CASE REPORT Year : 2022  |  Volume : 29  |  Issue : 1  |  Page : 59-65  

Intermediate uveitis in retinitis pigmentosa associated with a novel homozygous splice site mutation in PRPF8

Abdulrahman H Badawi1, Moustafa S Magliyah2, Patrik Schatz3, Abdulaziz Al-Shehri4
1 Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
2 Vitreoretinal Division, King Khaled Eye Specialist Hospital; Department of Ophthalmology, Prince Mohammed Medical City, Riyadh, Saudi Arabia
3 Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology, Clinical Sciences, Skane University Hospital, Lund University, Lund, Sweden
4 Department of Surgery, Taif University, Taif, Saudi Arabia

Date of Submission05-Dec-2021Date of Acceptance08-Dec-2021Date of Web Publication23-Nov-2022

Correspondence Address:
Dr. Abdulrahman H Badawi
Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al-Oruba Street, P.O. Box: 7191, Riyadh 11462
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/meajo.meajo_98_22

   Abstract 

The manifestation of intermediate uveitis (IU) in patients with retinitis pigmentosa (RP) is uncommon and poses diagnostic and management challenges. In this case, we describe the clinical features and management outcomes in an RP patient with a novel homozygous splice site mutation in PRPF8. A 21-year-old male presented with unilateral decrease of vision in the right eye for 1 week. Retinal dystrophy features were present in the left eye. After 2 weeks of topical steroid therapy, near-total resolution of IU was achieved and vision improved to 20/30. Signs of (RP) were present bilaterally, with the right eye more affected than the left. Genetic testing indicated a novel homozygous c. 3061-6_3061-3del mutation in the PRPF8 gene. IU in young patients with RP can be effectively treated with a short course of topical steroids, sparing the need for systemic immunosuppressives. After the improvement in IU, the right eye showed more advanced RP changes.

Keywords: Autosomal dominant retinitis pigmentosa, intermediate uveitis, PRPF8, retinitis pigmentosa, splice site mutation

How to cite this article:
Badawi AH, Magliyah MS, Schatz P, Al-Shehri A. Intermediate uveitis in retinitis pigmentosa associated with a novel homozygous splice site mutation in PRPF8. Middle East Afr J Ophthalmol 2022;29:59-65
How to cite this URL:
Badawi AH, Magliyah MS, Schatz P, Al-Shehri A. Intermediate uveitis in retinitis pigmentosa associated with a novel homozygous splice site mutation in PRPF8. Middle East Afr J Ophthalmol [serial online] 2022 [cited 2022 Nov 24];29:59-65. Available from: http://www.meajo.org/text.asp?2022/29/1/59/361882    Introduction 

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases that lead to rod and cone degeneration. A previous study reported numerous vitreous cells in younger patients with RP, with a higher number of inflammatory cells correlating with more severe visual dysfunction.[1] However, another study reported that Bardet–Biedl syndrome and Leber congenital amaurosis are the two most common genetic diseases associated with intermediate uveitis (IU), although the specific mutations were not described.[2] Faster progression of retinal dystrophy is associated with more severe vitritis.

IU presents with the clinical features of the anterior chamber and vitreous inflammation and management usually involves topical or periocular steroids and, if warranted, systemic steroids and other immunosuppressives.[3] Publications are rare on the management of IU in patients with RP. We report a case with RP that presented with IU and was successfully managed with topical steroids. The patient was homozygous for a novel splice site mutation in PRPF8.To the best of our knowledge, this is the first description of a disease-causing homozygous mutation in this gene, which is otherwise reported in autosomal dominant RP.[4],[5]

   Case Report 

A 21-year-old male with no history of nyctalopia or parental consanguinity presented to the vitreoretinal service at King Khaled Eye Specialist Hospital with a 1-week decrease of vision in the right eye. The patient had no known systemic disorders. On ophthalmic examination, best-corrected visual acuities (BCVAs) were hand motion in the right eye and 20/20 in the left eye. On anterior segment examination, there were 3+ cells in the right eye and the left eye was unremarkable.

Fundus examination indicated 3+ vitreous cells in the right eye, obscuring the view of the retina. In the left eye, bone spicules were present and were mostly condensed around attenuated retinal blood vessels. Optic disc or vascular leakage was not clearly evident on fundus fluorescein angiography (FFA) due to the hazy media from the vitreous haze. Systemic workup was negative for complete blood count, renal function test, liver function test, chest computed tomography, fluorescent treponemal antibody absorbed, purified protein derivative, and tuberculosis-quantiferon gold test. Erythrocyte sedimentation rate, C-reactive protein, angiotensin-converting enzyme, antinuclear antibodies, and antineutrophil cytoplasmic antibodies were within the normal limits.

