Brain Small Vessel Disease 2

A number sign (#) is used with this entry because of evidence that brain small vessel disease-2 (BSVD2) is caused by heterozygous mutation in the COL4A2 gene (120090) on chromosome 13q34.

Description

Brain small vessel disease-2 is an autosomal dominant disorder characterized by variable neurologic impairment resulting from disturbed vascular supply that leads to cerebral degeneration. The disorder is often associated with 'porencephaly' on brain imaging. Affected individuals typically have hemiplegia, seizures, and intellectual disability, although the severity is variable (summary by Yoneda et al., 2012).

For a discussion of genetic heterogeneity of brain small vessel disease, see BSVD1 (175780).

Clinical Features

Yoneda et al. (2012) reported a Japanese family with autosomal dominant inheritance of brain small vessel disease associated with porencephaly of varying severity. The proband was found to have an enlarged right lateral ventricle at age 31 weeks' gestation. He showed delayed early development, particularly of motor skills, with poor left hand use, abnormal leg movement, and delayed walking. At age 3, he showed spastic triplegia with left hemiplegic and diplegic gait. He developed seizures at age 10 months, and EEG showed focal spikes in the right frontal region, with later involvement of the right occipital to posterior temporal region and midcentral region. Brain MRI at age 6 years showed an enlarged right lateral ventricle, reduced volume of the right frontal white matter, and atrophic right cerebral peduncle and body of corpus callosum. IQ was 74. His mother had focal seizures at age 18 months, which were well-controlled. She had clumsiness of the left hand in later childhood, as well as transient headaches. At age 31 years, she had very mild monoparesis of the left upper extremity. Brain MRI showed a mildly enlarged right lateral ventricle, and evidence of mild porencephaly or periventricular venous infarction around the enlarged ventricular wall on FLAIR imaging. The proband's maternal uncle and maternal granduncle also had a history of congenital hemiplegia, suggesting a genetic predisposition in the family. A second unrelated Japanese proband was severely affected. He had low APGAR scores and mild asphyxia at birth. Brain ultrasound showed a parenchymal hemorrhage of the right cerebral hemisphere with an enlarged left lateral ventricle. He also showed a coagulation defect, with increased PT and APTT, and received fresh frozen plasma. The coagulation defect normalized at age 7 months. At age 37 days, he had a ventricular shunt placed for progressive enlargement of the lateral ventricles. CT scan at age 2 months showed extremely reduced white matter in the frontal lobes. At age 1 year, 4 months, he had spastic quadriplegia and very poor development. An elder sister had an intraventricular hemorrhage 2 days after birth and underwent ventriculoperitoneal shunting. Her development was almost normal, although internal strabismus was noted. However, she died in an accident at the age of 4 years, and DNA was unavailable.

Cavallin et al. (2018) reported 2 unrelated children, 4 and 11 years of age, with BSVD2. The patients were ascertained from a cohort of patients with cortical malformations. Both had small head circumference (-2 SD), and severe global developmental delay with no language and spastic tetraplegia; 1 had poor overall growth and a feeding tube. One had onset of refractory seizures at 5 months of age; the other had controlled focal seizures. Ophthalmologic examination showed normal fundus in both children, but 1 had intermittent eye fixation and small/tilted optic discs, and the other had esotropia. Brain imaging showed various abnormalities in both patients, including schizencephaly, polymicrogyria, pachygyria, and subcortical and subependymal nodular heterotopia. There were no signs of previous hemorrhage or calcifications.

Zagaglia et al. (2018) reviewed the epileptic seizure phenotype among patients with COL4A2 mutations, noting that most patients have focal onset associated with localization of porencephaly.

Inheritance

The transmission pattern of BSVD2 in the family reported by Yoneda et al. (2012) indicated autosomal dominant inheritance with incomplete penetrance, as 1 carrier was unaffected.

Molecular Genetics

In affected members of a family with BSVD2, Yoneda et al. (2012) identified a heterozygous mutation in the COL4A2 gene (G1152D; 120090.0001). A second heterozygous de novo mutation (G1037E; 120090.0002) was found in an unrelated Japanese boy with the disorder. Overall, these mutations were found in 2 of 35 Japanese patients with porencephaly on brain imaging. COL4A2 was selected as a candidate for sequencing because COL4A1 (120130), with which it forms a heterotrimer, causes BSVD1.

In 2 unrelated patients with BSVD2, Cavallin et al. (2018) identified heterozygous mutations in the COL4A2 gene (G1377R, 120090.0006 and c.1776+1G-A, 120090.0007). The mutations, which were found by direct analysis of the COL4A2 gene and confirmed by Sanger sequencing, were filtered against public databases. Both mutations were inherited from the mothers. The mother of patient 2 was unaffected, whereas the mother of patient 1 had periventricular white matter hypersignals, but had no neurologic symptoms. Family history of this family revealed that a previous pregnancy of the mother had been interrupted due to fetal cerebral hemorrhage; DNA analysis of the fetus found the mutation. In addition, the maternal grandfather of the proband had died of cerebral hemorrhage at age 40 years; DNA was not available from him. Functional studies of the variants and studies of patient cells were not performed, but the mutations were classified as pathogenic based on ACMG criteria.