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

The Impact of Blenderized Tube Feeding on Gastrointestinal Symptoms, a Scoping Review

Severe gastrointestinal symptoms are one of the main reasons for switching from conventional artificial tube feeding to blenderized tube feeding (BTF). This study aimed to describe and quantify the impact of BTF on gastrointestinal symptoms in children and adults. We analyzed four databases (PubMed, Scopus, Cochrane Library, and Google Scholar). The review was performed following the PRISMA extension for Scoping Reviews checklist. The methodological quality of articles was assessed following the NIH quality assessment tools. The initial search yielded 535 articles and, after removing duplicates and off-topic articles, 12 met the inclusion criteria. All included papers unanimously converged in defining an improvement of gastrointestinal symptoms during blenderized feeding: the eight studies involving pediatric cohorts report a decrease from 30 to over 50% in gagging and retching after commencing BTF. Similar rates are reported for constipation and diarrhea improvement in most critically ill adults. Experimental studies and particularly randomized controlled trials are needed to develop robust evidence on the effectiveness of BTF in gastrointestinal symptom improvement with prolonged follow-up and adequate medical monitoring

Metabolic Profile of Patients with Smith-Magenis Syndrome: An Observational Study with Literature Review

Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9–32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS ‘deleted’ patients may show a dyslipidemic pattern, while SMS ‘mutated’ patients are more likely to develop early-onset obesity along with hyperinsulinism

The Impact of Blenderized Tube Feeding on Gastrointestinal Symptoms, a Scoping Review

Severe gastrointestinal symptoms are one of the main reasons for switching from conventional artificial tube feeding to blenderized tube feeding (BTF). This study aimed to describe and quantify the impact of BTF on gastrointestinal symptoms in children and adults. We analyzed four databases (PubMed, Scopus, Cochrane Library, and Google Scholar). The review was performed following the PRISMA extension for Scoping Reviews checklist. The methodological quality of articles was assessed following the NIH quality assessment tools. The initial search yielded 535 articles and, after removing duplicates and off-topic articles, 12 met the inclusion criteria. All included papers unanimously converged in defining an improvement of gastrointestinal symptoms during blenderized feeding: the eight studies involving pediatric cohorts report a decrease from 30 to over 50% in gagging and retching after commencing BTF. Similar rates are reported for constipation and diarrhea improvement in most critically ill adults. Experimental studies and particularly randomized controlled trials are needed to develop robust evidence on the effectiveness of BTF in gastrointestinal symptom improvement with prolonged follow-up and adequate medical monitoring

Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in <i>MFSD8</i>

Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in MFSD8 in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including EXOSC9, SPATA5 and MFSD8. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted MFSD8 sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic

A systematic review on gender dysphoria in adolescents and young adults: focus on suicidal and self-harming ideation and behaviours

Abstract Introduction Gender dysphoria (GD) is characterized by the incongruence between one’s experienced and expressed gender and assigned-sex-at-birth; it is associated with clinically significant distress. In recent years, the number of young patients diagnosed with GD has increased considerably. Recent studies reported that GD adolescents present behavioural and emotional problems and internalizing problems. Furthermore, this population shows a prevalence of psychiatric symptoms, like depression and anxiety. Several studies showed high rates of suicidal and non-suicidal self-injurious thoughts and behaviour in GD adolescents. To increase understanding of overall mental health status and potential risks of young people with GD, this systematic review focused on risk of suicide and self-harm gestures. Methods We followed the PRISMA 2020 statement, collecting empirical studies from four electronic databases, i.e., PubMed, Scopus, PsycINFO, and Web of Science. Results Twenty-one studies on GD and gender nonconforming identity, suicidality, and self-harm in adolescents and young adults met inclusion criteria. Results showed that GD adolescents have more suicidal ideation, life-threatening behaviour, self-injurious thoughts or self-harm than their cisgender peers. Assessment methods were heterogeneous. Conclusion A standardised assessment is needed. Understanding the mental health status of transgender young people could help develop and provide effective clinical pathways and interventions

A systematic review on gender dysphoria in adolescents and young adults: focus on suicidal and self-harming ideation and behaviours

IntroductionGender dysphoria (GD) is characterized by the incongruence between one's experienced and expressed gender and assigned-sex-at-birth; it is associated with clinically significant distress. In recent years, the number of young patients diagnosed with GD has increased considerably. Recent studies reported that GD adolescents present behavioural and emotional problems and internalizing problems. Furthermore, this population shows a prevalence of psychiatric symptoms, like depression and anxiety. Several studies showed high rates of suicidal and non-suicidal self-injurious thoughts and behaviour in GD adolescents. To increase understanding of overall mental health status and potential risks of young people with GD, this systematic review focused on risk of suicide and self-harm gestures.MethodsWe followed the PRISMA 2020 statement, collecting empirical studies from four electronic databases, i.e., PubMed, Scopus, PsycINFO, and Web of Science.ResultsTwenty-one studies on GD and gender nonconforming identity, suicidality, and self-harm in adolescents and young adults met inclusion criteria. Results showed that GD adolescents have more suicidal ideation, life-threatening behaviour, self-injurious thoughts or self-harm than their cisgender peers. Assessment methods were heterogeneous.ConclusionA standardised assessment is needed. Understanding the mental health status of transgender young people could help develop and provide effective clinical pathways and interventions

Early development in Dravet syndrome; visual function impairment precedes cognitive decline

Aim of the study was to describe prospectively the early neuropsychological evolution including the first pre-cognitive stages of the Severe Myoclonic Epilepsy in Infancy (SMEI) or Dravet syndrome. Five cases, four of whom since before a diagnostic evidence of the Dravet syndrome, were followed up. Full clinical assessment including developmental, visual function and behaviour assessments were serially performed. In four cases, a variable onset age of cognitive decline assessed with developmental scales was preceded some months before by an impairment of visual function; the remaining patient during all the course of follow-up till 51 months of age showed a normal development without visual impairment. A cognitive decline with variable onset was generally confirmed in Dravet syndrome. The previous early impairment of visual function seems to herald the cognitive decline and provides useful prognostic information; furthermore, it possibly suggests some clues for a better understanding of the mechanisms of cognitive deterioration in this syndrome

Early thalamic injury associated with epilepsy and continuous spike-wave during slow sleep

Purpose: Mechanisms inducing continuous spike-wave during slow sleep (CSWS) in encephalopathy with electrical status epilepticus during sleep are still unclear. Recently, some sporadic cases with early thalamic injury associated with CSWS have been reported. The aim of the study was to investigate in a population of patients with an early thalamic injury the presence of an activation of paroxysmal activities during sleep, their characteristics, and possible relations to neuroimaging and neuropsychological features. Methods: Thirty-two patients with prenatal or perinatal thalamic injuries, mostly due to a vascular mechanisms, were fully examined, including neuroimaging, EEG monitoring, and cognitive follow-up. Results and conclusions: Twenty-nine of 32 patients showed major sleep EEG activation. Among these 29 patients, two different groups were distinguished: the first included the more or less typical CSWS (12 cases), generally with symmetry of spike and waves (SWs) and often with no spindle at all. The other cases had an usual asymmetry of SWs and presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of SWs. Behavioral disorders were significantly more present in patients with a true CSWS; their improvement (and in one case of the three thoroughly followed the improvement of cognitive competence) paralleled the disappearance of CSWS. The generally predominant injury of the lateral aspect of the thalamus included reticular nucleus and ventral nuclei. An imbalance of gamma-aminobutyric acid (GABA)(B)--versus GABA(A)--mediated receptors may be evoked as a cofactor predisposing to CSWS