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Clinical science
The RPGRIP1-related retinal phenotype in children
  1. Arif O Khan1,2,
  2. Leen Abu-Safieh2,
  3. Tobias Eisenberger3,
  4. Hanno J Bolz3,4,
  5. Fowzan S Alkuraya1,5,6
  1. 1Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  2. 2Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  3. 3Center for Human Genetics, Bioscientia, Ingelheim, Germany
  4. 4Institute of Human Genetics, University of Cologne, Cologne, Germany
  5. 5Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
  6. 6Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  1. Correspondence to Arif O Khan, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia; arif.khan{at}mssm.edu

Abstract

Aim To characterise the childhood retinal phenotype associated with recessive mutations in retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a gene that has been infrequently associated with Leber congenital amaurosis, the most severe form of childhood non-syndromic retinal dystrophy.

Methods This was a retrospective case series analysis.

Results Nine children (seven families) with homozygous RPGRIP1 mutations were identified. All were noted by their families to have had shaking eyes, variable eye turn and/or poor vision at or soon after birth and to be more comfortable in darkness than daylight. At the age of examination (2–7 years of age) fixation was poor or non-existent with hemeralopia, nystagmus, variable strabismus and often an oculodigital sign (6/9). Electroretinography was non-recordable. The posterior pole was grossly normal with mild vascular attenuation, but one girl did have a subtle abnormal macular reflex associated with decreased autofluorescence. Retinal pigment epithelium changes were seen in the periphery, ranging from mottling to bone spicules, and cycloplaegic refraction was hyperopic (+3 to +10 diopters). Two children were photophobic and two were developmentally delayed. One boy had oesotropia and nystagmus that decreased when hyperopic spectacles were worn. One girl decreased her nystagmus amplitude by adopting a particular gaze preference.

Conclusions Recessive RPGRIP1 mutations cause a severe cone–rod Leber congenital amaurosis phenotype, often with poor or no fixation and an oculodigital sign. In the first decade of life retinal changes are clinically most evident in the periphery. Despite the typical severity of the phenotype, fixation can improve for some affected children with wear of the associated hyperopic refraction or by a null point that dampens nystagmus. Spectacle correction of high refractive errors should be encouraged.

  • Child health (paediatrics)
  • Electrophysiology
  • Retina
  • Genetics

https://doi.org/10.1136/bjophthalmol-2012-303050

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    Introduction

    Rather than a single disease, Leber congenital amaurosis, considered the most severe form of childhood non-syndromic retinal dystrophy, is in fact phenotypically and genetically heterogeneous with at least 17 candidate genes identified to date.1 ,2 Molecular diagnosis is useful for genetic counselling, raising or decreasing the suspicion for syndromic disease and determining eligibility or non-eligibility for potential gene therapy trials. However, the many candidate genes can make molecular diagnosis challenging. Genotype–phenotype correlations are necessary to efficiently guide molecular testing. While such correlations are emerging,1 ,3–5 they are limited, particularly for children. In this study we describe the clinical features of children in the first decade of life with retinal dystrophy from recessive mutations in retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), which have been reported as an infrequent cause of Leber congenital amaurosis.1 ,2 RPGRIP1 interacts with RPGR in the photoreceptor cilium where it helps to maintain normal photoreceptor function.1 ,2

    Methods

    Institutional review board approvals were granted for this study, a retrospective review of children referred to one of the authors (AOK, 2009–2012) for genetic counselling of early childhood retinal dystrophy and found to harbour recessive RPGRIP1 mutations. When visual acuity could not be measured, fixation was recorded. Complete ophthalmic examination was performed, including orthoptic assessment, indirect ophthalmoscopy with a 20-dioptre (D) lens and cycloplaegic refraction (following cyclopentolate 1%). Spherical equivalents were recorded when astigmatism was ≤1.50 D. Standard full-field electroretinography was performed for all patients,6 under chloral hydrate sedation when necessary. Molecular diagnosis in these consanguineous and/or endogamous Saudi Arabian families was made by previously described strategies of homozygosity-mapping guided candidate gene analysis7 or by next-generation sequencing of a panel of candidate genes.8

    Results

    Clinical

    All nine children (aged 2–7 years old) were from consanguineous and/or endogamous families and had non-recordable full field electroretinography. Patient characteristics are summarised below and in table 1.

    View this table:
    Table 1

    Patient summary

    Patient 1 (sister of patient 2)

    A 7-year-old girl was noted to have variable eye turn and shaking eyes since birth. Her younger sister (patient 2) was similarly affected. Her visual difficulties were most obvious when she started walking at 1 year old. She had always been more comfortable in the dark. Visual acuity could not be measured and fixation was poor with variable nystagmus. Fundus examination was grossly normal (with mild vessel attenuation) but with peripheral retinal pigment epithelium mottling and bone spicules (figure 1). Cycloplaegic refraction was +3.75 D in both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Figure 1
    Figure 1

    Right eye of patient 1: this image of the mid-peripheral retina superior to the optic nerve in the right eye of patient 1 demonstrates the retinal pigment epithelium mottling often seen in the retinal periphery of affected children. Both eyes had this finding ×360°. This figure is only reproduced in colour in the online version.

