IRD information

IRD information

Inherited retinal diseases, sometimes called inherited retinal degenerations, inherited retinal dystrophies or IRDs are a group of genetic ophthalmic diseases caused by rare mutations in over 300 genes (Wright et al. 2010) and are characterized by visual impairment. IRDs represent the leading cause of severe vision loss in persons between 15 and 45 years of age with an estimated incidence of 1 in every 2,000 people (Cideciyan et al. 2019Cremers et al. 2018).

IRDs are highly heterogeneous and differ in many characteristics such as the onset of disease, varying from birth to adulthood; the rate of disease progression; the extent of visual impairment, and the involvement of other organ systems.

In 2016, the American Academy of Ophthalmology, in collaboration with IRD experts, published recommendations on clinical assessment of patients with IRDs. To know more about clinical diagnosis, genetic diagnosis and information to educate your patients, please follow this link to AAO recommendations.

Inherited Retinal Diseases explained

A video by Tim Stout, MD, PhD, MBA

Leber Congenital Amaurosis

Leber Congenital Amaurosis (LCA)

Leber congenital amaurosis (LCA) is a severe form of autosomal recessive IRD and the most common genetic cause of childhood blindness. It affects about 15,000 patients in the Western world and accounts for 20% of children attending schools for the blind. (den Hollander et al. 2008).

To date, 25 genes causing LCA have been identified, presenting various clinical features depending on the gene involved in the disease, therefore some key clinical symptoms must be considered as warning signs and should lead to patient referral to a specialist

Leber congenital amaurosis key clinical symptoms

Leber congenital amaurosis key clinical symptoms; Visual impairment in early life; Involuntary movement in both eyes (nystagmus); Eye poking, pressing and rubbing (Franceschetti’s oculodigital sign); Slow or no pupil response to changing light (amaurotic pupil)
  • Visual impairment in early life
  • Involuntary movement in both eyes (nystagmus)
  • Eye poking, pressing and rubbing (Franceschetti’s oculodigital sign)
  • Slow or no pupil response to changing light (amaurotic pupil) 

LCA type 10 (LCA10) is caused by mutations in the CEP290 gene and is a common and severe form of LCA (den Hollander et al. 2008). Patients with LCA10 present very poor vision in early childhood often ranging from counting fingers (CF) to non-light perception (NLP). At clinical examination, the retina could appear normal in the infant but does not respond to a light stimulus and the electroretinogram (ERG) is abnormal or nonrecordable. The retina generally degenerates by the second decade of life (Cideciyan et al. 2019).

The c.2991+1655A>G (p.Cys998* mutation is the most frequent CEP290 mutation), particularly in Europe and the USA, with between 60% and 90% of LCA10 individuals having at least one c.2991+1655A>G mutation. (Dulla et al. 2018). In LCA10 caused by CEP290 c.2991+1655A>G, the phototransduction is disrupted and both cone and rod photoreceptors cells degenerate.

Although there are currently no approved treatments for LCA10, new genetic therapies are in development and ongoing clinical trials can be proposed to patients. The most advanced program being our sepofarsen intravitreal RNA therapy, currently tested in the Illuminate study, a pivotal Phase 2/3 clinical trial. (Leroy et al. 2021)

Leber Congenital Amaurosis explained

A video by Tim Stout, MD, PhD, MBA

IRD assessment

IRD assessment

Inherited retinal diseases (IRDs) are heterogeneous and complex disorders that require a specialized evaluation. An early diagnosis of the IRD is crucial for the patient as it can help them receive appropriate advice, care and potentially give them the choice to access treatments and clinical trials.

As such IRDs require collaboration between healthcare professionals starting from the pediatricians and optometrists to the IRD specialists and the expertise of a multidisciplinary team (pediatric ophthalmologists, clinical geneticists, genetic counsellors, etc.)

At the first consultation, some clinical signs should lead to further examinations or referral to a specialist:

  • For an infant: involuntary movement of both eyes (nystagmus), signs of low vision or rapid decrease in visual acuity
  • For an adult: decrease in night vision, reduction of the visual field and/or visual acuity

Questions about patient medical ocular history and family history are also key to help establishing a diagnosis (e.g., potential cases of vision loss or blindness in the family, ideally a pedigree documenting family history of eye disease).

Once the clinical symptoms listed above are present, a patient should undergo additional physical and ophthalmic examinations. (AAO recommendations). Part of the evaluation include:

  • Best-corrected visual acuity (BCVA)
  • Refraction tests
  • Intraocular pressure
  • Anatomic features assessment from the front of the eye to the back of the eye

And more specific tests such as:

  • Electrophysiology (ERG),
  • Specialized imaging (such as OCT, autofluorescence fundus images, wide-field imaging),
  • Specialized functional testing (such as microperimetry, Goldmann visual field and dark-adapted perimetry, full-field stimulus test).

Those tests can be done in places that are devoted for these patients, usually at academic centers and they require preparations. All these examinations will give a higher level of understanding of these IRD and help to establish a clinical diagnosis.

Once an IRD is suspected/clinically diagnosed, there is an additional crucial component: genetic diagnosis. Genetic testing is complex, and the interpretation requires expertise to analyze the variants that are presented. For a patient, the decision for genetic testing is important and requires guidance from an IRD specialist and a genetic counselor.

Inherited retinal diseases assessment explained

A video by Tim Stout, MD, PhD, MBA

The expert

The expert

Professor J. Timothy Stout, MD, PhD, MBA received his medical degree and doctorate in molecular genetics from Baylor College of Medicine where he also completed a post-doctoral fellowship in Human Genetics. He completed his Ophthalmology residency and a surgical retinal fellowship at the Doheny Eye Institute and a medical retina fellowship at Moorfields Eye Hospital and earned his MBA at the University of Oregon. Since 2013, he is Sid W. Richardson Professor and Margarett Root Brown Chair of the Department of Ophthalmology, and Director of Cullen Eye Institute at Baylor College of Medicine. Prior to that, he served as Professor in the Departments of Ophthalmology and Molecular Genetics, VP Commercialization Strategies at Oregon Health & Science and has directed the Clayton Gene Therapy Laboratories since 1995. His research interests in inherited retinal disease include human gene and cell-based therapy, genotype-phenotype correlation and gene mapping and discovery culminating in numerous clinical trials.

Headshot of Tim Stout