Ankfn1-mutant vestibular defects require loss of both ancestral and derived paralogs for penetrance in zebrafish

How and to what degree gene duplication events create regulatory innovation, redundancy, or neofunctionalization remain important questions in animal evolution and comparative genetics. Ankfn1 genes are single copy in most invertebrates, partially duplicated in jawed vertebrates, and only the derived copy retained in most mammals. Null mutations in the single mouse homolog have vestibular and neurological abnormalities. Null mutation of the single Drosophila homolog is typically lethal with severe sensorimotor deficits in rare survivors. The functions and potential redundancy of paralogs in species with two copies is not known. Here we define a vestibular role for Ankfn1 homologs in zebrafish based on simultaneous disruption of each locus. Zebrafish with both paralogs disrupted showed vestibular defects and early lethality from swim bladder inflation failure. One intact copy at either locus was sufficient to prevent major phenotypes. Our results show that vertebrate Ankfn1 genes are required for vestibular-related functions, with at least partial redundancy between ancestral and derived paralogs.

Focal Cognitive Syndromes

The neurologic results of cortical lesions reflect the structural properties of the affected region. Lesions affecting primary sensorimotor cortices result in primary sensorimotor deficits that are qualitatively all-or-nothing, such as blindness (hemianopia) and paralysis (hemiparesis). Quantitatively, though, the severity of the deficit depends on the extent of the lesion (so that a hemiparetic patient may not be completely paralyzed but simply weak). Lesions affecting modality-specific association regions result in conceptually more complex disorders that are confined to a single modality, such as nonfluent aphasia (a form of motor speech disorder reflecting the language-dominant hemisphere) or prosopagnosia (a visual disorder impairing the ability to disambiguate visually similar entities, specifically faces, reflecting the “what” visual pathway in inferotemporal cortices).

Acute disseminated encephalomyelitis following endonasal resection of a craniopharyngioma: illustrative case

BACKGROUND Acute disseminated encephalomyelitis (ADEM) is a rare, acquired demyelination syndrome that causes cognitive impairment and focal neurological deficits and may be fatal. The potentially reversible disease mainly affects children, often after vaccination or viral infection, but may be seen rarely in adults. OBSERVATIONS A 50-year-old woman presented with loss of visual acuity of the left eye. Magnetic resonance imaging (MRI) revealed an intra- and suprasellar mass, which was removed successfully. On postoperative day 1, MRI showed gross total resection of the lesion and no surgery-related complications. On postoperative day 2, the patient presented with a progressive left-sided hemiparesis, hemineglect, and decline of cognitive performance. MRI showed white matter edema in both hemispheres. Cerebrospinal fluid analysis revealed mixed pleocytosis (355/µL) without further evidence of infection. In synopsis of the findings, ADEM was diagnosed and treated with intravenous immunoglobulins. Shortly thereafter, the patient recovered, and no sensorimotor deficits were detected in the follow-up examination. LESSONS Pituitary gland pathologies are commonly treated by transsphenoidal surgery, with only minor risks for complications. A case of ADEM after craniopharyngioma resection has not been published before and should be considered in case of progressive neurological deterioration with multiple white matter lesions.

Ankfn1 vestibular defects in zebrafish require mutations in both ancestral and derived paralogs.

How and to what degree gene duplication events create regulatory innovation, redundancy, or neofunctionalization remain important questions in animal evolution and comparative genetics. Ankfn1 genes are single copy in most invertebrates, partially duplicated in jawed vertebrates, and only the derived copy retained in most mammals. Null mutations in the single mouse homolog have vestibular and neurological abnormalities. Null mutation of the single Drosophila homolog is typically lethal with severe sensorimotor deficits in rare survivors. The functions and potential redundancy of paralogs in species with two copies is not known. Here we define a vestibular role for Ankfn1 homologs in zebrafish based on simultaneous disruption of each locus. Zebrafish with both paralogs disrupted showed vestibular defects and early lethality from swim bladder inflation failure. One intact copy at either locus was sufficient to prevent major phenotypes. Our results show that vertebrate Ankfn1 genes are required for vestibular-related functions, with at least partial redundancy between ancestral and derived paralogs.

