Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations

Abstract

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th–5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.

Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients

“…Clinical information was collected retrospectively at Hadassah-Hebrew University Medical Center, Rambam Health Care Center, and related research manuscripts that were published previously ( Dryja et al, 2001 ; Gerber et al, 2001 ; Hameed et al, 2003 ; Hanein et al, 2004 ; Galvin et al, 2005 ; Zernant et al, 2005 ; Jacobson et al, 2007 ; Vallespin et al, 2007 ; Seong et al, 2008 , 2015 ; McKibbin et al, 2010 ; Walia et al, 2010 ; Li et al, 2011 ; Abu-Safieh et al, 2013 ; Chen et al, 2013 ; Fakhratova, 2013 ; Huang et al, 2013 , 2016 , 2017 ; Khan et al, 2013 , 2014 ; Verma et al, 2013 ; Coppieters et al, 2014 ; Suzuki et al, 2014 ; Watson et al, 2014 ; Boulanger-Scemama et al, 2015 ; Maria et al, 2015 ; Saqib et al, 2015 ; Wang et al, 2015 , 2016 ; Abouzeid et al, 2016 ; Tiwari et al, 2016 ; Han et al, 2017 ; Jinda et al, 2017 ; Riera et al, 2017 ; Birtel et al, 2018 ; Hosono et al, 2018 ; Imani et al, 2018 ; Sanchez-Navarro et al, 2018 ; Avela et al, 2019 ; Jamshidi et al, 2019 ; Jespersgaard et al, 2019 ; Miyamichi et al, 2019 ; Sallum et al, 2020 ; Sato et al, 2020 ; Skorczyk-Werner et al, 2020 ). Clinical data included, when available, anamnestic information on disease onset, progression and different symptoms, best corrected visual acuity (BCVA), refractive error, clinical ocular exam by slit lamp biomicroscopy, full-field electroretinography (ffERG), Goldmann visual fields (VF, using the I4e, III4e, and/or V4e targets according to stage of disease), optical coherence tomography (OCT, using the Heidelberg Spectralis system), color, infrared, and fundus autofluorescence (FAF) imaging (using a Zeiss and/or Optos fundus camera and the Heidelberg Spectralis system) ( Beryozkin et ...…”

“…In order to provide numerical values for low BCVAs, the following conversions were made: no light perception (NLP) = 0, light perception (LP) = 0.0001, hand movement (HM) = 0.001, and finger count (FC) = 0.01. When necessary, LogMAR of BCVA was converted to the Snellen equivalent using an online converter program 6 ( Beryozkin et al, 2020 ).…”

A new mouse model for retinal degeneration due to Fam161a deficiency

“…Clinical analysis of 100 Israeli patients with biallelic FAM161A mutations revealed some unique features including relatively slow degeneration of the photoreceptor layer up to the age of ~ 30 and good preservation of the photoreceptor cells in the macula until late age 8 , features which will enable therapeutic intervention (gene therapy, for example) in the future. While the phenotype of FAM161A patients is well described, the exact function of the encoded protein/s and the pathological mechanisms of the disease remain unknown.…”

“…A mouse model for Fam161a deficiency, created using the GeneTrap system, has previously been reported 20 . Although retinal degeneration was evident in this model, the mutation site was considered "leaky" because it weakly express a truncated form of Fam161a in the inner segment of retinal photoreceptor cells, a situation that does not reflect the mutations identified in human patients that are considered null 6,8,[21][22][23][24][25][26][27][28][29][30][31][32][33] . This mouse model therefore is less pertinent to study complete FAM161A loss.…”

Consanguinity-based analysis of exome sequencing yields likely genetic causes in patients with inherited retinal dystrophy

“…In contrast, the proband in this current study exhibited additional phenotypes. A prior study also indicated that RDH12 mutation could lead to LCA with macular coloboma [ 49 ]. However, in our study, characteristic features of LCA, including nystagmus, photophobia, amaurotic pupils and flat or nondetectable ERG, were all absent [ 50 ].…”