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Cytosolic peptide: N-glycanase (PNGase/NGLY1 in mammals) is an amidase (EC:3.5.1.52) widely conserved in eukaryotes. It catalyzes the removal of N-glycans on glycoproteins, converting N-glycosylated Asn into Asp residues. This enzyme also plays a role in the quality control system for nascent glycoproteins. Since the identification of a patient with an autosomal recessive genetic disorder caused by NGLY1 gene dysfunction, known as NGLY1 deficiency or NGLY1 congenital disorder of deglycosylation (OMIM: 615273), in 2012, more than 100 cases have been reported worldwide. NGLY1 deficiency is characterized by a wide array of symptoms, such as global mental delay, intellectual disability, abnormal electroencephalography findings, seizure, movement disorder, hypolacrima or alacrima, and liver dysfunction. Unfortunately, no effective therapeutic treatments for this disease have been established. However, administration of adeno-associated virus 9 (AAV9) vector harboring human NGLY1 gene to an NGLY1-deficient rat model (Ngly1-/- rat) by intracerebroventricular injection was found to drastically improve motor function defects. This observation indicated that early therapeutic intervention could alleviate various symptoms originating from central nervous system dysfunction in this disease. Therefore, there is a keen interest in the development of facile diagnostic methods for NGLY1 deficiency. This review summarizes the history of assay development for PNGase/NGLY1 activity, as well as the recent progress in the development of novel plate-based assay systems for NGLY1, and also discusses future perspectives., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly., Materials and Methods: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics., Results: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%., Conclusions: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result., (© 2024. The Author(s).)

Rationale: Allan-Herndon-Dudley syndrome (AHDS) results from a pathogenic variant in the hemizygous subunit of the SLC16A2 gene, which encodes monocarboxylate transporter 8 and follows an X-linked recessive pattern. AHDS manifests as neuropsychomotor developmental delay, intellectual disability, movement disorders, and thyroid hormone abnormalities. It is frequently misdiagnosed as cerebral palsy or hypothyroidism., Patient Concerns: A 9-month-old male infant exhibited poor head control, hypodynamia, motor retardation, hypertonic limbs, and thyroid abnormalities. Despite levothyroxine supplementation and rehabilitation therapy, no improvements were observed. Whole-exome sequencing identified a novel nonsense mutation in SLC16A2 (c.124G > T, p.E42X), which unequivocally established the diagnosis., Diagnoses: AHDS was confirmed., Interventions: Levothyroxine treatment commenced early in infancy, followed by 3 months of rehabilitation therapy, starting at 5 months of age. The combined administration of levothyroxine and methimazole was initiated at 1 year and 10 months of age, respectively., Outcomes: While improvements were noted in thyroid hormone levels, neurological developmental delays persisted., Lessons: AHDS should be considered in patients presenting with atypical neurological features and thyroid hormone abnormalities such as elevated triiodothyronine and decreased thyroxine levels. The early utilization of exome sequencing aids in prompt diagnosis. The identified SLC16A2 nonsense mutation correlates with severe neurological phenotypes and adds to the spectrum of genetic variations associated with AHDS., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Sotos syndrome is a disorder characterised by distinctive facial features, excessive growth during childhood and intellectual disability. While these criteria apply to children and adults, they fall short when applied to neonates. Hyperbilirubinaemia, large for gestational age, hypotonia and seizures, along with cardiac and renal anomalies, are known to be common presentations in neonates. Reports have also added hyperinsulinaemic hypoglycaemia as a presenting feature of Sotos syndrome in neonates. Here, we report a case of Sotos syndrome in a neonate who presented in the neonatal period with recurrent apnoeic episodes with hypotonia, which were later attributed to severe gastro-oesophageal reflux., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM 300776) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients' symptoms. To date, less than 100 individuals have been reported with ALG13-CDG. In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Due to its rare nature and subtle dysmorphisms, Prader-Willi syndrome can be challenging to recognize and diagnose in the neonatal period. Feeding difficulties and hypotonia ('floppy infant') are the most striking characteristics. Prader-Willi syndrome requires specific follow-up and treatment, emphasizing the importance of early recognition.We encountered an infant of three months old with severe hypotonia. The hypotonia ameliorated spontaneously over time, although feeding per nasogastric tube was necessary. There were no apparent dysmorphisms. Extensive genetic investigations showed a maternal uniparental disomy of chromosome 15, fitting with Prader-Willi syndrome explaining all symptoms. After excluding contraindications, treatment with growth hormone therapy was started. Parents were educated regarding medical emergencies specific for Prader-Willi syndrome ('medical alerts'). Although Prader-Willi syndrome is rare, it should always be considered in cases of neonatal hypotonia. Early recognition is paramount as specific recommendations and treatment are warranted.

