RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile.

OBJECTIVES: The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome. METHODS: We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN. RESULTS: Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients. DISCUSSION: Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.

Nystagmus in the B6(CG)Tyr(c-2J)/J Albino Mouse: A Functional and RNA-Seq Analysis.

Purpose: Infantile nystagmus syndrome (INS) is a gaze-holding disorder characterized by conjugate, uncontrolled eye oscillations that can result in significant visual acuity loss. INS is often associated with albinism, but the mechanism is unclear. Albino mice have nystagmus; however, a pigmented mouse with a tyr mutation making it phenotypically albino, the B6(CG)-Tyr(c-2J)/J (B6 albino), had not been tested. We tested optokinetic response (OKR) in B6 albino and control mice. RNA-Seq was performed on extraocular muscles (EOM), tibialis anterior (TA) muscle, abducens (CN6), and oculomotor (CN3) neurons to uncover molecular differences that may contribute to nystagmus. Methods: OKR was measured using an ISCAN system. RNA was isolated from four tissues to identify differentially expressed genes and validated with qPCR and immunohistochemistry. Ingenuity pathway analyses identified top biological pathways. Results: All B6 albino mice tested had nystagmus. Differential RNA expression analysis showed 383 genes differentially expressed in EOM, 70 in CN3, 20 in CN6, and 639 in the TA. Two genes were differentially expressed in all four tissues: wdfy1 and nnt. Differences were validated by qPCR and immunostaining. Conclusions: The tyr mutation in B6 albino mice, genotypically pigmented and phenotypically albino, is sufficient to result in spontaneous nystagmus. The two genes with decreased expression in the B6 albino tissues examined, wdfy1 and nnt, have been implicated in mitochondrial dysfunction and stem cell maintenance in other systems. Their function in extraocular muscle is unknown. These studies suggest that this mouse model of nystagmus may allow molecular identification of candidate nystagmus-related genes.

Ophthalmologic and neuro-ophthalmologic findings in children with Down syndrome.

Down syndrome, also known as Trisomy 21, is a genetic disorder associated with mild-to-moderate intellectual disability, delays in growth, and characteristic facial features. A wide range of ocular complications are seen in children with Down syndrome, including strabismus, nystagmus, refractive errors, congenital cataracts, the presence of keratoconus, and decreased visual acuity. Early ophthalmic examination is needed for early diagnosis and treatment in patients. This narrative review examines ocular manifestations in children with Down syndrome and the importance of prompt ophthalmic interventions for treatment.

Case series: Downbeat nystagmus in SCA27B.

BACKGROUND: Spinocerebellar ataxia (SCA) 27B, first reported in late 2022, is caused by the abnormal expansion of GAA repeats in the first intron of the FGF14 gene, which encodes the fibroblast growth factor 14. CASE PRESENTATION: We present two late-onset cases, each manifesting mild cerebellar ataxia accompanied by omnidirectional downbeat nystagmus, which was enhanced in a suspended head position. None of the patients exhibited impaired head impulse or caloric tests. Repeat-primed PCR and targeted long-read nanopore sequence analysis of the FGF14 GAA repeat site identified more than 250 repeats, leading to the diagnosis of SCA27B. DISCUSSION: Downbeat nystagmus is reported to be associated with disturbances in the suppression of the vestibulo-ocular reflex (VOR). Our patients with SCA27B demonstrated downbeat nystagmus, likely due to a disruption of the VOR at the level of the cerebellar cortex, a potentially characteristic clinical feature of SCA27B. We have included video footages of eye movements recorded using Frenzel goggles for these cases. CONCLUSIONS: Omnidirectional downbeat nystagmus may be a distinctive clinical feature of SCA27B.

[Nystagmus in Children - a Survey]. / Nystagmus bei Kindern ­ eine Übersicht.

