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Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N‐sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53‐year‐old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH, and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo‐hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET‐CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA. [ABSTRACT FROM AUTHOR]

Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone–rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient's symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene. [ABSTRACT FROM AUTHOR]

Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone–rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient’s symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene.

Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: To study whether the ERG and other clinical findings help to distinguish between advanced hydroxychloroquine (HCQ) retinopathy and pericentral or diffuse retinitis pigmentosa (RP) with similar fundus appearance. Methods: We conducted a retrospective analysis of patients with advanced HCQ retinopathy ( n = 11), pericentral RP ( n = 8) and diffuse RP ( n = 8). Pericentral RP was defined as having limited fundus damage and relatively normal flicker ERG time-to-peak. Diffuse RP had typical loss of the rod ERG and flicker timing delay. All patients showed reduced amplitude of the ISCEV responses in the full-field electroretinogram (ERG). Aspects of history, visual field results, fundus appearance, fundus autofluorescence and ocular coherence tomography were also compared. Results: Relative to pericentral RP, patients with HCQ toxicity showed delayed flicker ERG time-to-peak and lower ERG amplitudes, particularly combined rod-cone responses. Relative to diffuse RP, most HCQ toxicity patients had some preserved rod ERG response, and there was no obvious predilection for rod over cone damage. In addition, patients with HCQ toxicity usually lacked markers of long-standing degeneration such as bone spicule figures or severe loss of peripheral field. History of familial disease and long-standing night blindness were specific to RP. Conclusions: While the early signs of HCQ damage are typically regional in the posterior pole, advanced disease is characteristically diffuse (unlike pericentral RP). This is appropriate for a systemic toxin, as is the finding that rods and cones were both affected in the ERG to a similar degree (unlike genetic rod-cone dystrophies). For patients with severe HCQ exposure and some of our discriminatory findings, and no family history or prior night blindness, HCQ toxicity is a sufficient diagnosis without invoking a second rare disease (Occam's razor). [ABSTRACT FROM AUTHOR]

The purpose of this paper was to describe a patient with pericentral retinitis pigmentosa (RP) and cystoid macular edema (CME) refractory to oral acetazolamide alone who was successfully treated with adjunctive pegaptanib sodium. A 33-year-old man presented with decreased vision and a best-corrected visual acuity (BCVA) in his left eye of 20/200 due to CME secondary to RP. Although he had been treated daily for 1 month with 500 mg of oral acetazolamide, the edema was unresponsive. When informed of the available treatment options, the patient requested adjunctive intravitreal pegaptanib sodium. One month after receiving an injection of pegaptanib sodium 0.3 mg and continued daily acetazolamide, the patient’s BCVA had improved to 20/40. At the 4-month follow-up visit, no recurrence of CME was found on fundus biomicroscopy, fundus-related perimetry, and optical coherence tomography. We conclude that intravitreal pegaptanib sodium combined with daily doses of acetazolamide appears to provide benefits in CME refractory to oral acetazolamide alone with regards to the improvement of visual acuity. [ABSTRACT FROM AUTHOR]

Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression. [ABSTRACT FROM AUTHOR]

Mutations in rhodopsin gene (RHO) are a frequent cause of retinitis pigmentosa (RP) and less often, congenital stationary night blindness (CSNB). Mutation p.G90D has previously been associated with CSNB based on the examination of one family. This study screened 60 patients. Out of these 60 patients, 32 were affected and a full characterization was conducted in 15 patients. We described the clinical characteristics of these 15 patients (12 male, median age 42 years, range 8–71) from three families including visual field (Campus Goldmann), fundus autofluorescence (FAF), optical coherence tomography (OCT) and electrophysiology. Phenotypes were classified into four categories: CSNB (N = 3, 20%) sector RP (N = 3, 20%), pericentral RP (N = 1, 6.7%) and classic RP (N = 8, 53.3% (8/15)). The phenotypes were not associated with family, sex or age (Kruskal–Wallis, p > 0.05), however, cystoid macular edema (CME) was observed only in one family. Among the subjects reporting nyctalopia, 69% (22/32) were male. The clinical characteristics of the largest p.G90D cohort so far showed a large frequency of progressive retinal degeneration with 53.3% developing RP, contrary to the previous report. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition., Competing Interests: The authors declare no conflict of interest.