REM sleep behaviour disorder (RBD) is common in narcolepsy type 1 (NT1). Abnormalities in the reward system have been observed in NT1, possibly related to impaired orexin projections towards the mesolimbic reward system, but also in RBD when associated with Parkinson's disease. Our study aimed to explore the psychobehavioural profile of NT1 patients with and without RBD compared with healthy controls (HC). Forty patients with NT1 were compared with 20 sex- and age-matched HC. All patients with NT1 underwent a video-polysomnography including a measure of REM sleep without atonia (RSWA). The following neuropsychobehavioural variables were assessed: apathy, impulsivity, depression, cognition, subjective and objective attention, sensation-seeking, and behavioural addictions. The patient population included 22 patients with NT1-RBD and 18 patients with NT1-noRBD. Compared with the healthy controls, patients with NT1 had higher scores of apathy, impulsivity, and depression; a lower score on global cognition, and poorer self-perceived attention. No differences were found between patients with NT1 with and without RBD in all neuropsychological variables, except for impaired objective attention in patients with NT1-RBD. In patients with NT1, a positive correlation was observed between RSWA and both apathy and impulsivity subscale. Moreover, in patients with NT1-RBD, RSWA was positively correlated with depression. Patients with NT1 showed higher depression, apathy, and impulsivity compared with controls. These measures correlate with the severity of RSWA, suggesting a transdiagnostic association between RBD and abnormalities of the reward system at least for patients with NT1., (© 2023 European Sleep Research Society.)

Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder characterized by peripheral thyrotoxicosis and severe cognitive and motor disability due to cerebral hypothyroidism. 3,3’,5-triiodothyroacetic acid (Triac) was shown to improve peripheral thyrotoxicosis but data on neurodevelopmental outcome are scarce. We present a case of MCT8 deficiency and the experience with Triac focusing on change in neurodevelopmental and peripheral features. A five-month-old boy was referred because of feeding difficulty, central hypotonia and global developmental delay. Despite six months of physiotherapy, physical developmental milestones did not improve, and distal muscle tone was increased. A hemizygous pathogenic variant in SLC16A2 was found and MCT8 deficiency was confirmed at 19-months. Thyroid stimulating hormone was 2.83 mIU/mL, free thyroxine 6.24 pmol/L (N=12-22) and free triiodothyronine (FT3) 15.65pmol/L (N=3.1-6.8). He had tachycardia, blood pressure and transaminases were elevated. Triac was started at 21-months. Two weeks after treatment, FT3 dramatically decreased, steady normal serum FT3 was achieved at 28-months. Assessment of neurodevelopmental milestones and signs of hyperthyroidism were evaluated at baseline, 6 months and 12 months after treatment. Signs of hyperthyroidism were improved by 6 months. Developmental composite scores of Bayley Scales of Infant Developmental 3 rd Edition remained the same but important developmental milestones (head control, recognition of caregiver, response to his name) were attained, regression in the attained milestones were not observed. Initial dose, management protocol for Triac and research into its efficacy on neurodevelopmental signs in MCT8 deficiency are progressing. This case presents evidence that Triac may resolve peripheral thyrotoxicosis successfully and may slow neurodevelopmental regression, while some developmental milestones were achieved after one year of treatment., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Study Objectives: Accurate diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial due to its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds applicable in varying clinical presentations in a contemporary cohort of patients with iRBD using submentalis (SM) and individual bilateral flexor digitorum superficialis (FDS) and anterior tibialis electromyography limb recordings during polysomnography., Methods: We analyzed RSWA in 20 patients with iRBD and 20 age-, REM-, apnea-hypopnea index-matched controls between 2017 and 2022 for phasic burst durations, density of phasic, tonic, and "any" muscle activity (number of 3-second mini-epochs containing phasic or tonic muscle activity divided by the total number of REM sleep 3-second mini-epochs), and automated Ferri REM atonia index (RAI). Group RSWA metrics were comparatively analyzed. Receiver operating characteristic curves determined optimized area under the curve (AUC) and maximized specificity and sensitivity diagnostic iRBD RSWA thresholds., Results: All mean RSWA metrics were higher in patients with iRBD than in controls ( P < .05), except for selected anterior tibialis measures. Optimized, maximal specificity AUC diagnostic cutoffs for coprimary outcomes were: SM "any" 6.5%, 14.0% (AUC = 92.5%) and combined SM+FDS "any" 15.1%, 27.4% (AUC = 95.8%), while SM burst durations were 0.72, and 0.72 seconds (AUC 90.2%) and FDS RAI = 0.930, 0.888 (AUC 92.8%)., Conclusions: This study provides evidence for current quantitative RSWA diagnostic thresholds in chin and individual 4 limb muscles applicable in different iRBD clinical settings and confirms the key value of SM or SM+FDS to assure accurate iRBD diagnosis. Evolving iRBD recognition underscores the necessity of continuous assessment with future large, prospective, well-harmonized, multicenter polysomnographic analyses., Citation: Leclair-Visonneau L, Feemster JC, Bibi N, et al. Contemporary diagnostic visual and automated polysomnographic REM sleep without atonia thresholds in isolated REM sleep behavior disorder. J Clin Sleep Med . 2024;20(2):279-291., (© 2024 American Academy of Sleep Medicine.)

Background: The monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease., Methods: Neurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls., Results: Ultrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density., Conclusions: These findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease., (© 2023. The Author(s).)

This study aimed to correlate REM sleep without atonia (RSWA) and neuropsychological data in patients with idiopathic/isolated REM sleep behaviour disorder (iRBD) and those with RBD associated with Parkinson's disease (PDRBD), in order to assess whether higher degrees of RSWA are related to poorer cognitive performance. A total of 142 subjects were enrolled: 48 with iRBD, 55 with PDRBD, and 39 PD without RBD (PDnoRBD). All participants underwent video-polysomnographic recording, clinical and neuropsychological assessment. RSWA was quantified according to two manual scoring methods (Montréal, SINBAR) and one automated (REM atonia index, RAI). Mild cognitive impairment (MCI) was diagnosed according to diagnostic criteria for MCI in Parkinson's disease. The relationship between neuropsychological scores and RSWA metrics was explored by multiple linear regression analysis and logistic regression models. Patients with iRBD showed significantly lower visuospatial functions and working memory, compared with the others. More severe RSWA was associated with a higher risk of reduced visuospatial abilities (OR 0.15), working memory (OR 2.48), attention (OR 2.53), and semantic fluency (OR 0.15) in the iRBD. In the whole group, a greater RSWA was associated with an increased risk for depressive symptoms (OR 3.6). A total of 57(40%) MCI subjects were found (17 iRBD, 26 PDRBD, and 14 PDnoRBD). Preserved REM-atonia was associated with a reduced odds of multi-domain MCI in the whole study population (OR 0.54). In conclusion, a greater severity of RSWA was associated with an increased risk for poor cognitive performance and depressive mood in patients with RBD. Moreover, higher RAI was associated with a lower risk of multi-domain MCI., (© 2023 European Sleep Research Society.)

