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Education – Case Studies


An 18 month old boy is referred to you with nystagmus and poor vision. Mother noticed he was not fixing and following or smiling at faces, and his eyes were constantly moving around. No other systemic features. They have had an array comparative genomic hybridisation (aCGH) at 6 months but this was negative with no deletions of 11p13 and WT1. No past medical history or drug history. He was born full-term with no complications and an unremarkable pregnancy. There was no family history or consanguinity reported. On examination, the vision was difficult to assess but 6/36 with both eyes open using Cardiff cards, intraocular pressure was 10 mmHg in both eyes, patient displays a clear cornea, iris hypoplasia and clear lens (Fig 1), fundus examination lacked a macular reflex (Fig 2) and foveal hypoplasia was confirmed on OCT (Fig 3). Ultrasound showed normal axial length.


Diagnosis is isolated aniridia, and PAX6 gene screening is undertaken which reveals a heterozygous nonsense variant in exon 10, c.781C>T p.(Arg261*). The parents were tested for segregation and this was negative so this is a de novo sporadic mutation. This child should be monitored by a paediatric ophthalmologist who can assess their visual development, referred to a general paediatrician if any concerns about systemic associations such as obesity, ataxia or sleep disorder and, as the vision is reduced, given access to a qualified teacher for children with visual impairment (QTVI) to address their current and future educational needs including their nursery placement. The patient requires regular follow-up to monitor progression of corneal disease, cataract and glaucoma with medical and surgical interventions where needed. Regular refraction and provision of tinted or photochromic lenses are required to reduce light sensitivity. Audiological evaluation may help identify and support early school age children with aniridia-associated central auditory processing deficits.

Genetic counselling:

If the parents want another child, they are not at any increased risk as this was not an inherited variant. This patient has a 50% chance of passing it to his offspring in the future (autosomal dominant) so he will benefit from future genetic counselling and family planning when he is an adult.

Clinical trials:

Nonsense suppression therapy is a new small molecule drug-based genetic treatment that can override the effect of in-frame nonsense variants. A drug called ataluren (or Translarna™) binds to the ribosome and weakens its fidelity to recognise a premature stop codon generated by the nonsense mutation, and so instead of translation terminating prematurely with a non-functional truncated protein, it overrides the signal and produced normal full-length functional protein in up to 20-25% levels or normal. There is a phase 2 randomized, double-masked, placebo-controlled study of ataluren in patients with aniridia caused by a nonsense mutations underway (NCT: 02647359). Children as young as 2 years old are eligible. Nonsense mutations account for up to 40% of the disease-causing mutations in aniridia. If this trial is successful, recruitment into a phase 3 study may be an option for the patient.
If the disease progresses and the child develops further complications with corneal keratopathy in the future, there are stem cell transplants in development for limbal stem cell deficiency.
Please follow this link for further updates on studies/trials linked to aniridia:

(Fig 1)  Fundus examination lacked a macular reflex

(Fig 2)  Foveal hypoplasia was confirmed on OCT

(Fig 3). Ultrasound showed normal axial length

USEFUL RESOURCE:  WSPOS World Wide Webinars series: “Episode 14 – Aniridia

Leber Hereditary Optic Neuropathy

An 18 year old University student went to his optician complaining that the vision of both eyes was becoming progressively blurred over the previous months. The visual acuity was 6/60 OD and 6/48 OS and was not improved by glasses (RE +2.00 sph, LE +0.50 sph). He had no past ocular or medical history of relevance and did not take any medications.  He did not smoke and drank ~12 units of alcohol per week.

There was a family history of glaucoma and ‘optic neuritis’ (both conditions had affected his maternal great grandmother) and two maternal cousins were visually impaired from childhood. He was born prematurely at 33 weeks and had a non-identical twin brother.  His twin developed hydrocephalus age 6 that was treated with a ventriculoperitoneal shunt, complicated by bilateral optic atrophy, right amblyopia and squint. 

The student was referred by his optician to eye casualty for further investigation.  On examination, he had normal colour vision and there was no relative afferent pupillary defect (RAPD) but he did have central scotomata detected by Amsler grid.  Fundus examination and autofluorescence imaging were unremarkable (Figures 1&2). The results of blood tests (blood count, liver function, renal function, thyroid function, lipid profile, vitamins B9, B12, D, A, E) were normal.  An autoimmune profile was negative for autoantibodies.

