COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease
A Systematic Review
Background and Purpose— A number of single gene disorders can cause cerebral small vessel disease. Mutations in the COL4A1 gene encoding the type IV collagen alpha 1 chain, which are already associated with porencephaly and infantile hemiparesis, have been recently recognized as a further monogenic cause of small vessel disease that can present in adulthood.
Methods— We performed a systematic review of published data from 1966 to January 8, 2010 to characterize the features of small vessel disease seen with COL4A1 mutations.
Results— We identified a total of 52 mutation carriers. A history of stroke was reported in 9 subjects (17.3%); in 6 cases it was attributable to subcortical hemorrhage and in 3 cases it was attributable to lacunar infarction. Stroke often occurred as first presentation of the disease, with a mean age of onset of 36.1 (SD, 12.95; range, 14–49). Hemorrhages, often recurrent, have been associated with physical trauma and activity and anticoagulant therapy. Brain imaging showed frequent leukoaraiosis (63.5%), microbleeds that are usually subcortical (52.9%), lacunar infarction (13.5%), and dilated perivascular spaces (19.2%). Extensive leukoaraiosis was seen in a number of asymptomatic adult mutation carriers. Asymptomatic intracranial aneurysms were common (44.4% of 18 with angiography). Migraine (with and without aura) was reported in 10 subjects, with a mean age at onset of 31.7. Systemic features are also frequent, affecting the eye (10/21, 47.6%), kidney (15.4%), and muscle (15.4%).
Conclusions— COL4A1 is a further cause of familial vasculopathy and may present with stroke, ischemic as well as hemorrhagic, in adult life and with radiological features of leukoaraiosis and microbleeds.
Cerebral small vessel disease (SVD) is an important cause of stroke and vascular cognitive impairment. Most cases are apparently sporadic and, for these, polygenic influences are thought to be important. However, an increasing number of single gene disorders causing SVD are being identified. The most common of these is cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which results from mutations in the notch 3 gene.1 A number of rarer monogenic forms of SVD have recently been identified, including cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy, resulting from mutations in the HtrA serine protease 1 (HTRA1) gene,2 and autosomal-dominant retinal vasculopathy with cerebral leukodystrophy attributable to mutations in TREX1, which encodes a DNA-specific exonuclease.3
Another recently recognized monogenic cause of CVD is COL4A1 mutations. COL4A1 is a gene encoding the type IV collagen alpha 1 chain, and it is already recognized that mutations in the gene can cause autosomal-dominant porencephaly and infantile hemiparesis.4,5 Recently, COL4A1 mutations have been identified in adult patients presenting with SVD.6,7,8 Clinical features described include both ischemic stroke and intracerebral hemorrhage, accompanied by radiological features of lacunar infarction, leukoaraiosis, and microbleeds.8 The proportion of SVD cases caused by COL4A1 mutations has not yet been examined systematically, and diagnosis currently depends on recognition by clinicians of the typical clinical and radiological phenotype. We performed a systematic review of published data to provide an overview of the clinical and neuroradiological features of disease, particularly those of SVD, in patients with COL4A1 mutations.
Materials and Methods
Search Strategy and Selection Criteria
References for this review were identified through a search of PubMed from 1966 to January 8, 201 with the terms “COL4A1,” “collagen, type IV, alpha 1,” “COL4A1 and stroke,” “COL4A1 and poroecephaly,” “COL4A1 and mutation,” and “COL4A1 and review.” Reference lists of relevant articles were also reviewed.
We identified reports of 13 families and 1 sporadic case with a total of 52 mutation carriers. Twenty-six (50%) were males.