    Patient 2 (sister of patient 1)

    A 4-year-old girl was noted to have variable eye turn and shaking eyes since birth. Her older sister (patient 1) was similarly affected. Her visual difficulties were most obvious when she started walking at 1 year old. She had always been more comfortable in the dark. Fixation was poor with nystagmus. Fundus examination was grossly normal (with mild vessel attenuation) but with peripheral retinal pigment epithelium mottling and bone spicules. Cycloplaegic refraction was +3.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Patient 3 (sister of patient 4)

    A 5-year-old girl was noted to have variable eye turn, wandering eye movements and poor vision since birth. Her younger brother (patient 4) was similarly affected. She had always been more comfortable in the dark. Her development was delayed, with limited speech and some behavioural issues. She had wandering eye movements with no fixation and an oculodigital reflex. Fundus examination was grossly normal (with mild vessel attenuation) but with peripheral bone spicules. Cycloplaegic refraction was +3.00 D for both eyes.

    Patient 4 (brother of patient 3)

    A 2-year-old boy was noted to have variable eye turn, wandering eye movements and poor vision since birth. His older sister (patient 3) was similarly affected. He had always been more comfortable in the dark. He had wandering eye movements and no fixation with an oculodigital reflex (figure 2). Fundus examination was grossly normal (with mild vessel attenuation) but with peripheral bone spicules. Cycloplaegic refraction was +4.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Figure 2
    Figure 2

    Patient 4: the typical wandering eye movement and oculodigital reflex are exemplified by this child. His eyes wander inferiorly or superiorly when an object of interest is directly in front of him, and he often pokes either eye (as pictured). Sunken globes from repeated eye poking can be appreciated. This figure is only reproduced in colour in the online version.

    Patient 5

    A 6-year-old girl was noted to have variable eye turn, shaking eyes and poor vision since soon after birth. There was no family history for a similar condition. The mother noted that she was more comfortable in the darkness than in daylight since infancy and has had progressive visual loss. The child was photophobic. She had poor fixation but adapted a moderate right face turn with a slight chin down position, which dampened her nystagmus and improved her fixation. Fundus examination was grossly normal (with mild vessel attenuation) but there was a subtle abnormality to macular reflex which autofluorescence testing confirmed to be associated with lack of autofluorescence (figure 3). There was peripheral retinal pigment epithelium mottling. Cycloplaegic refraction was +7.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Figure 3
    Figure 3

    Left eye of patient 5: (A) although the fundus was grossly normal other than mild vascular attenuation, a subtle abnormal macular reflex was noted in this girl. Both eyes were similar. (B) Autofluorescence testing (SPECTRALIS, Heidelberg Engineering, Heidelberg, Germany) confirmed the associated lack of autofluorescence signal in the macular region. Both eyes were similar. This figure is only reproduced in colour in the online version.

    Patient 6

    A 3-year-old boy was noted to have variable eye turn, shaking eyes and poor vision since soon after birth. There was no family history for a similar condition. He was developmentally delayed and had limited speech. When upset he would shake his entire body. Fixation was poor with nystagmus. The posterior pole was grossly normal (with mild vessel attenuation) but the periphery could not be assessed. Cycloplaegic refraction was +8.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Patient 7

    A 3-year-old girl was noted to have variable eye turn, shaking eyes and poor vision since soon after birth. There was no family history for a similar condition. The child was photophobic. Fixation was poor with nystagmus and an oculodigital reflex. The posterior pole was grossly normal (with mild vessel attenuation) but with peripheral retinal pigment epithelium mottling. Cycloplaegic refraction was +7.00 D for both eyes; corrective lenses were prescribed. When the child wore her full hyperopic correction glasses, the nystagmus and eye turn noticeably decreased.

    Patient 8

    A 2-year-old girl was noted to have variable eye turn, shaking eyes and poor vision since soon after birth. There was no family history for a similar condition. Fixation was poor with nystagmus and an oculodigital reflex. The posterior pole was grossly normal (with mild vessel attenuation) but with peripheral retinal pigment epithelium mottling. Cycloplaegic refraction was +6.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Patient 9

    A 2-year-old girl was noted to have variable eye turn, wandering eye movements and poor vision since soon after birth. There was no family history for a similar condition. Fixation was poor with nystagmus and an oculodigital reflex. The posterior pole was grossly normal (with mild vessel attenuation) but with peripheral retinal pigment epithelium mottling. Cycloplaegic refraction was +10.00 D for both eyes; corrective lenses were prescribed but the child was non-compliant with glasses wear.

