Vasculopathy, Retinal, With Cerebral Leukodystrophy

A number sign (#) is used with this entry because of evidence that retinal vasculopathy with cerebral leukodystrophy (RVCL) is caused by heterozygous mutation in the TREX1 gene (606609) on chromosome 3p21.

Description

Retinal vasculopathy with cerebral leukodystrophy is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud's phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by Richards et al., 2007).

Clinical Features

Grand et al. (1988) reported a family in which multiple individuals had a disorder characterized by central nervous system degeneration and retinal vasculopathy. Histopathologic analysis of brain tissue in affected persons demonstrated white matter 'necrosis' without vasculitis. The CNS lesions were considered unlike any previously reported, leading Grand et al. (1988) to conclude that this was a 'new' hereditary vasculopathy.

Gutmann et al. (1989) described the same disorder in a family with affected brother and sister and affected son of the brother and daughter of the sister. The proposita was a woman of Ashkenazi Jewish ancestry who developed progressive loss of vision in her right eye beginning at age 52. She also had had long-standing weakness and pain in her legs. Evaluation at the age of 57 showed retinal exudates and hemorrhage with decreased visual acuity as well as leg weakness and hyperreflexia. Westergren erythrocyte sedimentation rate was elevated. Magnetic resonance imaging and computerized tomography brain scan demonstrated bilateral white matter lesions which progressed. The daughter of the proposita developed transient visual loss and progressive forgetfulness in her early thirties. She had bilateral lower limb hyperreflexia. A biopsy of punctate skin lesions on her thighs demonstrated vasculitis. A brother of the proposita died of presumed brain tumor at the age of 51. In his late forties he had developed progressive visual loss, difficulty concentrating, speech difficulty, seizures, and a mild hemiparesis. The son of this man developed progressive visual loss, forgetfulness, and muscle pains in his legs in his late thirties. Fluorescein angiogram demonstrated retinal perivascular extravasation of dye. He had bilateral lower limb hyperreflexia, and by magnetic resonance imaging of his brain, lesions in the periventricular white matter.

Terwindt et al. (1998) described hereditary vascular retinopathy (HVR), Raynaud phenomenon (179600), and migraine in a large Dutch family originally reported by Storimans et al. (1991). The disorder showed autosomal dominant inheritance and was characterized by microangiopathy of the retina, accompanied by microaneurysms and telangiectatic capillaries that appeared preferentially around the macula (Storimans et al., 1991).

Ophoff et al. (2001) reported that abnormalities could be detected by use of fluorescein angiography in otherwise asymptomatic family members who were 25 to 30 years old, suggesting an age of onset in young adulthood. Later stages of the disease involved occlusion of branches of large retinal arteries, avascular areas in the retinal periphery, and sometimes proliferative retinopathy with extensive avascular areas, even close to the optic disc. Of affected members of this family, 80% also had Raynaud phenomenon and migraine was present in 70% of individuals with HVR; a combination of migraine and Raynaud phenomenon was observed in 55% of patients with HVR. Vascular retinopathy is also a prominent feature of the hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) described by Grand et al. (1988), Gutmann et al. (1989), and Jen et al. (1997). The distinctive feature in the families reported by Grand et al. (1988) and Jen et al. (1997) was the presence of progressive subcortical contrast-enhancing lesions with surrounding edema, mimicking tumors and prompting biopsy in numerous affected family members. In the North American family of Chinese ancestry with HERNS reported by Jen et al. (1997), electron microscopy showed distinctive multilamination of subendothelial basement membranes of capillaries in the brain and other tissues.

A notable similarity among the 3 families in whom linkage to the same region was demonstrated by Ophoff et al. (2001) was the high prevalence of migraine-like headaches. On the other hand, Raynaud phenomenon was reported only in patients with HVR, and pseudotumors as seen in both cerebroretinal vasculopathy and HERNS had not been reported in HVR.

Siveke and Schmid (2003) described 2 brothers with cerebroretinal vasculopathy who had elevated serum levels of gamma-glutamyltranspeptidase and alkaline phosphatase with normal transaminases for several years prior to the diagnosis of CRV and the onset of typical cerebroretinal manifestations. Cirrhosis developed in one of the brothers. Both brothers suffered from bilateral osteonecrosis of the femoral head at about 30 years of age, which required total hip arthroplasty.

Mateen et al. (2010) reported the clinical course of members of the large kindred reported by Grand et al. (1988). A 44-year-old woman belonging to this kindred had daily tension-type headaches and chronic sinusitis. Retinal examination showed microvascular disease with minimal progression and without visual loss, and laboratory studies showed mild elevation of liver transaminases. Brain MRI showed a lesion abutting the frontal horn of the right lateral ventricle, which appeared larger after 6 months and was surrounded by edema with a central zone of presumed necrosis. At 12 months, however, the lesion had regressed with near resolution of the surrounding edema without treatment. Her affected father and paternal grandfather also had histories of tumor-like lesions of the brain. Mateen et al. (2010) noted that in RVCL, these lesions may occur without neurologic symptoms. The authors also emphasized that treatment of these lesions is unclear.

Mapping

In the large Dutch family reported by Terwindt et al. (1998) with hereditary vascular retinopathy, Raynaud phenomenon, and migraine, Ophoff et al. (2001) mapped the locus for HVR to 3p21.3-p21.1. In the family with cerebral retinal vasculopathy reported by Grand et al. (1988) and in the family with HERNS reported by Jen et al. (1997), Ophoff et al. (2001) found linkage to the same region, suggesting allelism of these disorders.

Inheritance

Richards et al. (2007) demonstrated that retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant disorder.

Molecular Genetics

In 9 families with autosomal dominant retinal vasculopathy with cerebral leukodystrophy, including families previously described by Grand et al. (1988), Storimans et al. (1991), Jen et al. (1997), Weil et al. (1999), and Cohn et al. (2005), Richards et al. (2007) identified 5 different heterozygous frameshift mutations at the C terminus of the TREX1 gene (see, e.g., 606609.0008 and 606609.0009). In expression studies, the truncated proteins retained exonuclease activity but lost normal perinuclear localization.