Upward saccadic intrusions as the presenting feature for incomplete congenital stationary night blindness.

We describe the case of a 9-month-old boy presenting with isolated intermittent vertical eye movements most in keeping with upward saccadic pulses, a form of saccadic intrusions. Full-field electroretinogram was consistent with a generalized retinal dystrophy, and genetic testing revealed a hemizygous pathogenic mutation in the CACNA1F gene, confirming the diagnosis of incomplete congenital stationary night blindness (iCSNB). This case describes vertical saccadic pulses as the sole presenting sign of a retinal dystrophy.

Unilateral cataract and congenital stationary night blindness in a child with novel variants in TRPM1.

Unilateral cataract can cause pediatric vision impairment. Although the majority of unilateral cataracts are idiopathic in nature, genetic causes have been reported. We present the case of a 4-week-old child of nonconsanguineous parents who was affected with unilateral cataract. Whole-genome sequencing using DNA extracted from blood and the lens epithelial cells following cataract surgery revealed two presumed pathogenic variants in the TRPM1 gene, the founding member of the melanoma-related transient receptor potential (TRPM) subfamily. TRPM1 is responsible for regulating cation influx to hyperpolarized retinal ON bipolar cells, and mutations in this gene are a major cause of autosomal recessive congenital stationary night blindness (CSNB). Electroretinography revealed findings consistent with CSNB, a phenotype that was not initially suspected, and which would likely have been missed without genome sequencing. It remains unclear whether the TRPM1 variants are associated with the cataract phenotype.

Phenotypes and genotypes underlying paradoxical pupillary reaction in children.

Paradoxical pupillary reaction (initial pupillary constriction to darkness) has been most associated with the inherited retinal disorders congenital stationary night blindness and achromatopsia. However, underlying genotypes and associations with other pediatric retinal phenotypes are not well documented. A retrospective review for paradoxical pupillary reaction was performed at the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016-2020). Four children from 4 different families were identified, all of whom had had genetic confirmation of the clinical diagnosis. Associated pathogenic variants were in TRPM1 (biallelic; two boys; congenital stationary night blindness), CABP4 (biallelic; one boy, congenital cone-rod synaptic disorder) and PAX2 (monoallelic; one girl, papillorenal syndrome). Genetically confirmed affected relatives of the 2 probands with TRPM1-related congenital stationary night blindness did not show the phenomenon. This study documents novel genotypes and phenotypes that can be associated with paradoxical pupillary reaction in children and confirms potential intrafamilial variable expressivity for the phenomenon.

Clinical and genetic findings in TRPM1-related congenital stationary night blindness.

PURPOSE: Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy. METHODS: Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis. RESULTS: Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case. CONCLUSION: Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.

Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia.

Congenital stationary night blindness (CSNB) is a group of rare, mainly stationary disorders of the retina, resulting from dysfunction of several specific and essential visual processing mechanisms. The inheritance is often recessive and as such, CSNB may be more common among populations with a high degree of consanguinity. Here, we present a topic update and a review of the clinical and molecular genetic spectrum of CSNB in Saudi Arabia. Since a major review article on CSNB in 2015, which described 17 genes underlying CSNB, an additional four genes have been incriminated in autosomal recessive CSNB: RIMS2, GNB3, GUCY2D and ABCA4. These have been associated with syndromic cone-rod synaptic disease, ON bipolar cell dysfunction with reduced cone sensitivity, CSNB with dysfunction of the phototransduction (Riggs type) and CSNB with cone-rod dystrophy, respectively. In Saudi Arabia, a total of 24 patients with CSNB were identified, using a combination of literature search and retrospective study of previously unpublished cases. Recessive mutations in TRPM1 and CABP4 accounted for the majority of cases (5 and 13 for each gene, respectively). These genes were associated with complete (cCSNB) and incomplete (icCSNB), respectively, and were associated with high myopia in the former and hyperopia in the latter. Four novel mutations were identified. For the first time, we describe the fundus albipunctatus in two patients from Saudi Arabia, caused by recessive mutation in RDH5 and RPE65, where the former in addition featured findings compatible with cone dystrophy. No cases were identified with any dominantly inherited CSNB.