The patient was managed with topical steroids four times daily on a weekly taper. Two weeks after initiating therapy, BCVA had improved to 20/30 in the right eye with few vitreous cells and more densely distributed bone spicules than in the left eye [Figure 1]a and [Figure 1]b. Fundus autofluorescence indicated hypofluorescent areas corresponding to bone spicules and hyperfluorescent rings in the macular region in both eyes [Figure 1]c and [Figure 1]d. Spectral-domain optical coherence tomography indicated photoreceptor loss beyond the macular area bilaterally and a few vitreous cells in the right eye [Figure 1e and f]. Fundus full-field electroretinogram indicated profoundly reduced scotopic and photopic responses in both eyes with a greater reduction in the right eye [Figure 2]. Over 6 months follow-up, the patient maintained 20/20 vision with no recurrence of inflammation.

Figure 1: Clinical and multimodal findings of a 21 years old male with homozygous c. 3061-6_3061-3del (NM_006445.3) mutation in pre-mRNA processing factor 8 (PRPF8) 2 weeks after presenting with IU in the right eye. (a) Shows mild vitreous haze with bone spicules, attenuated blood vessels, and healthy optic discs in the right eye. (b) Shows less density of bone spicules, attenuated blood vessels, and healthy optic discs. (c and d) are FAF photos of the right and left eyes, respectively, showing hypofluorescence corresponding to the bone spicules and hyperfluorescent ring in the macular region. (e) SD-OCT showing loss of photoreceptors beyond the macular area with a few vitreous cells. (f) SD-OCT of the left eye showing loss of photoreceptors beyond the macular area. IU: Intermediate uveitis, FAF: fundus autofluorescence, SD-OCT: Spectral-domain optical coherence tomography

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Figure 2: Bilateral ffERG of a 21-year-old male with homozygous. 3061-6_3061-3del (NM_006445.3) mutation in PRPF8. a,b,c and d showing reduced scotopic and photopic responses in both eyes with more than profoundly reduced responses in the right eye. ffERG: Full field electroretinograms

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Whole exome sequencing was performed at Bioscientia, Ingelheim, Germany, revealed a novel homozygous c. 3061-6_3061-3del (NM_006445.3) mutation in premessenger RNA (mRNA) processing factor 8 (PRPF8; MIM 600059). This mutation leads to significant alteration of the acceptor 3' splice site based on in silico predictions using in-house prediction programs. The mutation was verified with polymerase chain reaction (PCR) followed by conventional Sanger sequencing. Allele frequency of this variant has not been documented in the normal population (GnomAD v2.1.1 controls; accessed on July 17, 2020). PRPF8 plays an integral role in pre-mRNA splicing and processing of intron-containing transcripts. Pathogenic variants in PRPF8 affect spliceosome assembly and function through interaction with SNRNP200, are present in autosomal dominant retinitis pigmentosa (ADRP).[4],[5]

   Discussion 

Compared to RP patients with mutations in other genes, patients with heterozygous PRPF8 mutations tend to preserve normal or subnormal vision until middle age and the deterioration of vision is slow.[4] However, this may not apply to our patient, who had a homozygous mutation in this gene. Furthermore, while frame-shift PRPF8 mutations and nonconservative amino acid changes typically cause severe clinical phenotypes compared to missense mutations, the clinical phenotype of splice site mutations is not well determined.[5] The findings of peripheral vascular leakage on FFA are known to be supportive of the diagnosis of IU, including in RP patients.[6] However, there are some challenges when applying this observation to RP patients. First, signs of vascular leakage are not an uncommon feature in RP patients. For example, between 31% and 60% show peripheral vascular leakage.[7],[8] Second, only 42.8% of RP patients who present with IU with clinically-evident vitritis manifest with vascular leakage on FFA.[9] In addition, the common finding of dense vitritis in RP patients with IU might prevent clear interpretation of the FFA, as shown in our patient.[9]

Previous studies have indicated that vitritis in RP patients, was associated with severe visual dysfunction and a rapid progression of retinal degeneration.[1],[3] Hettinga et al. reported IU in six genetically confirmed RP patients.[10] One patient had heterozygous p. Arg598Cys and p. Arg304Cys mutations in PRPF31 and SNRNP200, respectively. These two genes are also associated with ADRP and the small nuclear ribonucleoprotein 200 kDa (SNRNP200) ribonucleic acid (RNA) helicase requires the C-terminal tail of the pre-mRNA processing factor 8 PRPF8 for the adenosine triphosphate-dependent small nuclear RNA unwinding activity.[5] A previous study reported five cases that presented without nyctalopia, similar to our patient.[10] However, all six patients in the previous study had cystoid macular edema (CME) and were treated with periocular or intraocular steroids.[10] In addition, systemic immunosuppressive therapies, used in five patients, failed to reduce CME or permanently control inflammation.[10] However, 50% of RP patients with IU do not develop CME.[9] Based on the experience in our case, a short course of topical steroid can be effective and sufficient in these patients. Another possible explanation is that IU manifests in RP patients as a separate entity, with more advanced cases of RP resulting in IU. Although recognition of the association between retinal dystrophies and IU might be challenging due to the lack of nyctalopia on presentation and the variety of differential diagnoses, establishing this association might spare patients the use of systemic immunosuppressive medications and the attendant side effects. Segregation analysis of this variant was not performed because the parents were unavailable for genetic testing. Future studies may include reverse transcription-PCR analysis to understand the possible splice effect of this variant.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1], [Figure 2]