Hereditary Hyperekplexia: A New Family and a Systematic Review of GLRA1 Gene-Related Phenotypes

Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.(c) 2022 Elsevier Inc. All rights reserved

Application of the Sleep Disturbance Scale for Children (SDSC) in preschool age

BACKGROUND: The Sleep Disturbance Scale for Children (SDSC) was originally validated on a sample of healthy children aged 6-16 years, investigating the occurrence of sleep disorders during the previous 6 months. AIMS: The aim of this new study was to assess the psychometric properties of the SDSC in an Italian population of preschool children. METHODS: The SDSC was distributed to the primary caregivers of children recruited via nurseries. Letters describing the study design and requesting the co-operation of the caregivers (parents) and co-signed by the investigators and by the head teacher were distributed with the questionnaire and collected by the teachers. Reliability analysis for evaluating internal consistency and item-total correlation coefficients, and factor analysis were performed. RESULTS: During a 12-months study period, 601 questionnaires from healthy preschool age children (range 3-6 years) were collected. SDSC in preschool children showed a good level of internal consistency (Cronbach's alpha: 0.83) and six factors were derived from the factor analysis by using the principal component method of extraction and rotated with the varimax method: Parasomnias, Difficulty in initiating and maintaining sleep, Sleep disordered breathing, Disorders of excessive somnolence, Sleep hyperhydrosis and Non-restorative Sleep. CONCLUSIONS: The statistical analysis, the internal consistency and the factor analysis support the use of SDSC as an evaluation tool even at preschool age. A different factorial structure from the original SDSC was found due to a different prevalence of the sleep disturbances in younger children, but with similar cut-off total SDSC score

Lysophosphatidic acid enhances antimycobacterial response during in vivo primary Mycobacterium tuberculosis infection

Lysophospholipids may play an important protective role during primary infection of Mycobacterium tuberculosis (MTB) by enhancing innate antimycobacterial immune response of both macrophages and alveolar epithelial cells. Here, we show that treatment with lysophosphatidic acid (LPA) of mice aerogenically infected with MTB immediately after infection results in a significant early reduction of pulmonary CFUs and of histopathological damage in comparison with control mice. In contrast, treatment of acute disease does not result in any improvement of both microbiological and histopathological parameters. Altogether, these results show that LPA treatment can exert protective effect if administrated during primary infection, only

Pyridoxine supplementation in PACS2-related encephalopathy: A case report of possible precision therapy

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Visual Function in Children with GNAO1-Related Encephalopathy

Background: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit alpha of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. Objective: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. Methods: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. Results: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object-face exploration, recognition and environmental control, appeared to be preserved and improved with age. Significance: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less

Sleep-potentiated epileptiform activity in early thalamic injuries: Study in a large series (60 cases)

OBJECTIVE: The study aims at a better definition of continuous spike-waves during sleep (CSWS) with an early thalamic lesion, focusing on various grades of sleep-potentiated epileptiform activity (SPEA). Their possible relationship with different clinical features was studied to try to define prognostic factors of the epileptic disorder, especially relating to behavior/cognitive outcome, in order to improve prevention and treatment strategies. METHODS: Sixty patients with early thalamic injury were followed since the first registration of SPEA with serial neurological, long term EEG monitoring and neuropsychological examinations, as well as neuroimaging and a detailed clinical history. They were classified in three different groups according to the sleep spike-waves (SW) quantification: electrical status epilepticus during sleep (ESES), more than 85% of slow sleep; overactivation between 50% and 85% and simple activation between 10 and 50%). Results were then examined also with a statistical analysis. RESULTS: In our series of CSWS occurring in early brain injured children with unilateral thalamic involvement there is a common neuropathologic origin but with various grades of SPEA severity. Statistical analysis showed that patients evolving toward ESES presented more commonly the involvement of the mediodorsal part of thalamus nuclei and a bilateral cortico-subcortical brain injury, epilepsy was more severe with a delayed onset; moreover, in the acute stage .ESES patients presented the worst behavior/cognitive performances. As to cognitive and behavior outcome, longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase appear linked to a poor outcome; some particular neuropathology (ischemic stroke and haemorrhagic infarction) as well as hydrocephalus shunting are associated with behavior disorders. CONCLUSIONS: Discrete features seem to support different underlying mechanisms in ESES patients in comparison with less severe SPEA; they represent negative prognostic factors. Longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase seem predictive of a worse cognitive/behavior outcome