Brain Small Vessel Disease 1 With Or Without Ocular Anomalies

A number sign (#) is used with this entry because of evidence that brain small vessel disease-1 with or without ocular anomalies (BSVD1) is caused by heterozygous mutation in the COL4A1 gene (120130) on chromosome 13q34.

Description

Brain small vessel disease-1 is an autosomal dominant disorder with variable manifestations resulting from disruption of vascular basement membranes, particularly in the cerebral vasculature. The increased fragility of these vessels render them susceptible to hemorrhage, as early as in utero or by birth trauma, although the risk remains throughout life and some patients may present in adulthood. This genetic predisposition may extend beyond hemorrhagic stroke to include retinal and renal vascular defects. Clinical features thus reflect the location and severity of the vascular defect, including impaired neurologic development or function, hemiplegia, seizures, and variable ocular anomalies. The disturbed vasculature leads to cerebral degeneration, and brain imaging typically shows 'porencephaly,' hemosiderin deposition, calcifications, lacunar infarcts, enlarged ventricles, and leukoencephalopathy. Some patients may show 'schizencephaly' on brain imaging, which is also attributed to encephaloclastic processes, such as vascular injury. The disorder shows variable penetrance and expressivity (summary by Merello et al., 2008, Gould et al., 2006; Shah et al., 2012; van der Knaap et al., 2006; Yoneda et al., 2013).

'Porencephaly' is a term used for any cavitation or cerebrospinal fluid-filled cyst in the brain. One form, called encephaloclastic, or type 1, porencephaly, is usually unilateral and results from focal destructive lesions such as fetal vascular occlusion or birth trauma. Another form, called 'schizencephalic', or type 2, porencephaly, is usually symmetric and may represent a primary defect or arrest in the development of the cerebral ventricles. Encephaloclastic porencephaly is more common (Airaksinen, 1984; Sensi et al., 1990).

Genetic Heterogeneity of Brain Small Vessel Disease

See also BSVD2 (614483), caused by mutation in the COL4A2 gene (120090) on chromosome 13q34; and BSVD3 (618360), caused by mutation in the COLGALT1 gene (617531) on chromosome 19p13.

Clinical Features

Berg et al. (1983) provided the first description of familial porencephaly. In 1 family, a grandmother was hemiparetic; of her 9 children, 1 had seizures, 1 had hemiparesis and 1 had both, and all 3 children of her oldest son had porencephaly. In a second family, 2 sibs had porencephaly.

The same disorder appears to have been reported by Smit et al. (1984). Van der Knaap et al. (2006) provided follow-up of the family reported by Smit et al. (1984). Reexamination of the 3 affected individuals, a mother and her son and daughter, showed leukoencephalopathy in all 3 and lacunar infarcts, microbleeds, and macrobleeds in the mother. She had divergent squint at age 4 years, and CT scan at age 24 years, following the diagnosis of her children, showed porencephaly and mild diffuse hypodensity of the white matter. She had several stroke-like episodes in her forties. Examination at age 54 years showed mild expressive dysphasia, central facial paresis, and hemiparesis. Her son presented with developmental delay and hemiparesis at age 8 months. CT scan showed porencephaly, and he also had seizures, no active speech, and cognitive defects. Examination at age 33 years showed mild convergent squint, mild central facial paresis, and pseudobulbar dysfunction with masseter reflex and drooling. He had a severe spastic hemiparesis, extensor plantar responses, and polar cataracts. Her daughter developed progressive hydrocephalus at age 6 weeks. Pneumoencephalography showed dilated right lateral ventricle with midline shift. CT scan showed destruction of large parts of the right hemisphere with calcium deposits. She had seizures and delayed psychomotor development but learned to speak. Examination at age 30 years showed mild divergent squint, mild facial paresis, and pseudobulbar dysarthria. She also had hemiparesis and nuclear cataract. Electron microscopy of skin biopsies in the 2 offspring showed striking abnormalities, with about 20% of capillaries having a thickened and fragmented basement membrane. Van der Knaap et al. (2006) concluded that mutations in the COL4A1 gene are a major risk factor for microangiopathy and ischemic insult.

