De novo FRMD5 Missense Variants in Patients with Childhood-Onset Ataxia, Prominent Nystagmus, and Seizures.

BACKGROUND: FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. OBJECTIVES: We describe 2 patients presenting with childhood-onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co-expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. METHODS: Trio-based whole-exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA. RESULTS: Both patients presented with developmental delay, childhood-onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. CONCLUSIONS: We expanded the phenotype of FRMD5-related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood-onset ataxia and nystagmus. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Updates in neuro-otology.

PURPOSE OF REVIEW: Recent updates with clinical implications in the field of neuro-otology are reviewed. RECENT FINDINGS: Important updates relating to several neuro-otologic disorders have been reported in recent years. For benign positional paroxysmal vertigo (BPPV), we provide updates on the characteristics and features of the short arm variant of posterior canal BPPV. For the acute vestibular syndrome, we report important updates on the use of video-oculography in clinical diagnosis. For autoimmune causes of neuro-otologic symptoms, we describe the clinical and paraclinical features of kelch-like protein 11 encephalitis, a newly-identified antibody associated disorder. For cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we report recent genetic insights into this condition. SUMMARY: This review summarizes important recent updates relating to four hot topics in neuro-otology.

Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder.

ABSTRACT: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

Neuro-Visual and Vestibular Manifestations of Concussion and Mild TBI.

PURPOSE OF REVIEW: Mild traumatic brain injury, or concussion, is a major cause of disability. Vestibular and visual dysfunction following concussion is common and can negatively affect patients' well-being and prolong recovery. Etiologies of visual and vestibular symptoms are numerous, including ocular, neuro-ophthalmic, otologic, and neuro-vestibular conditions. Some etiologies are benign and may be treatable, while others are potentially vision or life-threatening, making a focused history and examination essential. This review offers an approach to the evaluation and treatment of the most common neuro-visual and vestibular impairments that may result from concussion. RECENT FINDINGS: Treatment of concussion including exercise, computerized programs, transcranial magnetic stimulation, gene therapy, stem cell therapy, and nanoparticles has shown promise. Many novel therapies are in the pipework for visual and vestibular recovery after concussion; however, the treatment mainstay remains therapy and evaluation for co-existing diseases.

Advances in diagnosis and treatment of vestibular migraine and the vestibular disorders it mimics.

Dizziness is one of the most common chief complaints in both the ambulatory care setting and the emergency department. These symptoms may be representative of a broad range of entities. Therefore, any attempt at treatment must first start with determining the etiology. In this current perspective, we focus specifically on the diagnosis of and treatment of vestibular migraine, which is common and overlaps clinically with a variety of other diagnoses. We discuss the traditional treatments for vestibular migraine in addition to the recent explosion of novel migraine therapeutics. Because vestibular migraine can mimic, or co-exist with, a variety of other vestibular diseases, we discuss several of these disorders including persistent postural-perceptual dizziness, benign paroxysmal positional vertigo, post-concussive syndrome, Ménière's disease, and cerebrovascular etiologies. We discuss the diagnosis of each, as well as overlapping and distinguishing clinical features of which the reader should be aware. Finally, we conclude with evidence based as well as expert commentary on management, with a particular emphasis on vestibular migraine.

Clinical Problem-Solving: Lower Extremity Weakness & Paresthesia in an Immunocompromised Patient With a Complex Cancer History.

We present a case of new onset bilateral lower extremity weakness, paresthesia, urinary retention and bowel incontinence in a 51-year-old man. He had a complicated history of acute myelogenous leukemia with known central nervous system (CNS) and leptomeningeal involvement status post allogenic stem cell transplant complicated by chronic graft versus host disease (GVHD). We review the differential diagnosis as the physical exam and diagnostic results evolved. We also provide a review of the relevant literature supporting our favored diagnosis, as well as other competing diagnoses in this complicated case. The ultimate differential diagnosis included viral myelitis, treatment-related myelopathies, and CNS GVHD. The case provides a sobering reminder that even with an appropriate diagnostic workup, some cases remain refractory to therapeutic efforts. It also underscores the importance of a sensitive neurologic exam, given the significant clinico-radiological delay, and reviews the complex differential diagnosis for myelopathy.