    Genetics

    Patients 1–4, 6, 7 and 9 were part of a previously published cohort of patients with retinal dystrophy who underwent a homozygosity analysis guided protocol for molecular diagnosis.7 Patients 5 and 8 underwent a previously described strategy of next-generation sequencing of retinal dystrophy candidate genes.8 The homozygous RPGRIP1 mutations found in patients 1–9 are summarised in table 1.

    Discussion

    These nine children with homozygous RPGRIP1 mutations had a severe cone–rod Leber congenital amaurosis phenotype with poor or no fixation, nystagmus since early infancy, hyperopia, a non-recordable electroretinogram and often an oculodigital reflex. Clinical fundus examinations revealed mild vascular attenuation but results were otherwise grossly normal for all, although a 6-year-old girl had a subtle abnormality to her macular reflex associated with decreased autofluorescence. All had peripheral retinal epithelium changes that ranged from mottling to bone spicules. In two children, nystagmus decreased with hyperopic spectacle correction or a compensatory gaze preference.

    With the exception of one study, in which four affected Pakistani families were diagnosed as having cone–rod dystrophy,9 the literature describes the RPGRIP1-related retinal phenotype as Leber congenital amaurosis.3 ,5 ,10–14 Clinical details in these reports are often limited, particularly for young children. In the first report of RPGRIP1-related retinal dystrophy, Dryja and colleagues10 screened RPGRIP1 as a candidate gene in a cohort of patients with Leber congenital amaurosis and found recessive RPGRIP1 mutations in 3 out of 57 patients (6%). At least two were hyperopic and at least one had peripheral bone spicules (at 15 years old). RPGRIP1 had been chosen as a candidate gene because its product specifically interacts with RPGR, which when mutated causes X-linked retinitis pigmentosa. RPGR and RPGRIP1 are both present in the ciliary structure that connects inner and outer segments of rod and cone photoreceptors. RPGRIP1 also localises to the photoreceptor outer segments and to amacrine cells in the inner retina.13 In the same year that Dryja and colleagues reported RPGRIP1 mutations as a cause for Leber congenital amaurosis,10 Gerber and colleagues11 screened 142 unrelated patients with Leber congenital amaurosis and found RPGRIP1 mutations in eight patients (5.6%); these authors had previously found RPGRIP1 mutations in two affected families for whom homozygosity mapping suggested RPGRIP1 as a candidate gene.11 No specifics were given regarding the RPGRIP1-related Leber congenital amaurosis phenotype in these patients. Subsequently, Hanein and colleagues5 reported clinical details and comprehensive mutational analysis of the all known Leber congenital amaurosis candidate genes at the time in 179 unrelated patients in an attempt to understand phenotype–genotype correlations. Based on four patients (2%) for whom they identified recessive RPGRIP1 mutations (but for whom age of phenotypic ascertainment was not provided), the authors suggested the RPGRIP1-related phenotype to be a severe cone–rod dystrophy with early peripheral and macular degeneration of the retina, bone spicule pigments in the peripheral retina and hyperopia less than 7 D. The authors also concluded that this specific phenotype could be caused by recessive AILP1 mutations but that when hyperopia was more than 7 D the most appropriate candidate gene was GUYC2D.5 In another phenotype–genotype study for Leber congenital amaurosis, Galvin and colleagues12 genotyped 110 patients with Leber congenital amaurosis and documented two patients (2%), aged 8 years and 2 years, to have recessive RPGRIP1 mutations. Their cycloplaegic refractions were +10.25 D and +10.00 D, respectively, contradicting the suggestion of Hanein and colleagues5 that hyperopia in RPGRIP1-related Leber congenital amaurosis does not exceed +7.00 D; other clinical features were not detailed for these two patients.12 In what is the largest series of RPGRIP1-related retinal dystrophy to date, McKibbin and colleagues3 documented features of four affected North Pakistani families (16 patients, aged 8–67 years old, mean 23.5 years old). The authors described cataracts (after the second decade) and bone spicules as common and keratoconus, macular atrophy (after the second decade) and nummular pigmentation as being less common. Nyctalopia and photophobia were described for approximately one-third of cases.3 RPGRIP1 mutations may be more common in Pakistan, where 4 out of a sample of 14 Leber congenital amaurosis families (29%) harboured homozygous RPGRIP1 mutations. Pakistan is also where the four families with RPGRIP1 mutations who were diagnosed as having cone–rod dystrophy rather than Leber congenital amaurosis originated; that phenotype seems to have been characterised by a rapid loss of vision in the second decade of life but further details were not provided.9