Objective: To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents., Methods: A female child who had presented at Linyi People's Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks' gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci., Results: The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+PM2&#95;Supporting+PM4), and c.1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2&#95;Supporting+PM3+PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor., Conclusion: The c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q) compound heterozygous variants of the PIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.

Competing Interests: The authors declare that they have no conflict of interest.

REM sleep behavior disorder (RBD) is a parasomnia with dream enactment and presence of REM sleep without atonia (RSWA). RBD diagnosed manually via polysomnography (PSG) scoring, which is time intensive. Isolated RBD (iRBD) is also associated with a high probability of conversion to Parkinson's disease. Diagnosis of iRBD is largely based on clinical evaluation and subjective PSG ratings of REM sleep without atonia. Here we show the first application of a novel spectral vision transformer (SViT) to PSG signals for detection of RBD and compare the results to the more conventional convolutional neural network architecture. The vision-based deep learning models were applied to scalograms (30 or 300 s windows) of the PSG data (EEG, EMG and EOG) and the predictions interpreted. A total of 153 RBD (96 iRBD and 57 RBD with PD) and 190 controls were included in the study and 5-fold bagged ensemble was used. Model outputs were analyzed per-patient (averaged), with regards to sleep stage, and the SViT was interpreted using integrated gradients. Models had a similar per-epoch test F1 score. However, the vision transformer had the best per-patient performance, with an F1 score 0.87. Training the SViT on channel subsets, it achieved an F1 score of 0.93 on a combination of EEG and EOG. EMG is thought to have the highest diagnostic yield, but interpretation of our model showed that high relevance was placed on EEG and EOG, indicating these channels could be included for diagnosing RBD.

Previous studies have shown that rapid eye movement sleep without atonia during polysomnography can predict the risk of phenoconversion to neurodegenerative disease in patients with isolated rapid eye movement sleep behaviour disorder. Discrepancy remains with regards to the morphology of rapid eye movement sleep without atonia that best predicts phenoconversion risk. This study aimed to ascertain the predictive value of tonic, phasic and mixed rapid eye movement sleep without atonia in patients with isolated rapid eye movement sleep behaviour disorder, at time of diagnosis. Sixty-four patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, including 19 who phenoconverted during follow-up, were identified from an existing database. Tonic, phasic, mixed and "any" rapid eye movement sleep without atonia activity from the mentalis, tibialis anterior and flexor digitorum superficialis muscles was analysed blind to status using the diagnostic polysomnography. Rapid eye movement sleep without atonia variables were compared between converters and non-converters. Rapid eye movement sleep without atonia cut-offs predicting phenoconversion were established using receiver-operating characteristic analysis. The mean follow-up duration was 5.50 ± 4.73 years. Phenoconverters (n = 19) had significantly higher amounts of tonic (22.2 ± 19.1%, p = 0.0014), mixed (18.1 ± 14.1%, p = 0.0074) and "any" (mentalis muscle; 58.7 ± 28.0%, p = 0.0009) and all muscles (68.0 ± 20.8%, p = 0.0049) rapid eye movement sleep without atonia at diagnosis than non-converters. Optimal rapid eye movement sleep without atonia cut-off values predicting phenoconversion were 5.8% for tonic (73.7% sensitivity; 75.6% specificity), 7.3% for mixed (68.4% sensitivity; 73.3% specificity) and 43.6% for "any" (mentalis muscle; 68.4% sensitivity; 80.0% specificity) activity. "Any" (mentalis muscle) rapid eye movement sleep without atonia had the highest area under the curve (0.809) followed by tonic (0.799). The percentage of tonic rapid eye movement sleep without atonia was the strongest biomarker of phenoconversion in this cohort of patients with isolated rapid eye movement sleep behaviour disorder., (© 2022 European Sleep Research Society.)