Nystagmus describes an involuntary, periodic movement of one or both eyes. About 1/600 children and adolescents have nystagmus, most of them idiopathic infantile nystagmus (IIN), also called "congenital nystagmus", which can be caused by mutations in the FRMD7 gene. Other frequent forms of nystagmus are latent nystagmus, which is usually associated with infantile strabismus, and nystagmus associated with albinism. Sometimes difficult to distinguish in young infants is a sensory nystagmus, where a defect in the visual system reduces vision and causes nystagmus. Causes include retinal dystrophies, congenital stationary night blindness and structural ocular defects including optic nerve hypoplasia or dense bilateral congenital cataracts. Unilateral nystagmus can be the sign of an anterior visual pathway lesion. Seesaw nystagmus may be associated with suprasellar and mesodiencephalic lesions and - rarely - with retinal dystrophies.The ophthalmology plays a key role in identifying the form of nystagmus. Children with new onset nystagmus, with spasmus nutans, with vertical or unilateral nystagmus and those with seesaw nystagmus require neurologic evaluation including imaging of the brain.The treatment of nystagmus depends on the underlying cause. Even minor refractive errors should be corrected, contact lenses offer advantages over glasses.Gabapentin and memantine, possibly also carbonic anhydrase inhibitors, are effective in treating IIN, nystagmus in albinism and sensory nystagmus. Nevertheless, pharmacologic treatment of nystagmus is rarely used in children; the reasons are the limited effects on vision, the need for lifelong therapy, and potential side effects. Eye muscle surgery (Anderson procedure, Kestenbaum procedure) can correct a nystagmus-related anomalous head posture. The concept of "artifical divergence" of Cüppers may help to decrease nystagmus intensity in patients whose nystagmus dampens with convergence. The four-muscle-tenotomy, which involves disinsertion and reinsertion of the horizontal muscles at the original insertion of both eyes, has a proven but limited positive effect on visual acuity.

Clinical and genetic characterization of CACNA1A-related disease.

Pathogenic variants in the CACNA1A gene have been associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia 6. With increasing use of clinical genetic testing, associations have expanded to include developmental delay, epilepsy, paroxysmal dystonia, and neuropsychiatric disorders. We report 47 individuals with 33 unique likely pathogenic or pathogenic CACNA1A variants. A machine learning method, funNCion, was used to predict loss-of-function (LoF)/gain-of-function (GoF) impact of genetic variants, and a heuristic severity score was designed to analyze genotype/phenotype correlations. Commonly reported phenotypes include developmental delay/intellectual disability (96%), hemiplegic migraines (36%), episodic ataxia type 2 (32%), epilepsy (55%), autism spectrum disorder (23%), and paroxysmal tonic upward gaze (36%). Severity score was significantly higher for predicted GoF variants, variants in the S5/S6 helices, and the recurrent p.Val1392Met variant. Seizures/status epilepticus were correlated with GoF and were more frequent in those with the p.Val1392Met variant. Our findings demonstrate a breadth of disease severity in CACNA1A-related disease and suggest that the clinical phenotypic heterogeneity likely reflects diverse molecular phenotypes. A better understanding of the natural history of CACNA1A-related disease and genotype/phenotype correlations will help inform prognosis and prepare for future clinical trials.

Eyelid nystagmus in a child with cardiofaciocutaneous syndrome associated with BRAF mutation.

Eyelid nystagmus, thought to reflect midbrain or hindbrain disease, is a rare condition that typically occurs in association with neurologic and neuroophthalmic abnormalities. Cardiofaciocutaneous (CFC) syndrome associated with B-raf protooncogene serine/threonine kinase (BRAF) mutation is a complex syndrome that is associated with neurologic and neuroophthalmologic abnormalities. We report the case of a 4-year-old girl with CFC syndrome with global developmental delay who was referred for evaluation of alternating exotropia, right-sided dissociated vertical deviation, bilateral upgaze nystagmus, and bilateral eyelid fluttering. Neurological work-up revealed bilateral frontocentral sharp waves without seizure activity on electroencephalogram and mild left-sided cerebral volume loss on magnetic resonance imaging. To our knowledge, this is the first reported case of eyelid nystagmus in CFC syndrome. Eyelid nystagmus warrants neurological evaluation, because it is commonly associated with significant neurological abnormalities.