He was referred for a specialist opinion. At this appointment, his visual acuities were further reduced and measured 2/60 OD and 6/60 OS.  His colour vision had deteriorated and he could read only 7/17 Ishihara test plates with his right eye and 8/17 Ishihara test plates with his left eye. OCT imaging showed thinning of the inner retina in the macular region (Figure 3).   There was no evidence of rod or cone system dysfunction in either eye, based on the results of full field electroretinograms (ERGs). However, flash and pattern-reversal visual evoked potentials (VEPs) were significantly reduced in amplitude, suggesting the patient had bilateral optic neuropathy.  Molecular genetic analysis for Leber hereditary optic neuropathy showed he was homoplasmic for the m.11778G>A mutation (p.Arg340His) in the ND4 gene found in mitochondrial DNA.


The patient was enrolled in the GenSight REVERSE clinical trial investigating the safety and efficacy of a single intraretinal injection of ND4 packaged in an adenovirus associated vector (rAAV2/2-ND4) in people diagnosed with LHON 6-12 months after the onset of visual symptoms.1 During follow-up appointments, his visual acuities stabilised at 2/60 OD and 4/60 OS; his central visual field improved slightly.

The patient was registered with sight impairment and referred to the visual support service at his University to provide vision aids, a support worker, scribe and dictaphone to help with writing lecture notes and completing essays during his studies.

Genetic counselling:

The 3 most common mutations (m.3460G>A, m.11778G>A, m.14484T>C) which cause Leber hereditary optic neuropathy affect the function of genes found in mitochondrial DNA. Mitochondrial DNA is inherited maternally, so men cannot pass mitochondrial mutations on to their children; while all females with mitochondrial mutations will pass them on to their children, even if they, themselves, are unaffected by the condition.2. In most cases a history of visual loss affecting maternal relatives at a young age is present, but up to 40% of cases are simplex (i.e., occur in a single individual in a family).

Both males and females can be carriers of LHON mitochondrial DNA (mt-DNA) mutations.  On average, 50% of males and 15% of females with a LHON mutation will lose vision in their lifetime.4 Onset can occur at any age in males and females, although mostly commonly occurs in males aged 15-35 years.5    Progressive visual loss can be very rapid (over a period of months) or may take longer (over years) but around 97% of people with LHON will have bilateral visual loss within one year of diagnosis.3

Clinical trials:

There are several clinical trials of interventions to treat LHON that are recruiting or have completed recruitment:

Idebenone is a short chain benzoquinone and anti-oxidant agent which acts on mitochondria.  In the multicenter RHODOS (Rescue of Hereditary Optic Disease Outpatient Study), a total of 85 affected individuals harbouring one of the three primary mtDNA LHON-causing variants were successfully enrolled. A dose of 300mg/3x/day was found to be safe with no significant drug-related adverse events. Affected individuals, with discordant visual acuities (defined as a difference of >0.2 LogMAR between the two eyes) and at highest risk for further visual loss in the least affected eye, were more likely to benefit from treatment with idebenone.6  In the follow-up study (RHODOS-OFU), the beneficial effect of six months of treatment with idebenone appeared to persist despite discontinuation of the active medication at the end of the trial.7. In a large retrospective study involving 103 individuals with LHON, 44 people with vision loss of less than one year’s duration were treated with idebenone and followed up for at least five years. A greater proportion of those in the treatment group recovered vision compared with the placebo group, and the most consistent factor associated with visual recovery was the early initiation of treatment during the acute phase of the disease process.8 It must be stressed that idebenone will not completely reverse visual loss if there has been significant damage already sustained to the optic nerve, but in those affected individuals who do respond, there is an increased rate and likelihood of visual recovery compared with the known natural history of LHON. There is no evidence to support the prophylactic use of idebenone among asymptomatic individuals with LHON-causing mtDNA variants.

Idebenone is a treatment that is authorised by the European Medicines Agency and marketed in the EU for LHON. The Scottish Medicines Consortium advised in May 2017 that idebenone (Raxone®) is accepted for restricted use within NHS Scotland for the treatment of visual impairment in patients with LHON who are not yet blind, i.e. they do not meet the UK criteria to be registered as severely sight impaired. This advice is contingent upon the continuing availability of the Patient Access Scheme in NHS Scotland or a list price that is equivalent or lower.9  Idebenone is not available in England.

