Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy). Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting. Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.

Objectives To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis. Design A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies. Participants Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis. Methods A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene. Main outcome measures Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype. Results Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod–cone dystrophy, but three patients had electroretinogram evidence of cone–rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma. Conclusion Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood- and juvenile-onset rod–cone and cone–rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood.

The pattern electroretinogram (PERG) is a localized retinal response evoked by a contrast-reversing pattern, usually a black and white checkerboard, which provides information about macular and retinal ganglion cell function. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org) presents an updated and revised Standard for clinical PERG testing. This replaces the 2013 and all earlier versions. Minimum protocols for basic PERG stimuli, recording methods and reporting are specified, to promote consistency of methods for diagnosis and monitoring purposes, while responding to evolving clinical practices and technology. The main changes in the updated ISCEV Standard for clinical PERG include expanded guidance about large stimulus fields, stimulus parameters for simultaneous PERG and pattern visual evoked potential recording, baseline drift correction, and use of consistent ambient room lighting. These changes aim to provide a clinically relevant document about current practice which will facilitate good quality recordings and inter-laboratory comparisons.

Non‐technical summary  Light stimulates ion flow through the retina. This generates a potential change at the cornea which is recorded as an electroretinogram (ERG). Our understanding of the role of potassium ions in generating the ERG is based on animal models. The KCJN10 gene constitutes Kir4.1, the principle potassium channel expressed on the retinal Muller cell. We have been able to study the impact of this potassium channel on the human retina for the first time by recording the ERGs of patients with EAST syndrome who have known mutations of KCJN10. Our data show a reduction in the amplitude of the photopic negative response of the light‐adapted ERG and a decrease in the sensitivity of the dark‐adapted ERG. These data increase our understanding of how the ERG is generated and why these ERG parameters may be affected in disease.

Purpose.: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone–rod homeobox (CRX) gene and to report a novel phenotype. Methods.: Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. Results.: Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod–cone dystrophy (RCD), five had cone–rod dystrophy (CORD), one had cone dystrophy (COD), and six had macular dystrophy with different phenotypes observed within 5 of 11 families. The macular dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients. Conclusions.: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.

We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.