Clinical Features of SVD: Stroke
A history of stroke was reported in 9 subjects (17.3%), with a mean age of onset of 36.1 (SD, 12.95) years. Three strokes were ischemic and 6 were hemorrhagic. All the ischemic strokes, occurring at ages 35,7 47,9 and 49,5 were lacunar, with MRI-confirmed lacunar infarction in 2 and a normal CT in the third case without MRI. Of the 6 cerebral hemorrhages, 3 occurred spontaneously, at ages 14,10 17,11 and 42,12 and were recurrent. In 1 of these, hemorrhages were associated with physical activity.11 All spontaneous hemorrhages were subcortical, involving the white matter, deep gray nuclei, or brain stem, except for 1 hemorrhage for which the location of a frontal hemorrhage was not described.12 In 2 patients, a subarachnoid hemorrhage and a left temporal contusion with surrounding subarachnoid hemorrhage occurred after major head injury at ages 3313 and 48,8 respectively. The latter patient was using anticoagulant therapy. The sixth patient experienced a subcortical intracerebral hemorrhage while using anticoagulant therapy at age 40.13 Antenatal intracerebral and intraventricular hemorrhage have also been reported in 2 pairs of preterm siblings.14,15
A history of migraine was reported in 5 families.5,9,10,13 In 1 family, 3 of 6 mutation carriers presented with migraine, all with visual or sensory aura. Presentation was at ages 20, 30, and 45 years.13 Migraine with aura was also reported in another otherwise asymptomatic mutation carrier.10 Common migraine was reported in 6 other subjects from 3 different families.5,9
Other Neurological Features
Eighteen subjects had a history of infantile hemiparesis, usually noted either at birth or during the first year of life.5,7,11–14,16 Developmental delay occurred in 5 patients.5,12 This was frequently associated with neuropsychological abnormalities; in 1 family in whom formal neuropsychological assessment was performed, the most common findings were low intelligence quotient, reduced verbal fluency learning and memory, and apraxia.16 No individuals had a diagnosis of dementia according to Diagnostic and Statistical Manual of mental disorders (DSM)-IV criteria. However, there were no reports of symptomatic cognitive impairment in individuals who presented with clinical features in adulthood, or who were detected as asymptomatic carriers in adulthood.
Seizures occurred in 11 subjects,5,7,12–13,16 and in 6 of these in whom data were available the age of onset was between 3 and 19 years. In 1 case, febrile seizures and may have been incidental,13 whereas in another a generalized seizure occurred as the presenting symptom of a large deep hematoma.11 A history of depression was reported in only 2 patients who presented with depression at age 3313 and age 37.7 In 1 case, the depression occurred after stroke.7 The age at onset of clinical features of SVD and other neurological features in patients with COL4A1 mutations are reported in Table 1.
Systemic Features: Ocular Involvement
There are frequent reports of ocular involvement. Ophthalmological examination was performed on 21 subjects from 6 families.7,9–10,12–14 Cataracts was reported in 10 subjects,7,10–12 4 of whom had congenital cataracts.7 Retinal vessel tortuosity was noted in 15 subjects from 5 different families.9,12–13 Five subjects experienced retinal hemorrhages,9,11,13 which occurred after trauma in 1 case.11 In 1 family presenting with leukoencephalopathy and stroke, congenital defects of the anterior segment of the eye (Anxfeld-Riger anomaly) were noted.7
Renal and Muscular Involvement
Plaisier et al9 described 3 families with COL4A1 mutations with an unusual phenotype characterized by cerebral angiopathy and aneurysms in combination with nephropathy with hematuria and bilateral renal cysts and muscle cramps. Additional patients presented with hematuria.6,13 A complete screening for renal involvement was normal in 1 family.14
Other Clinical Systemic Features
Cardiovascular abnormalities such as mitral valve prolapse and supraventricular arrhythmias have been reported respectively in 4 individuals16 and 3 individuals.9 Raynaud phenomenon was observed in 7 individuals,9 and 1 young man presented with skeletal abnormalities.10
Brain Imaging Findings
Brain imaging was performed for all the mutation carriers. Forty-four had MRI performed, 6 had CT only performed, and 2 preterm siblings had transcranial ultrasound performed.
Radiological Findings of SVD
White matter hyperintensities were common, being reported in 63.5%, with the mean age at MRI being 30.0 years (SD, 18.2; range, 7 days–68 years). In most cases, this was bilateral and symmetrical. Two studies reported a predominantly posterior pattern of white matter damage.9–13 Extensive confluent leukoaraiosis has been reported in some adult asymptomatic carriers5,10,13–14 (Figure). Other features of SVD included lacunar infarcts (13.5%) and dilated perivascular spaces (19.2%). Seventeen individuals had gradient echo MRI. In these, cerebral microbleeds were common, being present in 52.9%. They were predominantly located in the deep white matter, deep gray nuclei, and brain stem and cerebellum.