Airaksinen (1984) reported 2 affected sibs who were born after normal full-term pregnancies. One child was diagnosed with cerebral palsy at age 4 months after developing restlessness, abnormal movements, increased muscle tone, and seizures. Brain imaging showed a right-sided dilatation of lateral ventricles and a parietal porencephalic cyst. Her younger brother showed abnormal primitive reflexes and opisthotonos at 6 weeks of age. Brain imaging showed a right-sided cyst and dilated ventricles. Both children were severely handicapped.

Zonana et al. (1986) evaluated 2 families in which 6 persons were affected with infantile hemiplegia and 5 of these were shown to have congenital porencephaly. In the first family, a brother and sister were affected; a 42-year-old uncle had right-sided hemiplegia since infancy and a left-sided porencephalic cyst. In the second family, the proband was seen at 8.5 months of age for left-sided hemiplegia, and the father was said to have mild left-sided hemiplegia since infancy. A paternal uncle's son was said to have mild right-sided hemiplegia since infancy, but examination was impossible. Computerized tomography in patients with familial porencephaly usually shows unilateral enlargement of the lateral ventricle, although a few have had bilateral involvement. The frontal horn usually shows the most enlargement.

Vilain et al. (2002) performed cerebral imaging in 3 of 6 members of a family who had congenital hemiplegia and found porencephaly in all. Cerebral imaging in 3 asymptomatic obligate carriers in this family, including MRI in 1, was normal, indicating that cerebral imaging is unreliable as a means of detecting obligate carriers of familial porencephaly.

Aguglia et al. (2004) reported a 3-generation Italian family in which 9 individuals had type 1 porencephaly inherited in an autosomal dominant pattern. A high rate of miscarriages was reported. Four patients had a severe phenotype with unilateral porencephalic cyst, pyramidal signs, tetraparesis, limb dystonia, seizures, exotropia, visual field defects, and low IQ. The other affected members manifested some of these features. Three patients had perinatal asphyxia, and 4 patients had mitral valve prolapse. The pattern of brain abnormalities were consistent with in utero insults occurring late in the second trimester.

Vahedi et al. (2003) reported a French Caucasian family in which 6 of 8 members were affected over 3 generations by a retinal and central nervous system (CNS) disease consistent with an autosomal dominant pattern of inheritance. All 6 affected members of this family had retinal arteriolar tortuosity, including 1 member with retinal hemorrhage (Gould et al., 2006). Vahedi et al. (2003) noted hypopigmentation of the fundus. In addition, 2 of the genotypically affected persons had infantile hemiparesis, and 3 had migraine with aura. Neuroimaging showed diffuse leukoencephalopathy associated with dilated perivascular spaces in all affected family members. Microbleeds in several areas were observed on MRI scan of the brain, suggesting involvement of the cerebral vasculature in this family. Two members of the family had a fatal intracerebral hemorrhage. One died after cerebral trauma at age 33, and the second had a fatal intracerebral hemorrhage at age 40 while receiving anticoagulant therapy.

Vahedi et al. (2007) provided follow-up of the family reported by Vahedi et al. (2003) and Gould et al. (2006). During a 7-year period, 2 patients died from intracranial hemorrhage. None of 4 affected individuals reported stroke or retinal hemorrhage, and none had dementia. Follow-up brain MRI showed diffuse leukoencephalopathy in 3 of 4 patients. All had dilated perivascular spaces, and 3 had silent microbleeds mainly in the deep white matter. There was no progression of MRI signal abnormalities in severity, number, or location between baseline and follow-up imaging. The oldest affected family member was age 74 years at follow-up. Vahedi et al. (2007) concluded that mutation carriers show diversity in clinical expression and that some may remain clinically asymptomatic.