A Functional Signature in the Developing Cerebellum: Evidence From a Preclinical Model of Autism

Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions detected during childhood when delayed language onset and social deficits are observed. Children diagnosed with ASD frequently display sensorimotor deficits associated with the cerebellum, suggesting a dysfunction of synaptic circuits. Astroglia are part of the tripartite synapses and postmortem studies reported an increased expression of the glial fibrillary acidic protein (GFAP) in the cerebellum of ASD patients. Astroglia respond to neuronal activity with calcium transients that propagate to neighboring cells, resulting in a functional response known as a calcium wave. This form of intercellular signaling is implicated in proliferation, migration, and differentiation of neural precursors. Prenatal exposure to valproate (VPA) is a preclinical model of ASD in which premature migration and excess of apoptosis occur in the internal granular layer (IGL) of the cerebellum during the early postnatal period. In this study we tested calcium wave propagation in the IGL of mice prenatally exposed to VPA. Sensorimotor deficits were observed and IGL depolarization evoked a calcium wave with astrocyte recruitment. The calcium wave propagation, initial cell recruitment, and mean amplitude of the calcium transients increased significantly in VPA-exposed mice compared to the control group. Astrocyte recruitment was significantly increased in the VPA model, but the mean amplitude of the calcium transients was unchanged. Western blot and histological studies revealed an increased expression of GFAP, higher astroglial density and augmented morphological complexity. We conclude that the functional signature of the IGL is remarkably augmented in the preclinical model of autism.

Brachial Plexopathy from Metaldehyde Poisoning – A Case Report

We describe the case of a middle-aged female with schizophrenia, who developed acute sensorimotor deficits of the right upper limb within a week of ingesting large amounts of metaldehyde in a suicide attempt. A right-sided brachial plexopathy was diagnosed clinically and supported by electrophysiologic assessments and targeted magnetic resonance imaging scans. Although metaldehyde’s neurotoxicity typically affects the central nervous system, focal involvement of the peripheral nervous system remains unreported in medical literature, and its pathogenic processes await further elucidation. Therefore, we recommend the continued observation for the subsequent development of sensorimotor deficits during the first week of metaldehyde poisoning.

Paraproteinaemic neuropathy: MGUS and beyond

Paraproteinaemic neuropathies comprise a heterogeneous group of neuro-haematological conditions with some distinct neurological, haematological and systemic phenotypes. The spectrum of disease varies from mild to severe, indolent to rapidly progressive and from small fibre sensory involvement to dramatic sensorimotor deficits. The haematological association may be overlooked, resulting in delayed treatment, disability, impaired quality of life and increased mortality. However, the presence of an irrelevant benign paraprotein can sometimes lead to inappropriate treatment. In this review, we outline our practical approach to paraproteinaemic disorders, discuss the utility and limitations of diagnostic tests and the distinctive clinical phenotypes and touch on the complex multidisciplinary management approaches.

Fatty infiltration in cervical flexors and extensors in patients with degenerative cervical myelopathy using a multi-muscle segmentation model

Background In patients with degenerative cervical myelopathy (DCM) that have spinal cord compression and sensorimotor deficits, surgical decompression is often performed. However, there is heterogeneity in clinical presentation and post-surgical functional recovery. Objectives Primary: a) to assess differences in muscle fat infiltration (MFI) in patients with DCM versus controls, b) to assess association between MFI and clinical disability. Secondary: to assess association between MFI pre-surgery and post-surgical functional recovery. Study design Cross-sectional case control study. Methods Eighteen patients with DCM (58.6 ± 14.2 years, 10 M/8F) and 25 controls (52.6 ± 11.8 years, 13M/12 F) underwent 3D Dixon fat-water imaging. A convolutional neural network (CNN) was used to segment cervical muscles (MFSS- multifidus and semispinalis cervicis, LC- longus capitis/colli) and quantify MFI. Modified Japanese Orthopedic Association (mJOA) and Nurick were collected. Results Patients with DCM had significantly higher MFI in MFSS (20.63 ± 5.43 vs 17.04 ± 5.24, p = 0.043) and LC (18.74 ± 6.7 vs 13.66 ± 4.91, p = 0.021) than controls. Patients with increased MFI in LC and MFSS had higher disability (LC: Nurick (Spearman’s ρ = 0.436, p = 0.003) and mJOA (ρ = -0.399, p = 0.008)). Increased MFI in LC pre-surgery was associated with post-surgical improvement in Nurick (ρ = -0.664, p = 0.026) and mJOA (ρ = -0.603, p = 0.049). Conclusion In DCM, increased muscle adiposity is significantly associated with sensorimotor deficits, clinical disability, and functional recovery after surgery. Accurate and time efficient evaluation of fat infiltration in cervical muscles may be conducted through implementation of CNN models.