Angiography of the cerebral vessels with either intra-arterial angiography, MRA, or CTA was performed in 18 subjects. Of these, 8 (44.4%) had asymptomatic intracranial cerebral aneurysms. These were most common in the carotid distribution involving the intracranial carotid artery (7 subjects),5,9–10 middle cerebral artery (2 subjects),9 and top of the basilar artery (1 subject).7 Multiple aneurysms were observed in 4 subjects (50%).9,10
A poroencephalic cyst was found in 24 out of 52 subjects (46.1%) from 7 families.5,7,12,14,16 The poroencephalic cyst was unilateral in most of the subjects (18, 75%), bilateral in 1, and a detailed description is lacking in the others. A wide range of associated neuroradiological features have been reported. One subject presented small cysts affecting the white matter of the contralateral hemisphere.14 Hydrocephalus requiring shunting was observed in 3 subjects with neonatal onset of the disease.12,14 In 2 of these subjects, the proencephalic cyst was adjacent to a resolving antenatal hemorrhage.14
Other Abnormalities on Investigation
Biopsy results of other organs show evidence of widespread vascular changes. Six individuals from 4 different families had skin biopsy performed7,9,12–13 and a variety of abnormalities were described, including increased thickness9,12 and focal interruption of the basement membrane,12 and dermo-epidermal junction abnormalities.9 Kidney biopsy performed in 2 individuals from 1 family with nephropathy showed irregular thickening of the basement membrane with loss of integrity affecting the interstitial capillaries but not the glomerular basement membrane.9 Muscle biopsy results were normal in 2 individuals.7,9
The COL4A1 gene consists of 52 exons. Fourteen different mutations have been published. Twelve of these are missense mutations involving highly conserved glycine residues in the triple helical domain of the COL4A1 gene. These mutations result in destabilization of this triple helical domain, which is essential for macromolecular structure integrity.4–7,9–11,14 One mutation resulted in an elimination of the ATG start codon in exon 1, resulting in no protein, or in a translation initiation site moving upstream or downstream.7 The last mutation resulted in an insertion into the highly conserved noncollagenous domain.15 The noncollagenous domain has been shown to contain molecular recognition sequences encoding specificity of COL4A1 promoter and network assembly.17 Mutations involving this domain may result in impaired network assembly and, consequently, reduced basement membrane stability.
Parallels With COL4A1 Mutations in Animal Models
The clinical spectrum of disease closely parallels that found in COL4A1 mutant mice,6 which show many features similar to those in human disease, including porencephaly, perinatal-onset and later-onset hemorrhage, retinal vascular tortuosity, glomerular basement membrane defects, and microalbuminuria.4,6 Porencephaly was reported in <20% of mutant mice, and because all mutant mice were genetically identical, it was suggested this was a result of an interaction between the mutation and environment.4 Subsequent studies showed that all heterozygous mutant animals born by natural delivery had neonatal cerebral hemorrhage. In contrast, no surgically delivered animals experienced severe hemorrhage. This indicates that COL4A1 mutations can weaken vessels and confer increased susceptibility to trauma, in this case birth trauma, which can result in hemorrhage.
Some adult mutant mice presented with sudden-onset neurological events, including seizures and hemiparesis. It was assumed these resulted from intracerebral hemorrhage and, on histological examination, all mutant mice, even those without obvious neurological abnormalities, had intracerebral hemorrhage, almost all of which were subcortical.6
In addition to recurrent hemorrhages, mutant mice had other phenotypes that occur in some patients with COL4A1 mutations. These included retinal vascular tortuosity, defects in the glomerular basement membrane, and microalbuminuria. Interesting, vascular tortuosity was evident only in mice with a specific genetic background (C57BL/6J).6
Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, with lacunar infarcts, leukoaraiosis, and microhemorrhages on MRI.5,7–8,10–14 These features are part of a widespread systemic disease, although systemic features have been absent in a number of cases presenting with cerebral SVD.5,10,13,14 Therefore, a high index of suspicion may be required for diagnosis. It is now appreciated that COL4A1 mutations can present with a variable phenotype including neurological features, such as stroke, migraine, infantile hemiparesis, and epilepsy, and systemic features, including ocular, renal, and muscular involvement.