Sibon et al. (2007) reported a French Canadian family in which 5 individuals had diffuse small vessel disease of the brain and anterior chamber ocular malformations of the Axenfeld-Rieger type. The proband was a 37-year-old woman who had early onset of congenital cataract, congenital glaucoma, microcornea, peripheral opacities, and unilateral amblyopia. She developed sudden right hemiplegia at age 35, and brain imaging showed diffuse leukoencephalopathy. There were also periventricular diffuse white matter hyperintensities suggestive of old infarcts, as well as hypointensities in the basal ganglia and cerebellum suggestive of past microbleeds. She did not have retinal hemorrhages or arteriolar tortuosity. She later developed left retinal detachment, right spastic paraparesis, central facial palsy, and severe depression. The proband's daughter, brother, sister, and mother also had anterior chamber ocular anomalies and diffuse leukoencephalopathy. One patient had infantile hemiparesis and left paraventricular porencephaly. Retinal vessel tortuosity was not observed. Sibon et al. (2007) noted that Van Agtmael et al. (2005) had described a mouse Col4a1 mutant with ocular anterior segment dysgenesis consistent with Axenfeld-Rieger anomaly.

De Vries et al. (2009) reported 2 Dutch sibs with antenatal intracerebral hemorrhage and porencephaly. The sibs were born at 34 and 31 weeks' gestation, respectively. The first infant had a possible antenatal trauma at 23 weeks' gestation. Routine brain imaging in both infants at birth showed resolving intracranial hemorrhages in the left lateral ventricles with an ipsilateral porencephalic cyst and small cystic lesions in the periventricular white matter of the contralateral hemisphere. At age 18 months, the older child had right-sided hemiplegia, strabismus associated with a quadrant hemianopia, but no cataract or tortuosity of the retinal arteries. His developmental quotient was 68. At age 9 months, the second child had increased tone of the lower limbs and strabismus. Brain MRI of the mother showed mild ventricular dilatation and multiple hyperintense lesions in the periventricular white matter of both hemispheres, but no dilated perivascular spaces or evidence of microbleed. Her father had a history of transient ischemic attacks and died at age 52 years after a severe intracranial hemorrhage. MRI of the father showed porencephalic dilatation of the left lateral ventricle and hyperintense lesions in the periventricular white matter of both hemispheres. Genetic analysis identified a heterozygous mutation in the COL4A1 gene (G1580R; 120130.0011) in both sibs and the mother. De Vries et al. (2009) suggested that COL4A1 mutation carriers are at risk for intracranial hemorrhage from fetal life into adulthood and that antenatal intracerebral hemorrhage can lead to porencephaly in the newborn infant.

Coupry et al. (2010) reexamined affected members of the French Canadian family originally described by Sibon et al. (2007) and reported a similarly affected mother and daughter from an unrelated family. Additional ocular features observed in the French Canadian family included strabismus; myopia; increased intraocular pressure, which in 1 patient was intractable and resulted in glaucoma; microcornea; corneal opacities, with corneal neovascularization in 1 patient; corectopia, with polycoria in 1 patient; iridocorneal synechiae, with iridogoniodysgenesis in 1 patient; and macular hemorrhage, peripapillary atrophy, and choroidal atrophy in 1 patient. The affected mother from the second, unrelated family presented at age 47 years with acute hemiparesis due to spontaneous left lenticular nucleus hemorrhage. Two weeks later, she experienced left central facial palsy and dysarthria due to a contralateral subcortical cerebral hemorrhage. Brain MRI revealed extensive periventricular leukoencephalopathy and 2 recent cerebral hemorrhages. Eye examination showed severe hyperopia and lens opacities without visual impairment. Her 10-year-old daughter had bilateral congenital cataract, prominent Schwalbe line (posterior embryotoxon), and relative microcornea; brain MRI showed periventricular leukoencephalopathy. Both mother and daughter had a history of migraine headaches, which occurred without aura in the daughter.

Shah et al. (2012) performed a retrospective review of the clinical records of 4 unrelated families with COL4A1 mutations in which 5 affected children had recurrent childhood-onset strokes, infantile hemiplegia/spastic quadriplegia, and infantile spasms (seizures). Ocular features such as congenital cataracts, astigmatism, hypermetropia, and nystagmus were noted; 1 patient also exhibited microphthalmia and anterior segment dysgenesis. Microcephaly and developmental delay or learning difficulties were present in 3 cases. In 3 of the families, one or more family members were affected in multiple generations, with a total of 11 affected individuals identified. Shah et al. (2012) noted wide intrafamilial variation in clinical presentation: in 1 family, the female proband was severely affected with microcephaly, seizures, developmental delay, microphthalmia, congenital cataracts, and anterior segment dysgenesis, with white matter changes on brain MRI, while her mutation-positive mother had only congenital cataracts, with no neurologic symptoms and no abnormalities detected on MRI.