    Our study characterises RPGRIP1-related disease in children during the first decade of life. The fact that, unlike previous authors who provided some phenotypic details,3 ,5 we did not observe frank macular abnormalities, keratoconus, or cataracts is likely related to the age of phenotypic ascertainment in our study versus that of previous studies. Hanein and colleagues5 did not mention the age of their phenotypic ascertainment when they described frank macular abnormalities in their four patients with RPGRIP1 mutations, while McKibbin and colleagues3 characterised the finding as occurring after the second decade of life. With time children from our cohort may indeed develop visible macular atrophy, cataracts and/or keratoconus. We did observe a subtle abnormal macular reflex in one child (patient 5) that autofluorescence testing confirmed to be associated with atrophy. This is the only child in our cohort who was able to cooperate for such testing, and it is possible that with more detailed macular assessment, which is often difficult in young children with poor vision, additional subtle macular findings could have been noted in our cohort.

    An important finding in our series was that two patients had nystagmus that could be decreased and thus fixation that could be improved. In a 3-year-old girl (patient 7), strabismus and nystagmus noticeably decreased when she wore her hyperopic spectacle correction, although we were unable to quantitate this with objective measurements. In a 6-year-old girl (patient 5), nystagmus abated when she adapted a moderate right face turn and mild chin-down position, which she did when she wanted to visually concentrate on an object. Appropriate strabismus surgery would be expected to improve her fixation in primary position but was not performed because the parents were not bothered by her abnormal head position. Although the RPGRIP1-related retinal phenotype is typically severe, these two cases are evidence that there can be a role for spectacles or extraocular muscle surgery in improving fixation. The wear of spectacles to correct high refractive error should be encouraged in these patients.

    Although RPGRIP1 mutations are considered an infrequent cause of Leber congenital amaurosis, accounting for only 2% to 6% of cases in large series,3 ,5 ,10–14 we have found it to be a recurrent cause for the phenotype in our population. In a recent study of retinal dystrophies from Saudi Arabia that included a sample of 16 Leber congenital amaurosis index cases for whom gene mutations were identified, 9 out of 16 (56%) harboured homozygous RPGRIP1 mutations.7 That same study suggested that RPGRIP1 mutations are not a typical cause for retinal dystrophy phenotypes other than Leber congenital amaurosis.7 Surprisingly, an older study that performed candidate gene analysis (including RPGRIP1 analysis) for 37 Leber congenital amaurosis families from Saudi Arabia reported no causative RPGRIP1 mutations.15 The reason for the discrepancy is unclear, because we continue to find homozygous RPGRIP1 mutations in Saudi Arabian children with the Leber congenital amaurosis phenotype described in this study. Our finding of four different homozygous RPGRIP1 mutations in seven Saudi families is not surprising. Multiple mutations rather than a single mutation in a given disease gene is a common phenomenon for recessive genetic eye disease in the region, and we have attributed this phenomenon to preference for consanguinity and large family size superseding single founder effect.16–22 Recently in the neighbouring United Arab Emirates, two siblings with the Leber congenital amaurosis phenotype we describe were reported with yet another homozygous RPGRIP1 mutation.23 Early recognition of this recurrent form of Leber congenital amaurosis in the region is important for early accurate diagnosis and genetic counselling, and could become of even greater importance if gene-specific therapies become available.24–26

    To date, recessive mutations in RPGRIP1 have only been associated with non-syndromic retinal ciliopathy.9–14 ,27 However, RPGRIP1 also has important interactions in the renal cilium cells and there is at least one cilium gene homologous to RPGRIP1, namely RPGRIP1-like (RPGRIP1L), important for maintenance of multiple organs. RPGRIP1 interacts with nephrocystin-4/nephroretinin (NPHP4), mutations in which have been associated with retinal–renal ciliopathies.27 ,28 Recessive mutations in the RPGRIP1 homologue RPGRIP1L cause multisystem ciliopathies such as Joubert syndrome and Meckel–Gruber syndrome, which often include developmental delay.27 ,28 In our case series two out of nine patients had non-specific developmental delay. Whether this was coincidental or related to their recessive RPGRIP1 mutations is difficult to ascertain.

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    Footnotes

    • Contributors The authors were responsible for conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval.

    • Funding This study was funded in part by a KACST grant (08-MED497-20) to FSA. The providers of the grant had no role in the conduct, design, or interpretation of the research.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Institutional review boards of the King Khaled Eye Specialist Hospital and of the King Faisal Hospital and Research Center.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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    • Correction
      Correction
      BMJ Publishing Group Ltd.BMA House, Tavistock Square, London, WC1H 9JR
      British Journal of Ophthalmology 2014; 98 420-420 Published Online First: 11 Feb 2014. doi: 10.1136/bjophthalmol-2012-303050corr1