EPI-743: In an open-label study of five individuals with acute LHON treated within 90 days of disease conversion with the antioxidant α-tocotrienol-quinone (EPI-743), a vitamin E derivative, arrested disease progression and reversed vision loss in all but 1 of 5 consecutively treated patients with LHON.  However, an adequately powered, double-blind, randomized placebo-controlled trial is needed to confirm the visual benefit of this agent in both acute and chronic LHON.10  

Gene therapy.   Targeted gene therapy for LHON is being actively explored for affected individuals harbouring the m.11778G>A pathogenic variant. Promising pre-clinical data based on in vitro and rodent models have resulted in the launch of clinical trials of intravitreal injection of a modified adeno-associated virus (AAV2) vector carrying the MTND4 subunit for affected individuals with the m.11778G>A pathogenic variant.11-16   

LUMEVOQ® (Lenadogene nolparvovec) is the gene therapy developed by GenSight Biologics for the treatment of Leber Hereditary Optic Neuropathy (LHON). The RESCUE and REVERSE trials for LUMEVOQ® in Europe were completed in 2019; and patients from those trials have been invited to participate in a long-term follow-up study. In addition, GenSight Biologics has been conducting a natural history study (REALITY) and mechanistic studies in animals to supplement the data from RESCUE and REVERSE.17 The results of RESCUE and REVERSE showed clinically meaningful improvements in visual function.18,19

Gensight is meeting with the European Medicines Agency to prepare a marketing authorization application (MAA) in September 2020 to launch the Company’s lead product LUMEVOQ® (GS010; lenadogene nolparvovec) in Europe.20

Hormone therapy. The marked male bias in LHON could reflect the protective influence of female sex hormones, and this hypothesis was recently investigated using LHON cybrid cell lines. Treatment with oestrogens was found to reduce reactive oxygen species levels in LHON cybrids, with increased activity of the antioxidant enzyme superoxide dismutase. The beneficial effects of oestrogen translated into more efficient mitochondrial oxidative phosphorylation.21. Further research is needed to determine whether females with LHON-causing variants are at increased risk for visual loss around the onset of menopause. 

Mitochondrial replacement. In vitro fertilization (IVF) techniques aimed at preventing the maternal transmission of mtDNA pathogenic variants from mother to child are being developed. Pronuclear transfer and metaphase II spindle transfer are the two approaches that are being investigated, and further experimental work to validate the safety and potential clinical applicability of these IVF strategies is currently ongoing.22

The following links provide additional information and updates on clinical trials linked to Leber Hereditary Optic Neuropathy:

Leber hereditary optic neuropathy. Genetics Home Reference (GHR). 2013;


  2. Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. 2000 Oct 26 [Updated 2016 Jun 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020
  3. McClelland, C., Meyerson, C. and Van Stavern, G.McClelland, C., Meyerson, C., & Van Stavern, G. (2015). Leber hereditary optic neuropathy: current perspectives. Clinical Ophthalmology, 1165. doi: 10.2147/opth.s62021
  5. Fraser, J., Biousse, V. and Newman, N. (2010) “The Neuro-ophthalmology of Mitochondrial Disease”, Survey of Ophthalmology, 55(4), pp. 299-334. doi: 10.1016/j.survophthal.2009.10.002.
  6. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Rummey C, Metz G, Leinonen M, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677–86. PubMed PMID: 21788663
  7. Klopstock T, Metz G, Yu-Wai-Man P, Büchner B, Gallenmüller C, Bailie M, Nwali N, Griffiths PG, von Livonius B, Reznicek L, Rouleau J, Coppard N, Meier T, Chinnery PF. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain. 2013;136:e230. PubMed PMID: 23388409.
  8. Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P. Idebenone treatment in Leber’s hereditary optic neuropathy. 2011;134:e188.
  10. Sadun, A. (2012) “Effect of EPI-743 on the Clinical Course of the Mitochondrial Disease Leber Hereditary Optic Neuropathy”, Archives of Neurology, 69(3), p. 331. doi: 10.1001/archneurol.2011.2972.
  11. Qi X, Lewin AS, Hauswirth WW, Guy J. Suppression of complex I gene expression induces optic neuropathy. Ann Neurol. 2003;53:198–205. PubMed PMID: 12557286.
  12. Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J. SOD2 gene transfer protects against optic neuropathy induced by deficiency deficiency of complex I. Ann Neurol. 2004;56:182–91. PubMed PMID: 15293270.
  13. Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J. Use of mitochondrial antioxidant defences for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol. 2007;125:268–72. PubMed PMID: 17296905.
  14. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83:373–87. PubMed PMID: 18771762.
  15. Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J. Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Arch Ophthalmol. 2010;128:1129–35. PubMed PMID: 20837795.
  16. Lam BL, Feuer WJ, SchiffmanSchiffmanSchiffman Schiffman JC, Porciatti V, Vandenbroucke R, Rosa PR, Gregori G, Guy J. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol. 2014; 2014;132:428–36. PubMed PMID: 24525545.
  18. Patrick Yu-Wai-Man, Nancy J Newman, Valerio Carelli, Valerie Biousse, Alfredo A. Sadun, Mark L Moster, Catherine Vignal-Clermont, Robert C Sergott, Thomas Klopstock klopstock, Laure Blouin, Magali Taiel, Pierre Burguière, Caroline Chevalier, Barrett Katz, Jose Alain Sahel; Bilateral Visual Improvement with Unilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON). Invest. Ophthalmol. Vis. Sci. 2020;61(7):5181.
  21. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun AA, d’Amati G, Carelli V. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. 2011;134:220–34
  22. Chinnery PF, Craven L, Mitalipov S, Stewart JB, Herbert M, Turnbull DM. The challenges of mitochondrial replacement. PloS Genet. 2014;10:e1004315