La utilidad diagnóstica del electrorretinograma negativo / The diagnostic usefulness of the negative electroretinogram

La respuesta negativa del electrorretinograma de campo completo se define como una disminución de la onda b con conservación de la onda a (ratio b/a<1) en la respuesta combinada de conos y bastones. La presencia de este patrón denota una alteración en las células bipolares, en las células de Müller o en la transmisión del estímulo fotorreceptor-células bipolares, con preservación de la función de conos y bastones. Este hallazgo puede verse de forma bilateral y simétrica en diferentes enfermedades hereditarias como la ceguera nocturna estacionaria congénita, la retinosquisis juvenil ligada a X y las distrofias musculares de Duchenne y Becker. Por otro lado, también se puede encontrar de forma unilateral en enfermedades adquiridas como algunos tipos de retinitis inmunomediadas (retinocoroiditis en perdigonada o Birdshot), retinopatías autoinmunes, retinopatía asociada a cáncer/melanoma o toxicidad retiniana. El objetivo de esta revisión es resumir las características de las afecciones en las que puede observarse este hallazgo, de gran utilidad en el diagnóstico diferencial de enfermedades de la retina (AU)

The definition of the negative response of the full field electroretinogram is the presence of a b-wave with less amplitude than the a-wave (b/a ratio<1) in the combined response of cones and rods. The presence of this pattern reflects an alteration in the bipolar cells, the Müller cells, or in the transmission of the stimulus from the photoreceptors to the bipolar cells, with preserved photoreceptor function. This finding can be seen bilaterally and symmetrically in different hereditary conditions, such as congenital stationary night blindness, juvenile X-linked retinoschisis, and Duchenne and Becker muscular dystrophies. On the other hand, it can also be found unilaterally (or asymmetrically) in acquired pathologies, such as some types of immuno-mediated retinitis (Birdshot retinochoroiditis), autoimmune retinopathies, cancer/melanoma associated retinopathy, or retinal toxicity. The objective of this review is to summarise the characteristics of the pathologies in which this finding can be observed, in order to highlight its usefulness in the differential diagnosis of retinal conditions (AU)

Photoreceptor and postreceptor responses in congenital stationary night blindness.

PURPOSE: To investigate photoreceptor and postreceptor retinal function in patients with congenital stationary night blindness (CSNB). METHODS: Forty-one patients with CSNB (ages 0.19-32 years) were studied. ERG responses to a series of full-field stimuli were obtained under scotopic and photopic conditions and were used to categorize the CSNB patients as complete (cCSNB) or incomplete (iCSNB). Rod and cone photoreceptor (R(ROD), S(ROD), R(CONE), S(CONE)) and rod-driven postreceptor (V(MAX), log σ) response parameters were calculated from the a- and b-waves. Cone-driven responses to 30 Hz flicker and ON and OFF responses to a long duration (150 ms) flash were also obtained. Dark-adapted thresholds were measured. Analysis of variance was used to compare data from patients with cCSNB, patients with iCSNB, and controls. RESULTS: We found significant reduction in saturated photoreceptor amplitude (R(ROD), R(CONE)) but normal photoreceptor sensitivity (S(ROD), S(CONE)) in both CSNB groups. Rod-driven postreceptor response amplitude (V(MAX)) and sensitivity (log σ) were significantly reduced in CSNB. Log σ was significantly worse in cCSNB than in iCSNB; this was the only scotopic parameter that differed between the two CSNB groups. Photopic b-wave amplitude increased monotonically with stimulus strength in CSNB patients rather than showing a normal photopic hill. The amplitude of the 30-Hz flicker response was reduced compared with controls, more so in iCSNB than in cCSNB. The mean dark-adapted threshold was significantly elevated in CSNB, more so in cCSNB than in iCSNB. CONCLUSIONS: These results are evidence of normal photoreceptor function (despite the low saturated photoresponse amplitude) and anomalous postreceptor retinal circuitry.

Alterações eletrofisiológicas na doença de Oguchi / Electrophysiological findings in Oguchi disease

Descrever as alterações eletrofuncionais em um caso raríssimo da Doença de Oguchi. Paciente do sexo feminino, italiana de 17 anos de idade se queixava de cegueira noturna. A resposta escotópica de bastonetes, do ERG era não registrável. A resposta escotópica ao estímulo branco forte demonstrava uma diminuição de amplitude da onda B. As respostas ao flicker de 30Hz e ao EOG eram dentro dos limites da normalidade. Era presente o fenômeno de Mizuo-Nakamura. Os exames eletrofuncionais são muito importantes no diagnóstico de certeza da doença de Oguchi. É nítida, no presente caso, a discordância entre EOG e ERG. Considerando a função dos bastonetes, as respostas normais do EOG contrastam com a ausência de respostas dos bastonetes em condições escotópicas no ERG. Mais estudos são necessários para entender o complexo mecanismo eletrofuncional dessa doença e melhor definir a origem dos componentes sensíveis à luz do EOG...

