Retinal Arteries, Tortuosity Of

A number sign (#) is used with this entry because of evidence that retinal arterial tortuosity (RATOR) is caused by heterozygous mutation in the COL4A1 gene (120130) on chromosome 13q34. One such family has been reported.

Description

Familial retinal arterial tortuosity is characterized by marked tortuosity of second- and third-order retinal arteries with normal first-order arteries and venous system. Two-thirds of patients experience variable degrees of symptomatic transient vision loss due to retinal hemorrhage following minor stress or trauma (summary by Nischler et al., 2011).

Clinical Features

Beyer (1958) described tortuous retinal arteries with foveal hemorrhage in a 43-year-old man and his 17-year-old son. A 12-year-old son showed early changes. Polycythemia was present in the 17-year-old. Werner and Gafner (1961) described tortuous arteries in a 47-year-old man and his son and 2 daughters. Cagianut and Werner (1968) observed 4 persons in 1 family with retinal arteriolar tortuosity and recurrent hemorrhages. Goldberg et al. (1972) described a family with 12 cases of retinal vascular tortuosity and/or retinal hemorrhage in 5 sibships, including 3 instances of father-to-son transmission. One of the 12 had retinal hemorrhage without tortuosity.

Wells and Kalina (1985) reported 3 families with autosomal dominant retinal arteriolar tortuosity and spontaneous retinal hemorrhages. All hemorrhages resolved with recovery of normal vision. Arteriolar tortuosity was often not present in children with hemorrhages but later became apparent during adolescence. Several members of 2 families showed either tortuosity alone or hemorrhages alone, and the authors noted that these findings may be independent manifestations. Wells and Kalina (1985) concluded that the vascular anomaly is acquired and progressive rather than static and congenital, and that the disorder may be overlooked in children.

Clearkin et al. (1986) reported a family with retinal arteriolar tortuosity affecting 6 members over 3 generations. Three members developed tortuosity in late adolescence. Four members also had retinal hemorrhage, and 2 had tortuosity only. The proband suffered permanent visual impairment in one eye due to optic disc infarction.

Sears et al. (1998) reported a family with typical features of the disorder.

Zenteno et al. (2014) studied a Spanish father and 2 daughters with retinal arterial tortuosity. The 53-year-old father presented with photophobia, and examination revealed marked tortuosity of second- and third-order arterioles bilaterally as well as discrete hypopigmentation of the retinal pigment epithelium. The venous system appeared normal, and there was no evidence of previous retinal hemorrhage. The proband's 21-year-old daughter had an episode of exercise-related mild retinal hemorrhage at age 15 years, at which time retinal examination revealed increased tortuosity of second- and third-order arterioles, several round areas of perifoveal intraretinal hemorrhage on the right, and foveal hemorrhage on the left. The hemorrhage resolved spontaneously, but she experienced several recurrences over the next 5 years. The proband's 18-year-old daughter had an episode of exercise-related retinal hemorrhage at 13 years of age, at which time she was found to have increased tortuosity of retinal arterioles and bilateral intraretinal hemorrhage. The hemorrhage resolved spontaneously and she had no recurrences. None of the patients had any anterior segment anomalies, neurologic symptoms, or history of muscle cramps. Hemograms and urinalyses were normal in all 3 patients, as were glomerular filtration rates and creatine phosphokinase levels. Renal ultrasound showed no abnormalities of the kidneys; doppler echography did not detect any aortic or renal arterial abnormalities; and magnetic resonance angiography showed no evidence of leukoencephalopathy or structural anomalies, except for a small (3 mm) internal carotid artery aneurysm in the father.

Inheritance

Goldberg et al. (1972) suggested autosomal dominant inheritance of retinal arterial tortuosity based on reports of male-to-male transmission and occurrence in parents and their children in the absence of consanguinity.

Molecular Genetics

In a Spanish father and 2 daughters with tortuosity of the retinal arteries, Zenteno et al. (2014) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the COL4A1 gene (G510R; 120130.0013). The mutation, which segregated with disease in the family, was not found in 200 ethnically matched control alleles or in 8,600 exomes in the NHLBI Exome Variant Server database. The G510R mutation was previously detected in heterozygosity in affected members of a French family who exhibited features of angiopathy associated with nephropathy, aneurysms, and muscle cramps (HANAC syndrome; 611773) by Plaisier et al. (2010).. Zenteno et al. (2014) suggested that environmental factors and/or other genetic modifiers may influence the phenotypic expression and extent of organ involvement in COL4A1-related disease.