Lemmens et al. (2013) reported 2 unrelated families, of Belgian and Dutch descent, with brain small vessel disease with hemorrhage. In the Belgian family, the 48-year-old male proband had a history of retinal detachment and developed an acute left-sided hemiparesis due to a right thalamic hemorrhage. Skin biopsy of this patient showed ultrastructural abnormalities of the capillaries, with increased basement membrane thickness, focal interruptions, and formations of pools of fragmented basement membranes. His 21-year-old daughter showed hemiparesis at age 1 year, which was associated with unilateral porencephaly potentially caused by stroke in utero. Brain MRI as a young adult showed supratentorial white matter abnormalities. The proband's 74-year-old mother reported no neurologic abnormalities, but brain MRI showed severe white matter disease. In the Dutch family, 4 affected family members were described. The phenotype was variable but included unilateral porencephaly with hemiparesis and intracerebral hemorrhages confirmed by brain imaging.

Rodahl et al. (2013) restudied a large 4-generation family, originally described by Odland (1981), in which there was variable presentation of anterior segment dysgenesis accompanied in some individuals by cerebrovascular disease. Examination revealed that the ocular malformations and their severity varied considerably among family members. Corneal clouding was present bilaterally in 5 individuals and unilaterally in 2; visual acuity in the patients with corneal opacities ranged from 20/25 to light perception. All 7 patients with corneal clouding also exhibited an irregular Schwalbe line, and anterior synechiae extending to the Schwalbe line were present in 5; no family member had elevated intraocular pressure. Iris hypoplasia was present in 6 of the 7 family members with corneal clouding, and the remaining individual had mild sectorial involvement. Mild corectopia was seen in 3 of the 7 patients, and 3 patients underwent cataract surgery before 45 years of age. One patient exhibited fundus abnormalities consisting of irregular vessels around the optic disc. Cerebral hemorrhage occurred at birth or within the first year of life in 3 patients, resulting in spastic paraparesis, hemiparesis, and/or impaired psychomotor development. Signs of cerebral involvement developed in 3 more family members within the first decade of life: 1 had multiple intracerebral hemorrhages, 1 had ischemic cerebellar stroke and optic neuritis, and 1 died from a neurologic disease of unclear origin. Brain CT and/or MRI scans were available in 8 affected individuals, of which 5 showed extensive leukoencephalopathy, 1 showed mild white matter lesions, and 2 were normal; signs of previous hemorrhage were present in 5 individuals. Other systemic abnormalities observed included slight dysphonia in 2 patients, 1 of whom also had hearing loss and cardiomyopathy, and another patient exhibited supraventricular tachycardia. In addition, there were 6 family members who had minor ocular anomalies but no neurologic disease.

Yoneda et al. (2013) reported 15 Japanese probands with mutations in the COL4A1 gene. The brain imaging finding represented a phenotypic spectrum. Ten of the patients had porencephaly, which is clinically associated with hemi- or quadriparesis, seizures, and intellectual disability. Five patients had imaging more consistent with schizencephaly, which is characterized by transmantle clefts bordered by polymicrogyria in adjacent cortex. One patient had both schizencephaly and porencephaly. The brain abnormalities in about half of the patients were associated with calcification or hemosiderin deposition. Two patients had pontocerebellar atrophy, 1 had cerebellar hypoplasia, and 1 had focal cortical dysplasia. Other variable features included ocular abnormalities (4 patients), increased serum creatine kinase levels (6 patients), and hemolytic anemia (5 patients). Two patients had evidence of antenatal hemorrhage, and 2 others had evidence of severe hemorrhagic destructive lesions. Five mutations were confirmed as de novo events; 1 mutation cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents.

