COL4A1-A2 Angiopathies

Retinal arteriolar tortuosity is a hereditary disease of small vessels in the retina. It can sometimes cause recurrent retinal haemorrhage. In some families, the syndrome is associated with small vessels disease of the brain causing abnormalities in white matter (leukoencephalopathy), formation of small cavities, bleeds or atrophy in one hemisphere. The association of retinal arteriolar tortuosity’s with these cerebral abnormalities can be due to mutations of the COL4A1 gene.

Definition

Retinal arteriolar tortuosity is a hereditary disease of small vessels in the retina. It can sometimes cause recurrent retinal haemorrhage. In some families, the syndrome is associated with a small vessel disease of the brain causing abnormalities in white matter (leukoencephalopathy), formation of small cavities, bleeds or atrophy in one hemisphere. The association of retinal arteriolar tortuosity’s and these cerebral abnormalities can be due to mutations of the COl4A1 gene.

Epidemiology

The prevalence (number of cases) of the isolated form of hereditary retinal arteriolar tortuosity is currently not known with precision. Some twenty families and more than a hundred cases have been observed and described in the medical literature. The frequency is probably underestimated because the disease does not always produce symptoms and the visual impairment observed is usually reversible.

The link between “arterial tortuosity’s” and “cerebral abnormalities” (leukoencephalopathy, cavities in the cerebral tissue, hemispheric atrophy or hemorrhages) as a result of mutations in gene Col4A1 was reported in only 6 families in 2007. The frequency of this association is probably underestimated.

Clinical description and prognosis

Retinal arteriolar tortuosity’s syndrome is usually benign. It is rarely responsible for retinal bleeds. Such haemorrhage can be silent and there may be no symptom. In certain cases, it may lead to a loss of visual acuity in one eye. This visual impairment is usually reversible.

When associated with cerebral damage, the disease may also lead to various neurological disorders:

• infantile hemiplegia (weakness and lack of development in one half of the body in infants)
• slight mental retardation
• epilepsy
• migraine with aura (visual or sensory impairments accompanying headaches)
• ICHs (possibly stimulated by trauma or certain treatments)

Other abnormalities have sometimes been observed in the eye (cataract) or kidneys (haematuria or presence of blood in urine). Mutations in the Col4A1 gene may also produce other clinical signs, in particular muscle cramps, various abnormalities in the anterior chamber of the eye, renal problems and aneurysms in the intracranial arteries. It is also more than likely that the full spectrum of the disease has not yet been discovered.

Because of the recent discovery of the gene, not all the symptoms and signs of the disease are yet known.

Etiology – Pathophysiology

The origin of the familial forms of isolated retinal arteriolar tortuosity is still unknown.

The association of retinal arteriolar tortuosity’s and leukoencephalopathy is connected to mutations in the COL4A1 gene on chromosome 13. The genetic abnormality is responsible for changes in a protein, collagen Type IV which is a constituent part of basal membranes (in blood vessels for example). It may therefore be a cause of vessel fragility.

In mice, mutations of the COL4A1 gene are responsible for traumatic hemorrhages in the brain (especially at birth) and abnormalities in blood vessel walls.

Diagnosis (criteria – methods)

Retinal arteriolar tortuosity are initially diagnosed during an examination of the fundus by an ophthalmologist.

Photographs of the retina (using a device called a retinograph), sometimes completed by angiography of the blood vessels in the retina (injection of a dye into a vein in the arm to see the vessels more clearly), show that the branches of the central retinal artery in the retina (after the 2nd or 3rd division) are tortuous. These abnormalities are limited to the small arteries and may sometimes be associated with minor retinal hemorrhages.

When the vessel abnormalities are associated with cerebral damage, an MRI must be carried out and include at least the weighted sequences in T1, T2 and T2*weighted imaging.

This examination is used to screen for the abnormalities described during the syndrome:

• lesions in the cerebral white matter (usually in the posterior regions of the brain)
• cavities of variable sizes (possibly corresponding to dilatation around the blood vessels in the brain)
• atrophy of a cerebral hemisphere
• sequels of cerebral haemorrhage or traces of minor bleeds.

If the retinal arteries are tortuous and there are cerebral abnormalities, genetic screening will be used to confirm the diagnosis. The test will reveal any abnormality in the COL4A1 gene encoding for a collagen protein that is a major constituent of the vessel wall.

Treatment

At present, there is no specific treatment for this disorder.

An ophthalmological examination and the repeated examination of the fundus is required if there is any retinal haemorrhage although these hemorrhages are usually benign, and are responsible for regressive visual impairment.

It is usually recommended to avoid the factors leading to retinal haemorrhage – intense physical effort (especially with respiratory blockage), activities with a high risk of ocular and head trauma.

After a brain haemorrhage, the treatment is the same as the treatment for ICH of any other origin.

When the diagnosis of a retinal and cerebral disorder associated with a Col4A1 mutation is certain, any factors likely to cause an ICH must be limited:

• Any anticoagulant medication should always be discussed and closely monitored
• Because of the potential risk of ICH in new-borns at childbirth, a caesarean section may be discussed
• After an ICH, violent sports and intense physical effort are not recommended

For further information regarding this disease and networks of expert center, please click here.