Development of Nystagmus With the Absence of MYOD Expression in the Extraocular Muscles.

Purpose: Myoblast determination protein 1 (MYOD) is a critical myogenic regulatory factor in muscle development, differentiation, myofiber repair, and regeneration. As the extraocular muscles significantly remodel their myofibers throughout life compared with limb skeletal muscles, we hypothesized that the absence of MYOD would result in their abnormal structure and function. To assess structural and functional changes in the extraocular muscles in MyoD-/- mice, fiber size and number and optokinetic nystagmus reflex (OKN) responses were examined. Methods: OKN was measured in MyoD-/- mice and littermate wild-type controls at 3, 6, and 12 months. The extraocular muscles were examined histologically for changes in mean myofiber cross-sectional area, total myofiber number, and nuclei immunostained for PAX7 and PITX2, markers of myogenic precursor cells. Results: The MyoD-/- mice developed nystagmus, with both jerk and pendular waveforms, in the absence and in the presence of moving visual stimulation. At 12 months, there were significant losses in mean myofiber cross-sectional area and in total number of orbital layer fibers in all rectus muscles, as well as in global layer fibers in the superior and inferior rectus muscles. Haploinsufficient mice showed abnormal OKN responses. PITX2-positive cell entry into myofibers of the MyoD-/- mice was significantly reduced. Conclusions: This study is the first demonstration of the development of nystagmus in the constitutive absence of expression of the muscle-specific transcription factor MYOD. We hypothesize that myofiber loss over time may alter anterograde and/or retrograde communication between the motor nerves and extraocular muscles that are critical for maintaining normalcy of extraocular muscle function.

Development of the vertebrate retinal direction-selective circuit.

The vertebrate retina contains an array of neural circuits that detect distinct features in visual space. Direction-selective (DS) circuits are an evolutionarily conserved retinal circuit motif - from zebrafish to rodents to primates - specialized for motion detection. During retinal development, neuronal subtypes that wire DS circuits form exquisitely precise connections with each other to shape the output of retinal ganglion cells tuned for specific speeds and directions of motion. In this review, we follow the chronology of DS circuit development in the vertebrate retina, including the cellular, molecular, and activity-dependent mechanisms that regulate the formation of DS circuits, from cell birth and migration to synapse formation and refinement. We highlight recent findings that identify genetic programs critical for specifying neuronal subtypes within DS circuits and molecular interactions essential for responses along the cardinal axes of motion. Finally, we discuss the roles of DS circuits in visual behavior and in certain human visual disease conditions. As one of the best-characterized circuits in the vertebrate retina, DS circuits represent an ideal model system for studying the development of neural connectivity at the level of individual genes, cells, and behavior.

Cognitive deficits in episodic ataxia type 2 mouse models.

Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder characterized by motor incoordination, paroxysmal dystonia, vertigo, nystagmus and more recently cognitive deficits. To date over 100 mutations in the CACNA1A gene have been identified in EA2 patients leading to a loss of P/Q-type channel activity, dysfunction of cerebellar Purkinje cells and motor incoordination. To determine if the cerebellum is contributing to these cognitive deficits, we examined two different EA2 mouse models for cognition impairments where CACNA1A was removed specifically from cerebellar Purkinje or granule cells postnatally. Both mutant mouse models showed anxiolytic behavior to lighted, open areas in the open field and light/dark place preference tests but enhanced anxiousness in the novel suppressed feeding test. However, EA2 mice continued to show augmented latencies in the light/dark preference test and when the arena was divided into two dark zones in the dark/dark preference test. Moreover, increased latencies were also displayed in the novel object recognition test, indicating that EA2 mice are indecisive and anxious to explore new territories and objects and may have memory recognition deficits. Exposure to a foreign mouse led to deficiencies in attention and sniffing as well as in social and genital sniffing. These data suggest that postnatal removal of the P/Q type calcium channel from the cerebellum regulates neuronal activity involved in anxiety, memory, decision making and social interactions. Our EA2 mice will provide a model to identify the mechanisms and therapeutic agents underlying cognitive and psychiatric disorders seen in EA2 patients.