Meuwissen et al. (2015) reported the experience of the Erasmus University Medical Center in sequencing the COL4A1 and COL4A2 genes in 183 index patients, mostly with cerebral hemorrhage or porencephaly, between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). A review of the literature brought the total to 137 individuals with a COL4A1 mutation, 54 of whom had periventricular leukencephaly or small vessel disease and 53 had porencephaly. Sixteen had cerebral calcifications or microbleeds, and 15 had intracerebral hemorrhage. Twelve had cerebellar atrophy. Other brain MRI complications were rarer. Ophthalmologic findings included 29 with cataracts, 26 with retinal arteriol tortuosity, 10 with strabismus, and 10 with iris hypoplasia, as well as 9 with posterior embryotoxon. Renal cysts and hematuria were present in 4 patients each. Elevated creatine kinase was present in 25, and 18 had muscle cramps.

Matsumoto et al. (2015) reported the prenatal sonographic findings in a patient who had a de novo mutation in the COL4A1 gene. Mild ventriculomegaly was seen at 21 weeks' gestation, progressive dilatation of bilateral ventricle and multiple hyperechogenic lesions at 25 weeks, and a large open cleft extending to the ependymal zone at 28 weeks. Neonatal brain CT showed bilateral open-lip schizencephaly, cortical atrophy, and absence of corpus callosum.

Zagaglia et al. (2018) examined the prevalence and manifestation of epilepsy among 55 previously reported and 44 newly identified patients with mutations in the COL4A1 and COL4A2 genes. The vast majority of patients had mutations in the COL4A1 gene (only 5 patients had COL4A2 mutations). Among 123 previously reported patients, 55 had epilepsy; among the 44 newly identified patients, 38 had epilepsy. Among the new patients, the mean age at seizure onset was 15.4 months, and most (73.7%) had focal onset. Almost 40% developed status epilepticus. About half of patients with focal seizures had porencephaly, and focal seizures tended to localize to the porencephalic region. However, about 50% with focal seizures did not have porencephaly; these patients had diffuse brain abnormalities, including enlarged ventricles, periventricular leukoencephalopathy and extensive white matter loss. Drug resistance was reported in 66.6%. Of the 55 published patients with epilepsy, 5 of 11 with focal seizures had porencephaly; overall, porencephaly was found in 31 of 55 (56%) of published patients. Epilepsy was the presenting feature in 7% of the published patients and 13% of the newly identified patients. Impaired intellectual development was found in 39 of 55 previously published cases and in 36 of 38 new patients; motor abnormalities showed a more insidious onset. There were a few cases of adult patients with normal neurologic examinations who had a milder seizure phenotype phenotype. Zagaglia et al. (2018) noted the nonspecific brain imaging abnormalities in patients without frank porencephaly.

Clinical Management

Because of reduced penetrance with possible modifying factors and variable phenotype in patients with COL4A1 or COL4A2 mutations, Meuwissen et al. (2015) recommended initial workup in families with a mutation, including neurologic, ophthalmologic, renal, and cardiac screening in mutation carriers and first-degree relatives with a 50% chance of harboring the mutation.

Inheritance

In families with porencephaly or schizencephaly reported by Yoneda et al. (2013), transmission was consistent with autosomal dominant inheritance with incomplete penetrance.

Sensi et al. (1990) described a family with type 2 porencephaly in which male-to-male transmission was observed.

The transmission pattern of small vessel disease with hemorrhage in the families reported by Lemmens et al. (2013) was consistent with autosomal dominant inheritance.

The family reported by Haar and Dyken (1977) may have had this disorder; see 306960.

Mapping

In affected members of an Italian family with a diagnosis of autosomal dominant type 1 porencephaly, Aguglia et al. (2004) found linkage of the disorder to a locus on chromosome 13qter (maximum multipoint lod score of 3.16 at marker D13S285).

In 7 affected individuals from a 4-generation family with multiple ocular anomalies, brain hemorrhage, and extensive leukoencephalopathy, Rodahl et al. (2013) performed a genomewide scan using SNP markers and identified a shared 14-cM interval at the terminal part of chromosome 13q, extending from 110,173,324 to 115,045,259 (GRCh37). This region included the COL4A1 gene.

