Choroideremia: X-linked retinal degeneration, diagnosis and gene therapy research

Choroideremia is a progressive degeneration of the retina and the tissue that supports it. A review by Oxford authors in Expert Review of Ophthalmology describes it as an X-linked recessive retinal dystrophy caused by mutations in the CHM gene, which encodes a protein called Rab escort protein-1 (REP1). Loss of function mutations cause a progressive loss of retinal pigment epithelium (RPE), the layer that supports the photoreceptors, with photoreceptor loss following.

The name comes from the appearance of a prominent choroid on examination, though the review explains that the disease arises mainly from RPE and photoreceptor degeneration with loss of the choroid following later. Unlike most forms of retinitis pigmentosa, narrowing of the retinal vessels and waxy pallor of the optic disc are not features.

MedlinePlus Genetics describes the first symptom as usually an impairment of night vision, which can occur in early childhood, followed by a progressive narrowing of the visual field (tunnel vision) and a decrease in the ability to see detail. The Oxford review adds that poor night vision may pass unnoticed by both child and parents until chance events such as trips to the cinema or countryside at night, and that most patients retain normal central acuity until the end stages of disease.

The same review describes reduced night vision in early adulthood with blindness in late middle age, noting that the disease is slowly progressive. MedlinePlus Genetics says that the vision impairment worsens over time, that progression varies between individuals, and that all individuals with the condition will develop blindness, most commonly in late adulthood.

• Difficulty seeing in dim light, often from childhood.

• Gradual narrowing of the field of vision.

• Central vision usually preserved until later stages.

• Carriers (usually women) are generally unaffected but may have patchy retinal changes.

The CHM gene sits on the X chromosome. MedlinePlus Genetics explains that males have only one X chromosome, so one altered copy is enough to cause the condition, whereas females have two copies and are usually carriers. A female carrier can pass on the altered gene, and fathers cannot pass X-linked traits to their sons.

The Oxford review notes that observation of diffuse or patchy RPE mottling in carriers within the family is very helpful to strengthen the diagnosis in the clinic, and that confirmation of the pathogenic mutation is required for genetic counselling and trial enrolment.

The Oxford review says the fundal appearance of choroideremia is highly characteristic, though a few rare retinal dystrophies may mimic the picture, including carriers of dominant RPE65 mutations, Oliver-McFarlane syndrome and gyrate atrophy. Diagnosis combines the retinal appearance, an X-linked family history, retinal imaging, field testing and electrophysiology, and is confirmed by genetic testing for CHM mutations.

Because choroideremia may be mistaken for retinitis pigmentosa, referral to a specialist inherited retinal disease service is valuable, particularly for families wanting to understand inheritance.

There is currently no established treatment that halts the degeneration. Management is supportive: monitoring, refractive and low vision support, and genetic counselling. Choroideremia has, however, become a leading target for gene therapy. The Oxford review explains that it is readily diagnosed in the clinic, relatively uniform in appearance and slow progressing, giving a wide therapeutic window, and that trials of retinal gene therapy using an adeno-associated viral vector have demonstrated safety and early efficacy. A phase II trial, REGENERATE, began in the United Kingdom in 2015.

A review in Cold Spring Harbor Perspectives in Medicine reports that gene therapy has demonstrated some benefit in clinical trials, but that challenges remain in gaining regulatory approval, in part because slow progression makes benefit difficult to show in short pivotal trials, and because the surgical detachment of the fovea needed to deliver the treatment can cause initial harm to vision. People interested in trials should discuss them with their retinal specialist, who will know what is currently open.

Practical planning includes lighting at home and work, mobility training before night vision becomes a safety issue, and low vision aids as central vision eventually declines. Charity-run peer support and counselling can help families, particularly when a diagnosis is made in a child or when several relatives are affected.

Because the condition is passed on through families, genetic counselling is important for female relatives who might be carriers and for decisions about pregnancy. Clinical genetics services can discuss testing options.

On the NHS, diagnosis is made through hospital ophthalmology and a specialist inherited retinal disease service, with clinical genetics for testing and counselling. These services are concentrated in a small number of centres, so referral from local ophthalmology may be needed.

Private care can offer faster imaging, but genetic confirmation and trial access generally run through NHS specialist centres. Ask any provider how information will be shared with those services.