To describe the electrophysiological alterations in a very rare case of Oguchi's disease. A 17-year-old italian girl complaining of night blindness underwent complete ophthalmological exams, including electrophysiological tests. Rod responses were nondetectable in full-field electroretinogram (ERG). The photopic ERG funtions, including the 30 Hz flicker ERG response was normal, while the scotopic b-wave was diminished in amplitude. The electrooculography (EOG) ratios within the normal range were 208% in the right eye and 222% in the left eye. The Mizuo-Nakamura phenomenon was present. The electrophysiological tests are important tools in Oguchi's disease diagnosis. In the present case, it's clear the non correspondance between EOG and ERG. Considering the rod function, the normal EOG ratio contrast with non-detectable rod ERG responses. More studies are necessary to understand the compless electrofuntional mecanism of the disease helping to understand the origin of the light-sensitive component of the EOG...

Retinal horizontal cells reduced in a rat model of congenital stationary night blindness.

This work was conducted to determine whether congenital stationary night blindness (CSNB), which is caused by a Cacna1f mutation, could affect development of second-order neurons in the retina, such as horizontal cells (HCs). The CSNB rats and age-matched wild type rats were sacrificed at postnatal days (PND) 15, 30 and 60. Morphometric analyses of HCs, which were labeled by a primary antibody to calbindin D-28K, were performed at the light microscopic level on retinal cross sections and whole mount retinas. Calbindin D-28K was measured by western blotting in retinal samples. We found that the average number and density of HCs, Calbindin level and thickness of OPL were all decreased significantly in CSNB group compared to control group. These results indicated that second-order retinal neurons, such as horizontal cells, are affected by retinal degeneration. The relationship between the absence of HCs and the gene defect of CSNB requires further research.

An extended 15 Hz ERG protocol (2): data of normal subjects and patients with achromatopsia, CSNB1, and CSNB2.

The amplitude versus flash strength curve of 15 Hz electroretinograms (ERGs) shows two minima. The minima are caused by interactions between the primary and the secondary rod pathways (first minimum), and the secondary rod pathway and the cone-driven pathway (second minimum). Furthermore, cone pathway contributions cause higher-order harmonics to occur in the responses. We measured 15 Hz ERGs in 20 healthy subjects to determine normal ranges and in patients to verify our hypotheses on the contributions of the different pathways and to investigate the clinical application. We analyzed the amplitudes and phases of the 15, 30, and 45 Hz components in the ERGs. The overall shape of the 15 Hz amplitude curves was similar in all normal subjects and showed two minima. The 30 and 45 Hz amplitude curves increased for stimuli of high flash strengths indicating cone pathway contributions. The 15 Hz amplitude curve of the responses of an achromat was similar to that of the normal subjects for low flash strengths and showed a minimum, indicating normal primary and secondary rod pathway function. There was no second minimum, and there were no higher-order harmonics, consistent with absent cone pathway function. The 15 Hz ERGs in CSNB1 and CSNB2 patients were similar and of low amplitude for flash strengths just above where the first minimum normally occurs. We could determine that in the CSNB1 patients, the responses originate from the cone pathway, while in the CSNB2 patients, the responses originate from the secondary rod pathway.

TRPM1: new trends for an old TRP.

TRPM1, initially named Melastatin, is the founding member of the TRPM subfamily of Transient Receptor Potential (TRP) ion channels. Despite sustained efforts, the molecular properties and physiological functions of TRPM1 remained elusive until recently. New evidence has uncovered novel TRPM1 splice variants and revealed that TRPM1 is critical for a non-selective cation conductance in melanocytes and retinal bipolar cells. Functionally, TRPM1 has been shown to mediate retinal ON bipolar cell transduction and suggested to regulate melanocyte pigmentation. Notably, TRPM1 mutations have also been associated with congenital stationary night blindness in humans. This review will summarize and discuss our present knowledge of TRPM1: its discovery, expression, regulation, and proposed functions in skin and eye.

Contribution of post-receporal cells to the cone a-wave of the human electroretinogram in congenital stationary night blindness and autoimmune-like retinopathy.

In normal subjects the later part of the cone a-wave to a brief flash increases in amplitude after 50-100 ms darkness due to a contribution from secondary hyperpolarising cells. We recorded these responses along with clinical ON and OFF ERGs in patients with inner retinal dysfunction to see if this part of the a-wave is affected. Patients with autoimmune-like retinopathy and CSNB2 had abnormal ON and OFF responses but the a-wave increased in amplitude in the dark as in normals. Conversely, the OFF-response was normal in CSNB1 but the a-wave did not increase in the dark. Contrary to expectation these results show some hyperpolarising cell function in autoimmune-like disease and CSNB2 and some OFF-pathway abnormality in CSNB1. The a- and d-wave are needed to assess OFF-pathway function.

Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses.