Dr Georgios Karastatiras & Dr Denize Atan, Bristol Eye Hospital

(Fig 1)  Colour photographs of the right and left fundus

(Fig 2)  Autofluoresent images of the right and left fundus

(Fig 3)  OCT images of the right and left macular region

Stargardt’s Disease

A 20-year-old gentleman presented to medical retina clinic with a slow but steady decline in visual acuity since he was aged 14 years. In particular, he struggled to the see the whiteboard at school and experienced more difficulty navigating in the dark than his brothers and sisters. There was no family history of consanguinity and no family history of vision problems. Past medical history included acne vulgaris, but he was not on any medication.

 At initial examination, his unaided visual acuities measured 0.40 OD and 0.40 OS LogMAR and was not improved with glasses. Fundoscopy revealed multiple, yellow fleck-like deposits at the macula of both eyes (Figure 1). Autofluorescence imaging demonstrated a central area of hypofluorescence surrounded by a circle of hyperfluorescence at the macula of both eyes (Figure 2). Electrodiagnostic tests provided evidence of focal macular dysfunction affecting both eyes (abnormal pattern ERG but normal full field ERG) consistent with Stargardt macular dystrophy.


A few months later, the patient reported that his vision had further declined and he was struggling to see in both dim and bright light settings.   His unaided visual acuities measured 0.68 OD and 0.74 OS LogMAR.  He felt that he might have to stop his further education.

Our clinical practice is to monitor individuals for changes in visual acuity and field and offer help to improve function with visual aids, such as illuminated magnifiers. With his current level of visual impairment, this gentleman can be offered registration as sight-impaired under UK regulations. Should he experience further deterioration in his visual field or if his visual acuity falls below 1.0 LogMAR, he could be classed as severely sight-impaired and become eligible for financial benefits. He was referred to the vision support services available at his University to see how they could assist him to complete his studies. Dietary advice was given regarding avoidance of vitamin A and E multivitamins and to consider supplementation with lutein and zeaxanthin. In addition, he was advised to wear sunglasses to avoid ultraviolet damage and consider cessation of smoking. He was advised against learning how to drive.


Genetic counselling:

The phenotypic features combined with the results of electrodiagnostic testing suggest the most likely diagnosis is Stargardt disease. Genetic testing identified two gene alterations in the ABCA4 gene consistent with autosomal recessive inheritance: c.2588G>C (p. Gly863Ala) is a non-synonymous single nucleotide mutation leading to the substitution of the amino acid Glycine with Alanine, which is known to be pathogenic; the second variant c.*147 C>T affecting the 3-prime UTR region is also a single nucleotide mutation but has unknown effect on the protein structure of ABCA4, NM_000350.2.  It is therefore classified as a variant of unknown clinical significance (VUS). The parents were not tested for segregation, which meant it was not possible to confirm either allele originated from each parent or as sporadic mutations. In our experience, it is not uncommon to make a clinical diagnosis of Stargardt disease but only find one pathogenic variant in the ABCA4 gene. Further work on the growing number of VUS in ABCA4 is required to facilitate accurate genetic counselling for these families.