Molecular Genetics

Gould et al. (2005) assessed families previously described by Smit et al. (1984) and Aguglia et al. (2004) with brain small vessel disease for mutations in the COL4A1 gene. The first family had a heterozygous gly-to-arg substitution at codon 1236 (120130.0001); the second family had a heterozygous gly-to-ser substitution at codon 749 (120130.0002). Both mutations changed conserved glycine residues within the Gly-X-Y repeats in the triple helical domain.

Phenotypic similarities between Col4a1 (120130)-mutant mice and the French family with small vessel disease reported by Vahedi et al. (2003) prompted Gould et al. (2006) to assess the family for COL4A1 mutations. Upon sequence analysis of the COL4A1 gene, Gould et al. (2006) identified a heterozygous mutation (G562E; 120130.0003).

In affected members of 3 unrelated Dutch families with BSVD1, Breedveld et al. (2006) identified heterozygous missense mutations in the COL4A1 gene (120130.0004-120130.0005). Two of the families (families A and B) had previously been reported by Mancini et al. (2004).

In 5 affected members of a French Canadian family with leukoencephalopathy associated with Axenfeld-Rieger and other ocular anomalies, Sibon et al. (2007) identified heterozygosity for a missense mutation in the COL4A1 gene (G720D; 120130.0010).

In a mother and daughter with migraine headaches, ocular anomalies, periventricular leukoencephalopathy, and cerebral hemorrhage, Coupry et al. (2010) directly sequenced the COL4A1 gene and identified a heterozygous missense mutation (G755R; 120130.0020).

In 5 affected children from 4 unrelated families with recurrent stroke, infantile hemiplegia/spastic quadriplegia, infantile spasms, and ocular anomalies, Shah et al. (2012) identified heterozygosity for 4 different missense mutations in the COL4A1 gene, including the G755R substitution in 1 boy and a G773R substitution (120130.0021) in 2 sibs.

Yoneda et al. (2013) identified heterozygous COL4A1 mutations in 10 (16.4%) of 61 patients with porencephaly who did not have mutations in the COL4A2 gene and in 5 (50%) of 10 additional patients who also showed schizencephaly on brain imaging (see, e.g., G1326R; 120130.0017). The patients with schizencephaly also had hemosiderin deposition and calcification, consistent with an encephaloclastic process. Nine mutations occurred at highly conserved glycine residues in the gly-X-Y repeat of the collagen triple-helical domain, and Yoneda et al. (2013) noted that impairment of the collagen IV heterotrimer assembly caused by mutant COL4A1 is a common pathologic mechanism. The findings also demonstrated that COL4A1 mutations can result in both porencephaly and schizencephaly on brain imaging, supporting the same pathologic mechanism for these 2 imaging findings.

In affected members of 2 unrelated families, one Belgian and the other Dutch, with brain small vessel disease with hemorrhage, Lemmens et al. (2013) identified 2 different heterozygous truncating mutations in the COL4A1 gene (120130.0018 and 120130.0019). Analysis of patient cells suggested that the mutations caused haploinsufficiency rather than a dominant-negative effect. However, the affection status of members of the Dutch family differed in the text and figure 1 of the article, calling into question the segregation of the mutation (120130.0019) with the phenotype. Lemmens (2014) stated that 'Some of the patients were only clinically or genetically assessed which made statements about affection status difficult at the time.'

In 9 affected members of a 4-generation family with multiple ocular anomalies, brain hemorrhage, and extensive leukoencephalopathy mapping to chromosome 13q, Rodahl et al. (2013) identified a heterozygous missense mutation in the COL4A1 gene (N1627K; 120130.0022). The mutation was present in all 7 family members who had corneal clouding with other ocular and neurologic symptoms as well as in 2 relatives with minimal ocular anomalies and neurologic disease; however, it was not found in 6 family members who had minor ocular anomalies but no neurologic symptoms, or in 185 blood-donor controls.