Clinical and radiological features of SVD in patients with COL4A1 mutations share many similarities with sporadic SVD in hypertensive patients. A number of features may help differentiation from sporadic disease. These include the early age of onset and coexistence of systemic features not seen in sporadic disease, including ocular,7,9–10,12–13 renal,6,9,13 and muscle involvement,9 and the not infrequent coexistence of intracerebral aneurysms.5,7,9–10 Family history may also be a useful pointer, but the wide spectrum of disease within families means questions should not be limited to stroke but should include the full spectrum of systemic disease. A feature of hemorrhages in COL4A1 mutations is that they may be associated with trauma, and this parallels the association with birth trauma present in mutant mice.6
Similarities and differences between the clinical features associated with COL4A1 mutations and other single gene disorders causing SVD are summarized in Table 2. The most common single gene disorder causing SVD is CADASIL. Like COL4A1 syndrome, this results in a radiological picture of lacunar infarcts, leukoaraiosis, and microbleeds. However, ischemic stroke is much more common and hemorrhage is very rare, in contrast to COL4A1. In addition, migraine appears more common and, when it occurs, is almost exclusively with aura.1 Intracerebral aneurysms, infantile hemiparesis, and developmental delay have not been reported in CADASIL but are common in COL4A1. Although arterial abnormalities, with granular osmiophilic material on electron microscopy, can be found in vessels throughout the body in CADASIL, clinical features are limited to the central nervous system, unlike in COL4A1. A characteristic pattern of leukoaraiosis is seen in CADASIL, with particular involvement of the anterior temporal poles, which is present in 90% of individuals.18 Involvement of this region has not been reported in COL4A1.
Cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy appears to be a much rarer single gene disorder causing SVD, which has been described in Japan and which recently has been identified as being attributable to mutations in the HTRA1 gene. Like CADASIL, this results in leukoaraiosis and lacunar stroke and frequently progresses to early-onset dementia, but migraine appears less frequent. Alopecia and spondylosis are common, but the systemic features seen in COL4A1 have not been reported.2 Autosomal-dominant retinal vasculopathy with cerebral leukodystrophy can also present with lacunar stroke-like events; however, in contrast to COL4A1 and CADASIL, hemorrhage and microbleeds have not been reported. This is also a multisystem disorder in which ocular involvement (retinopathy with microangiopathy, microaneurysms, and telangiectatic capillaries, proliferative retinopathy), renal disease (renal insufficiency and proteinuria), muscle cramps, and Raynaud phenomena can occur.3 Amyloid angiopathy also results in intracerebral hemorrhage, microbleeds, and leukoaraiosis.19 However, in contrast to COL4A1, hemorrhage is usually lobar rather than subcortical, and microbleeds, although common, usually occur at the gray–white matter boundary rather than in the subcortical regions.
Almost all mutations resulting in COL4A1 reported so far have been missense mutations involving highly conserved glycine residues in a triple helical domain of the gene. Mutations in codons encoding glycine have been shown to be pathogenic in multiple species.4–7,9–11,14 It has been suggested that the mutation site may relate to phenotype.8 For example, a hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome was reported in 3 families with 2 closely localized COL4A1 mutations.8 Asymptomatic radiological features of SVD and cerebral aneurysms were common in these families. However, other families have shown a widely varying phenotype in different family members.10,13–14 Further data are required to fully evaluate genotype–phenotype correlations. The animal studies demonstrate that environment can have a major effect on phenotype.6 Gene–environment interactions have been shown in other single gene disorders causing stroke; for example, cardiovascular risk factors have been associated with accelerated disease in CADASIL.20–21 Such influences may play a role in COL4A1. It is also possible that modulating genes may influence phenotypes. It has been speculated that these have a major effect on phenotype in CADASIL,21 accounting for as much as 60% of phenotypic variability. It has been hypothesized that COL4A1 mutations may interact with environmental stimuli such as hypertension or exercise-induced stress to which the vessels are particularly susceptible because of their fragility.6 Evidence for this is reported by an association of hemorrhage with exercise in 1 patient.11
COL4A1 demonstrates that abnormalities of the vascular basement membrane can result in lacunar stroke and leukoaraiosis, as well as cerebral hemorrhage and microbleeds. The radiological pattern of disease is similar to that seen in sporadic hypertensive SVD. It has been hypothesized that changes in the basement membrane might explain the predominance of lesions in the basal ganglia.6 Microvasculature devoid of supporting tissue and branching at large angles would be highly susceptible to hemorrhage. Lenticulostriate vessels, small penetrating vessels that supply the basal ganglia and branch off their parent vessels at right angles creating a point of increased stress, meet these susceptibility criteria. This raises the intriguing possibility that other basement membrane genes, such as those other collagens, could also genetically predispose to SVD. However, whether this is the case, or whether more common variants in COL4A1 predispose to apparently “sporadic” SVD, remains to be determined.
- Received February 13, 2010.
- Accepted April 16, 2010.
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