Dr Akshay Narayan MBBS BSc
Foundation Year 2 Doctor, Aberdeen Royal Infirmary, NHS Grampian 

Introduction

Leber Congenital Amaurosis (LCA) is a rare genetic eye disorder that is the most common cause of inherited sight loss in children. It is estimated to affect 1 in 40,000 newborns and leads to severe, irreversible loss of vision by affecting the retina (1). LCA was named in 1957 after it was first described by Theodor Karl Gustav von Leber in 1869 (2). He was responsible for the first description of Leber’s hereditary optic neuropathy, a completely different condition that is easy to confuse LCA with. In current literature, LCA is thought to represent 5% of all retinal dystrophies and accounts for 20% of visual impairment amongst children in special schools (3).

Aetiology

LCA is a monogenic hereditary retinal condition that is predominantly inherited using an autosomal recessive pattern of inheritance. In especially rare cases, LCA is inherited in an autosomal dominant fashion. Thus far, 27 genes have been implicated in the aetiology of LCA with 24 genes associated with recessive, 2 associated with dominant and 1 associated with either form of the disease (4). Mutations in the CEP290, CRB1, GUCY2D, and RPE65 genes are the most commonly observed and account for approximately 45% of cases (5). Although our understanding of the genetics of LCA has progressed leaps and bounds in the recent years, the genetic cause of the disease is still unknown in approximately 20% of cases.

Risk factors

LCA is thought to affect males and females equally. As it is a genetic eye condition, the main risk factor for being born with it is parent/parents who are affected or carriers of the disease-causing variant. These individuals can be identified through genetic testing prior to pregnancy or prenatal screening.

Clinical Presentation

Babies with LCA are usually born with very poor sight and it tends to deteriorate through childhood. Within the first few months, parents may notice that their child is not responding to visual cues. Upon close observation of their eyes they may also notice involuntary movement of the eyes. As the child grows, he/she may be prone to rubbing, pressing and rubbing the eye. This phenomenon is known as the oculo-digital sign and is done to mechanically stimulate the dysfunctional retina (6). Prolonged rubbing and pressing of the eye may lead to them looking sunken. Extra-ocular symptoms such as hearing loss, disruption of sense of smell and developmental delay may also be present.

Upon referral to an ophthalmologist, quick inspection of the eyes is highly likely to demonstrate nystagmus. By exploring the clinical history further, the child is also likely to complain of photophobia and nyctalopia. Pupillometric assessment is likely to demonstrate sluggish or absent pupillary response. Examination by a slit lamp is also likely to shows signs of keratoconus. Assessing the child’s refractive status is also likely to reveal hyperopia.

Upon visualizing the fundus of the child, they are likely to have a normal fundus appearance in the early stages of the disease. As the disease progresses, fundus abnormalities such as bone-spicule pigmentation, chorioretinal degeneration and subretinal flecks may present later in life.

Differential diagnosis

Differential diagnoses include early-onset retinitis pigmentosa, Senior-Loken syndrome, Joubert syndrome, Alström syndrome, Stargardt disease, Conorenal syndrome and infantile neuronal ceroid lipofuscinosis (7).

Investigations

Electroretinogram (ERG) is vital to perform in patients with suspected LCA. ERG is a diagnostic test that measures the electrical response of the retina in response to a light stimulus. In patients with LCA, both scotopic and photopic ERGs are severely reduced or extinguished/non-recordable and produce a characteristic flat ERG (8).

Molecular genetic testing can be utilized to assess for mutations in the genes associated with LCA and help to confirm the diagnosis.

Management

Until recently, there was no treatment or cure present for patients with LCA. For these patients, the main aim of management was supportive and to help them cope with the symptoms of the condition. In order to avoid the effects of photophobia, light exposure is kept to a minimum for these individuals. For most of these children, a low vision referral is also instigated to provide them with access to low-vision aids. In children with a high degree of hypermetropia, correction of the refractive error may also be offered. It is vital to ensure that these children have optimal access to educational and work-related opportunities. Genetic counseling is also recommended to patients and their families so that they have an appreciation of the risk posed to further offspring and future generations.

In recent years, a new treatment modality has come to the fore: gene therapy. The main aim of gene therapy is to replace the faulty gene, with a mutation in it, with a normal copy of the gene so as to restore normal function. The main vector that is used to deliver the normal copy of the gene to the target cell is an adeno-associated virus and these are delivered to the retina by subretinal injections.

A randomised controlled phase III clinical study conducted in 2017 found that sequential and bilateral subretinal injection of voretigene neparvovec-rzyl (Luxturna) into patients with LCA produced significant visual improvement at 1-year follow-up (9). Given the encouraging results, this was the first gene therapy product targeting the eye to be approved by the United States Food and Drug Administration and NICE.

However, it is important to point out that Luxturna is only licensed for the treatment of Leber Congenital Amaurosis type 2. Patients must have viable retinal cells as a prerequisite for the intraocular administration of Luxturna. This constitutes only a very small proportion of patients with LCA and for patients with other mutations, there is no proven treatment as yet. Nonetheless, this is an encouraging step in the right direction as it highlights potential therapeutic targets to be investigated in future clinical trials.

Conclusion

LCA is a rare inherited retinal dystrophy that is the most common cause of inherited sight loss in children. Predominantly inherited in an autosomal recessive fashion, these children common present with severe and early visual impairment that is accompanied by poor pupillary response and severely reduced ERG. Although the mainstay of treatment at present is symptomatic and supportive, gene therapy may be of therapeutic benefit in patients with mutations in RPE65.

References

1. “Leber congenital amaurosis”. Genetics Home Reference. August 2010. Retrieved 22 December 2021

2. Heher KL, T.E., Maumenee IH, The natural history of Leber’s congenital amaurosis. Age-related findings in 35 patients. Ophthalmology, 1992. 99: p. 241-245.

3. Kumaran, N., Moore, A. T., Weleber, R. G., & Michaelides, M. (2017). Leber congenital amaurosis/early-onset severe retinal dystrophy: Clinical features, molecular genetics and therapeutic interventions. British Journal of Ophthalmology, 101(9), 1147.

4. Chacon-Camacho, O.F. and J.C. Zenteno, Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases, 2015. 3(2): p. 112-24

5. Stone EM (December 2007). Leber congenital amaurosis – a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. American Journal of Ophthalmology. 144 (6): 791–811. 

6. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372(20):1887–97. 13.

7. Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372(20):1920–6.

8. den Hollander, A.I., et al., Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res, 2008. 27(4): p. 391-419.

9. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2- hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017;390(10097): 849-60