Mutations in ARL13B lead to Joubert syndrome, a ciliopathy with neurological and retinal abnormalities. In photoreceptors, ARL13B localizes to the connecting cilia and outer segments. However, the specific function and the need for ARL13B in photoreceptor cilia remain unclear. We used a knock-in mouse model with the Arl13b V358A mutation, which disrupts ciliary localization while preserving guanine exchange factor (GEF) activity, to investigate the role of ARL13B in the photoreceptor cilia. Using female and male littermates, we show by electroretinogram (ERG) that the exclusion of ARL13B from photoreceptor cilia leads to an early loss of cone-mediated vision followed by a decline in rod-mediated vision. This phenotype was unique to the cilia-excluded V358A model, as analysis using the GEF-impaired R79Q model did not show similar changes in photoreceptor function. Morphological analyses using immunohistochemistry (IHC) and transmission electron microscopy revealed shortened cone axonemes and structural abnormalities in cone outer segments. IHC staining further demonstrated that loss of ciliary ARL13B disrupts the localization of intraflagellar transport protein 88 (IFT88) in photoreceptors. In addition, the phosphoinositol-4,5-bisphosphate (PIP2) binding protein, Tubby-like protein 1 (TULP1), associated with inherited retinal diseases, was mislocalized to cone outer segments in the V358A model. These findings establish an essential role for ciliaryARL13B in maintaining cone photoreceptor axoneme length, outer segment organization, and proper protein localization. They also suggest that phosphoinositide gradients are critical for cone photoreceptor function and morphology. Together, our findings provide new insights into the molecular mechanisms regulating photoreceptor cilia and the pathogenesis of ciliopathies.

Visual electrophysiology is a valuable tool for evaluating the visual system in various systemic syndromes. This review highlights its clinical application in a selection of syndromes associated with hearing loss, mitochondrial dysfunction, obesity, and other multisystem disorders. Techniques such as full-field electroretinography (ffERG), multifocal electroretinography (mfERG), pattern electroretinography (PERG), visual evoked potentials (VEP), and electrooculography (EOG) offer insights into retinal and optic nerve function, often detecting abnormalities before clinical symptoms manifest. In hearing loss syndromes like Refsum disease, Usher syndrome (USH), and Wolfram syndrome (WS), electrophysiology facilitates the detection of early retinal changes that precede the onset of visual symptoms. For mitochondrial disorders such as maternally-inherited diabetes and deafness (MIDD), Kearns-Sayre syndrome (KSS), and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, these tests can be useful in characterizing retinal degeneration and optic neuropathy. In obesity syndromes, including Bardet-Biedl syndrome (BBS), Alström syndrome, and Cohen syndrome, progressive retinal degeneration is a hallmark feature. Electrophysiological techniques aid in pinpointing retinal dysfunction and tracking disease progression. Other syndromes, such as Alagille syndrome (AGS), abetalipoproteinemia (ABL), Cockayne syndrome (CS), Joubert syndrome (JS), mucopolysaccharidosis (MPS), Neuronal ceroid lipofuscinoses (NCLs), and Senior-Løken syndrome (SLS), exhibit significant ocular involvement that can be evaluated using these methods. This review underscores the role of visual electrophysiology in diagnosing and monitoring visual system abnormalities across a range of syndromes, potentially offering valuable insights for early diagnosis, monitoring of progression, and management.

Senior-Løken syndrome is a rare autosomal recessive ciliopathy characterized by nephronophthisis and early-onset retinal dystrophy. It is typically diagnosed in childhood, and adult-onset diagnosis is rare and may delay renal-protective interventions. Here, we report a rare case of Senior-Løken syndrome in an adult with an IQCB1/NPHP5 mutation. A 20-year-old Turkish male presented with rotatory nystagmus since birth, progressive visual impairment from childhood, and chronic kidney disease that began during adolescence. The patient exhibited polyuria and polydipsia, and the ocular electrophysiology results were consistent with retinitis pigmentosa. Initial laboratory results were as follows: hemoglobin 11.03 g/dL, urea 56.65 mg/dL, creatinine 2.59 mg/dL, estimated glomerular filtration rate 34.14 mL/min/1.73 m2. Renal ultrasonography revealed increased parenchymal echogenicity, and abdominal computed tomography revealed small cystic lesions in both kidneys. Kidney biopsy revealed predominantly tubulointerstitial changes (tubular atrophy, basal membrane thickening, and interstitial fibrosis), and immunostaining was negative. Whole-exome sequencing identified homozygous full-gene deletion of IQCB1/NPHP5, confirming the diagnosis of SLS. The patient was managed with conservative and supportive treatments. Chronic kidney disease in Senior-Løken syndrome is often diagnosed late, leading to a poor clinical outcome. Early diagnosis and timely management of renal complications can prevent the progression to end-stage renal disease.

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder characterized by malformations of the cerebellum and brainstem, most notably the pathognomonic "molar tooth sign" on magnetic resonance imaging (MRI). Clinical manifestations are heterogeneous and include dysmorphic features, motor and ocular abnormalities, and, in most patients, intellectual developmental disorder (IDD). We describe the case of a nine-year-old boy with prenatal suspicion of ventricular asymmetry and postnatal findings of macrocephaly and facial dysmorphisms. In infancy, he exhibited nystagmus, oculomotor apraxia, irregular breathing, ataxia, and delayed motor milestones; MRI at 18 months revealed cerebellar vermis hypoplasia with a "molar tooth sign," supporting the diagnosis of JS despite the absence of a causative variant in extended genetic testing. Over time, motor and coordination deficits improved with sustained physical and occupational therapy, complemented by school and family support. Cognitive abilities remained within the expected range, although expressive language delay and motor coordination difficulties were present. At the age of eight years, he was diagnosed with attention-deficit/hyperactivity disorder, inattentive subtype, and responded well to methylphenidate, with marked improvements in attention, concentration, handwriting, and academic performance. This case illustrates a milder neurological phenotype of JS with preserved learning abilities, emphasizing the importance of MRI in diagnosis and highlighting the benefit of early individualized rehabilitation and targeted treatment of comorbidities. It also underscores the role of genetic counseling, although no pathogenic variants were identified, reflecting the syndrome's genetic diversity.

Oculomotor apraxia (OMA), the clinical manifestation of impaired voluntary initiation of saccadic eye movements, has long been associated with several disorders and genetic mutations in the literature. The present study aims to review all the disorders and genetic mutations associated with OMA reported in the literature. PubMed, MEDLINE, Scopus, EMBASE, and Web of Science databases were systematically searched for related keywords, and related publications from January 2000 to January 2024 were reviewed. All the disorders and genetic mutations presented with OMA in the literature were reported. Clinical manifestations of the congenital disorders- particularly members of autosomal recessive cerebellar ataxias- including Joubert syndrome, ataxia with oculomotor apraxia, ataxia-telangiectasia, and other disorders were discussed, Additionally, the pathophysiology of the genetic mutations in the anatomical pathway of OMA is discussed in this paper. Most of the cases with OMA present this sign early in their disease course; thus, evaluating the possible differential diagnoses can guide clinicians to a more accurate diagnosis. Understanding the spectrum of disorders and clinical manifestations with OMA also provides valuable insights into further clinic-pathological and genetic evaluations of this clinical manifestation.