Discordant phenotypes in twins with infantile nystagmus.

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism.

PAX6 is considered the master regulator of eye development, the majority of variants affecting this gene cause the pan-ocular developmental eye disorder aniridia. Although no genotype-phenotype correlations are clearly established, missense variants affecting the DNA-binding paired domain of PAX6 are usually associated with non-aniridia phenotypes like microphthalmia, coloboma or isolated foveal hypoplasia. In this study, we report two missense heterozygous variants in the paired domain of PAX6 resulting in isolated foveal hypoplasia with nystagmus in two independent families: c.112 C > G; p.(Arg38Gly) and c.214 G > C; p.(Gly72Arg) in exons 5 and 6, respectively. Furthermore, we provide evidence that paternal postzygotic mosaicism is the cause of inheritance, with clinically unaffected fathers and reduced affected allele fraction. This work contributes to increase the phenotypic spectrum caused by PAX6 variants, and to our knowledge, is the first report to describe the presence of postzygotic parental mosaicism causing isolated foveal hypoplasia with nystagmus. These results support the growing evidence that suggest an overestimation of sporadic cases with PAX6 variants, which has strong implications for both genetic counselling and family planning.

Episodic Vestibular Syndrome with Hyperventilation-Induced Downbeat Nystagmus.

Hyperventilation-induced downbeat nystagmus (HV-DBN) has been reported in cerebellar disorders and explained by a loss of the inhibitory cerebellar output via a metabolic effect on cerebellar Ca2+ channels. The aim of this study was to determine the clinical characteristics and underlying pathogenesis of episodic vestibular syndrome (EVS) with HV-DBN. Of 667 patients with EVS, we recruited 22 with HV-DBN and assessed their clinical characteristics, video-oculographic findings, and the results of molecular genetic analyses. The age at symptom onset was 47.5 ± 13.0 years (mean ± SD), and there was a female preponderance (n = 15, 68%). The duration of vertigo/dizziness attacks ranged from minutes to a few days, and 11 patients (50%) fulfilled the diagnostic criteria for vestibular migraine. HV-induced new-onset DBN in 8 patients, while the remaining 14 showed augmentation of spontaneous DBN by HV. The maximum slow-phase velocity of HV-DBN ranged from 2.2 to 11.9°/s, which showed a statistical difference with that of spontaneous DBN (median = 4.95, IQR = 3.68-6.55 vs. median = 1.25, IQR = 0.20-2.15, p < 0.001). HV-DBN was either purely downbeat (n = 11) or accompanied with small horizontal components (n = 11). Other neuro-otologic findings included perverted head-shaking nystagmus (n = 11), central positional nystagmus (n = 7), saccadic pursuit (n = 3), and horizontal gaze-evoked nystagmus (n = 1). Gene expression profiling with a bioinformatics analysis identified 43 upregulated and 49 downregulated differentially expressed genes (DEGs) in patients with EVS and HV-DBN and revealed that the downregulated DEGs were significantly enriched in terms related to the ribosome pathway. Our results suggest that the underlying cerebellar dysfunction would be responsible for paroxysmal attacks of vertigo in patients with EVS and HV-DBN.

Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay.

INTRODUCTION: Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. CASE STUDY: A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD). METHODS: Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed. RESULTS: After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products. DISCUSSION: This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.