Clinical trials:

Stargardt disease is caused by mutations that affect the function of the ABCA4 (ATP Binding Cassette subtype A4) protein, which is important for the processing of vitamin A and photoreceptor function (1).  In the absence of the ABCA4 protein, toxic vitamin A aggregates form, such as bisretinoid A2E pigment. These pigments accumulate in the retina and lead to retinal pigment epithelium cell death and photoreceptor toxicity (1).

Gene therapy offers the chance to replace the defective gene with a working copy of the gene injected into the subretinal space in the macular region, and thereby increase the local production of ABCA4.  The main obstacle to scientists over the last decade to develop a gene therapy for Stargardt disease is that the ABCA4 gene is too large for standard viral vectors. A new adeno-associated virus (AAV) dual vector has been developed which is able to include the full length of the ABCA4 gene and its regulatory elements. Early evidence has shown this vector successfully enhances ABCA4 gene expression in murine models (2).

There have been several clinical trials of gene therapy for Stargardt disease. A summary is found below.

Phase I/II Study of SAR422459 in Patients With Stargardt’s Macular Degeneration (NCT01367444)

 27 patients were enrolled into this study of SAR422459 which involved sub-retinal injection of a lentiviral vector expressing ABCA4 at three difference doses (3). Outcome measures included best-corrected visual acuity, visual field analysis and fundus autofluorescence images to determine delay in retinal degeneration.  This study was terminated in January 2020 due to lack of continued funding.

Zimura Compared to Sham in Patients With Autosomal Recessive Stargardt disease (STGD1)

The aim of this randomised control trial is to determine the efficacy of Zimera, a complement factor C5 inhibitor, in preventing changes to the appearance of photoreceptor cells measured by Optical Coherence Tomography (OCT) (4). 95 participants with recessive Stargardt disease will be recruited. The C5 inhibitor packaged in a recombinant adeno-associated virus vector will delivered by sub-retinal injection.  Evidence from animal models of Stargardt disease have shown increased expression of C5 in the retinal pigment epithelium delivered by AAV subretinal injection (5).

Safety and Efficacy of Emixustat in Stargardt Disease (SeaSTAR) (NCT03772665)

This randomised controlled trial is currently enrolling up to 162 individuals to study the efficacy and safety of Emixustat compared to placebo on macular atrophy in Stargardt disease (6). Emixustat hydrochloride is a small molecular inhibitor of RPE65 (retinal pigment epithelium-specific 65kDA protein), an enzyme involved in the visual cycle. Preclinical studies demonstrated Emixustat reduced the accumulation of lipofuscin and A2E in an animal model of Stargardt disease (7).


  1. Tanna P, Strauss RW, Fujinami K, et al Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options British Journal of Ophthalmology 2017;101:25-30.
  1. Dyka FM, Molday LL, Chiodo VA, Molday RS and Hauswirth WW. Dual ABCA4-AAV vector treatment reduces pathogenic retinal A2E accumulation in a mouse model of autosomal recessive Stargardt disease. Hum Gene Ther. 2019 Sep 30. doi: 10.1089/hum.2019.132.
  1. Sanofi (2019). Phase I/II Study of SAR422459 in Patients With Stargardt’s Macular Degeneration. [online] Clinical trials repository. Available at:
  1. Ophthotech (Ophthotech Corporation) (2018). Zimura Compared to Sham in Patients With Autosomal Recessive Stargardt Disease (STGD1). [online] Clinical trials repository. Available at:
  1. Lenis TL, Sarfare S, Jiang Z, Lloyd MB, Bok D, Radu RA. Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease. Proc Natl Acad Sci U S A. 2017;114(15):3987–3992. doi:10.1073/pnas.1620299114
  1. Acucela Inc. (2018). Safety and Efficacy of Emixustat in Stargardt Disease (SeaSTAR). [online] Clinical trials repository. Available at:
  1. Rosenfeld, P.J., Dugel, P.U., Holz, F.G., Heier, J.S., Pearlman, J.A., Novack, R.L., Csaky, K.G., Koester, J.M., Gregory, J.K. and Kubota, R. (2018). Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology, 125(10), pp.1556–1567. 


Dr Selina Khan & Dr Amanda Churchill, Bristol Eye Hospital 


Dr Denize Atan

(Fig 1)  Colour fundus photographs showing symmetrical distribution of yellow fleck-like deposits at the macula of both eyes.

(Fig 2)  Fundus autofluorescence photographs showing a central area of hypofluorescence and surrounding ring of hyperfluorescence at the macula of both eyes, creating a bull’s eye appearance.


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