Deml et al. (2014) reported a Hispanic brother and sister with congenital cataracts, marked microcornea, moderate microphthalmia, and mild intellectual disability, who were both negative for mutation in 71 known microphthalmia-associated genes. By performing whole-exome sequencing in the sibs, the authors identified heterozygosity for the G773R missense mutation in the COL4A1 gene. The mutation, which was confirmed by Sanger sequencing, was not found in blood samples from their unaffected parents or in a maternal buccal sample, suggesting that 1 parent had gonadal mosaicism for the COL4A1 mutation. Brain MRI at age 6 years in the sister showed nonspecific changes compatible with a small vessel disease process, but magnetic resonance angiography was normal. Analysis of COL4A1 in 24 additional patients with anophthalmia/microphthalmia of unknown genetic etiology revealed heterozygosity for another missense mutation (G708R; 120130.0023) in a 5-year-old Indian girl with congenital cataract, bilateral microcornea and Peters anomaly, unilateral microphthalmia, and unilateral retinal detachment. She had no history of developmental delay, and the only nonocular clinical feature reported was clinodactyly; imaging studies were not performed. The mutation was not found in her mother, and her father was unavailable for screening. Deml et al. (2014) stated that microphthalmia had been reported in 4 of 97 previously published cases of COL4A1-associated cerebrovascular disease.

Animal Model

Gould et al. (2005) identified and characterized a novel mouse mutant generated by random mutagenesis with severe perinatal cerebral hemorrhage. In addition to cerebral hemorrhage, mutant mice were smaller than control littermates and had multiple pleiotropic phenotypes including ocular abnormalities, mild renal abnormalities, and reduced fertility that appeared to be influenced by genetic context. Homozygous mutant mice were not viable after midembryogenesis, and about 50% of heterozygous mice died within a day of birth. The authors suggested that reduced viability may be explained by variability in the severity and/or location of cerebral hemorrhages that were externally visible in most mutant pups. Detailed analysis of a subset of postnatal day 0 pups identified cerebral hemorrhages in 12 of 12 mutant pups but in 0 of 9 littermate controls. About 18% of adult heterozygous mutant mice had obvious porencephalic lesions (6 of 33) that were not observed in wildtype controls (0 of 17). Mutant mice carried a splice site mutation causing excision of exon 40 of the Col4a1 gene. COL4A1 gives strength to basement membranes. Gould et al. (2005) found that compared with controls, mice heterozygous for the Col4a1 exon 40 deletion had uneven basement membranes with inconsistent density and focal disruptions. The major site of hemorrhage was the brain.

Gould et al. (2006) showed that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha-1, predisposes both newborn and adult mice to intracranial hemorrhage. Surgical delivery of mutant mice alleviated birth-associated trauma and hemorrhage. Although surgical delivery prevented cerebral hemorrhage, it did not prevent perinatal death. Newborn pups were often cyanotic and in respiratory distress. Mutant pups had compact lungs with few or no terminal air spaced visible. This finding suggested that respiratory defects contributed to perinatal mortality.

Van Agtmael et al. (2005) identified an allelic series of 3 induced dominant mouse mutants with missense mutations in the Col4a1 gene: Svc (small with vacuolar cataracts), Raw (retinal arteriolar wiring), and Bru (bruised). Bru heterozygotes showed ocular anterior segment defects similar to Axenfeld-Rieger anomaly, including iris defects, corneal opacities, vacuolar cataracts, iris/corneal adhesions, buphthalmos, and optic nerve cupping, as well as retinal detachment. Bru mice also developed a renal glomerulopathy. The Raw mice showed a silvery appearance of the retinal arterioles. The observed phenotypes were associated with generalized basement membrane defects, but showed a high degree of tissue-specific variability. All mutations affected crucial glycine residues in a Gly-Xaa-Yaa repeat in the central collagen domain.

Mao et al. (2015) tested the effects of a Col4a1 mutation in 2 different genetic backgrounds in mice to compare how genetic context influences ocular dysgenesis, intraocular pressure (IOP), and progression to glaucoma. Col4a1 mutant mice maintained on a C57BL/6J (B6) background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny analyzed. The CAST/EiJ inbred strain had a relatively uniform and profound suppression on the effects of the Col4a1 mutation, and mutant CASTB6F1 mice were only mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe anterior segment dysgenesis and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.