Leopard Complex spotting occurs in several breeds of horses and is caused by an incompletely dominant allele (LP). Homozygosity for LP is also associated with congenital stationary night blindness (CSNB) in Appaloosa horses. Previously, LP was mapped to a 6 cm region on ECA1 containing the candidate gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) and decreased expression of this gene, measured by qRT-PCR, was identified as the likely cause of both spotting and ocular phenotypes. This study describes investigations for a mutation causing or associated with the Leopard Complex and CSNB phenotype in horses. Re-sequencing of the gene and associated splice sites within the 105 624 bp genomic region of TRPM1 led to the discovery of 18 SNPs. Most of the SNPs did not have a predictive value for the presence of LP. However, one SNP (ECA1:108,249,293 C>T) found within intron 11 had a strong (P < 0.0005), but not complete, association with LP and CSNB and thus is a good marker but unlikely to be causative. To further localize the association, 70 SNPs spanning over two Mb including the TRPM1 gene were genotyped in 192 horses from three different breeds segregating for LP. A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150) was identified. Illumina sequencing of 300 kb surrounding this haplotype revealed 57 SNP variants. Based on their localization within expressed sequences or regions of high sequence conservation across mammals, six of these SNPs were considered to be the most likely candidate mutations. While the precise function of TRPM1 remains to be elucidated, this work solidifies its functional role in both pigmentation and night vision. Further, this work has identified several potential regulatory elements of the TRPM1 gene that should be investigated further in this and other species.

TRPM1 mutations are associated with the complete form of congenital stationary night blindness.

PURPOSE: To identify human transient receptor potential cation channel, subfamily M, member 1 (TRPM1) gene mutations in patients with congenital stationary night blindness (CSNB). METHODS: We analyzed four different Japanese patients with complete CSNB in whom previous molecular examination revealed no mutation in either nyctalopin (NYX) or glutamate receptor, metabotropic 6 (GRM6). The ophthalmologic examination included best-corrected visual acuity, refraction, biomicroscopy, ophthalmoscopy, fundus photography, Goldmann kinetic perimetry, color vision tests, and electroretinography (ERG). Exons 2 through 27 and the exon-intron junction regions of human TRPM1 were sequenced. RESULTS: Five different mutations in human TRPM1 were identified. Mutations were present in three unrelated patients with complete CSNB. All three patients were compound heterozygotes. Fundus examination revealed no abnormalities other than myopic changes, and the single bright-flash, mixed rod-cone ERG showed a "negative-type" configuration with a reduced normal a-wave and a significantly reduced b-wave amplitude. Our biochemical and cell biologic analyses suggest that the two identified IVS mutations lead to abnormal TRPM1 protein production, and imply that the two identified missense mutations lead to the mislocalization of the TRPM1 protein in bipolar cells (BCs). CONCLUSIONS: Human TRPM1 mutations are associated with the complete form of CSNB in Japanese patients, suggesting that TRPM1 plays an essential role in mediating the photoresponse in ON BCs in humans as well as in mice.

Nightblindness-associated transient tonic downgaze (NATTD) in infant boys with chin-up head posture.

Eleven infant boys presented with chin-up head posture, tonic downgaze and, on attempted upgaze, large-amplitude upward saccades with deceleration during the slow phase downward. The gaze-evoked upward saccades disappeared at the age of 2 or 3 years. In addition, they had high-frequency, small-amplitude horizontal pendular nystagmus that remained. Among these infant boys were 2 pairs of maternally related half-brothers, 2 cousins, and 2 siblings. Visual acuity ranged from 0.1 to 0.6, ERG-amplitudes (both A- and B-wave) were reduced, and severe myopia was found in 5 cases. Eight boys had CACNA1F mutations, and 1 boy had a NYX mutation, compatible with incomplete or complete congenital stationary nightblindness (iCSNB or cCSNB), respectively. This points to a defective synapse between the rod and the ON-bipolar cell causing the motility disorder: CACNA1F is located on the rod side of this synapse, whereas NYX is located on the side of the ON-bipolar cell. The coexistence of horizontal and vertical nystagmus has been previously described in dark-reared cats.

Mutations in TRPM1 are a common cause of complete congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity. We report here that six out of eight female probands with autosomal-recessive complete CSNB (cCSNB) had mutations in TRPM1, a retinal transient receptor potential (TRP) cation channel gene. These data suggest that TRMP1 mutations are a major cause of autosomal-recessive CSNB in individuals of European ancestry. We localized TRPM1 in human retina to the ON bipolar cell dendrites in the outer plexifom layer. Our results suggest that in humans, TRPM1 is the channel gated by the mGluR6 (GRM6) signaling cascade, which results in the light-evoked response of ON bipolar cells. Finally, we showed that detailed electroretinography is an effective way to discriminate among patients with mutations in either TRPM1 or GRM6, another autosomal-recessive cCSNB disease gene. These results add to the growing importance of the diverse group of TRP channels in human disease and also provide new insights into retinal circuitry.

TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness.

Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in approximately 60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells.