 mutation. Although 5 to 7% of extremely preterm infants do develop a parenchymal hemorrhage in the neonatal period, an associated COL4A1 mutation has only been reported once in a set of twins. In the familial cases, there is a wide variability in age of onset and phenotype between the affected members, including both cerebrovascular and extracerebral manifestations. Many asymptomatic mutation carriers are known; however, at magnetic resonance imaging screening SVD or aneurysms are often identified. Other genetic and environmental factors probably contribute to the variability. COL4A1 mutations may also be associated with extracerebral clinical features, such as cataracts, microcornea, Axenfeld–Rieger anomaly, and retinal hemorrhage.