Objectives: To study the clinical and genetic features of Joubert syndrome (JS) in children., Methods: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022., Results: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1 , RPGRIP1L , MKS1 , CC2D2A , CEP120 , and AHI1 genes., Conclusions: For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

The present review focuses on REM sleep without atonia (RSWA) scoring methods. In consideration of the numerous papers published in the last decade, that used different methods for the quantification of RSWA, their systematic revision is an emerging need. We made a search using the PubMed, Embase, Scopus and Web of Science Databases, from 2010 until December 2021, combining the search term "RSWA" with "scoring methods", "IRBD", "alfasyn disease", and "neurodegenerative disease", and with each of the specific sleep disorders, diagnosed according to current criteria, with the identification of the references of interest for the topic. Furthermore, a Meta-analysis of the diagnostic performance of RSWA scoring methods, in terms of sensitivity and specificity, was carried out. The comparison of the hierarchical summary receiver-operating characteristic curves obtained for visual methods and that obtained for the automated REM sleep atonia index (RAI), shows substantially similar prediction areas indicating a comparable performance. This systematic review and meta-analysis support the validity of a series of visual methods and of the automated RAI in the quantification of RSWA with the purpose to guide clinicians in the interpretation of their results and their correct and efficient use within the diagnostic work-up for REM sleep behavior disorder., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Study Objectives: To identify a fast and reliable method for rapid eye movement (REM) sleep without atonia (RWA) quantification., Methods: We analyzed 36 video-polysomnographies (v-PSGs) of isolated REM sleep behavior disorder (iRBD) patients and 35 controls' v-PSGs. Patients diagnosed with RBD had: i) RWA, quantified with a reference method, i.e. automatic and artifact-corrected 3-s Sleep Innsbruck Barcelona (SINBAR) index in REM sleep periods (RSPs, i.e. manually selected portions of REM sleep); and ii) v-PSG-documented RBD behaviors. We quantified RWA with other (semi)-automated methods requiring less human intervention than the reference one: the indices proposed by the SINBAR group (the 3-s and 30-s phasic flexor digitorum superficialis (FDS), phasic/"any"/tonic mentalis), and the REM atonia, short and long muscle activity indices (in mentalis/submentalis/FDS muscles). They were calculated in whole REM sleep (i.e. REM sleep scored following international guidelines), in RSPs, with and without manual artifact correction. Area under curves (AUC) discriminating iRBD from controls were computed. Using published cut-offs, the indices' sensitivity and specificity for iRBD identification were calculated. Apnea-hypopnea index in REM sleep (AHIREM) was considered in the analyses., Results: RWA indices from FDS muscles alone had the highest AUCs and all of them had 100% sensitivity. Without manual RSP selection and artifact correction, the "30-s phasic FDS" and the "FDS long muscle activity" had the highest specificity (85%) with AHIREM < 15/h. RWA indices were less reliable when AHIREM≥15/h., Conclusions: If AHIREM<15/h, FDS muscular activity in whole REM sleep and without artifact correction is fast and reliable to rule out RWA., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

A 5-month-old healthy infant presented with acute flaccid weakness, anisocoria, and urinary retention with clinical suspicion of acute flaccid myelitis versus acute transverse myelitis.

Background: Joubert syndrome is a rare genetic condition with a prevalence of 1:80,000-1:100,000. In most cases, it shows an autosomal autosomal recessive hereditary pattern, although X-linked and autosomal dominant cases have been described. The distinctive characteristic of this syndrome is the malformation at cerebral and cerebellar levels, known as the "molar tooth sign," hypotonia, and delayed neurodevelopment., Case Report: We describe the case of a newborn with transient tachypnea. However, during hospital stay, he showed other clinical signs not corresponding to the admission diagnosis, such as bradycardia, apneas, hypotonia, and alteration in swallowing mechanics. To rule out etiologies of central origin, we conducted a magnetic resonance of the brain and identified the "molar tooth sign," where the pathognomonic sign of Joubert syndrome., Conclusions: Rare genetic diseases may manifest as early as the neonatal period with non-specific signs. The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling., (Copyright: © 2023 Permanyer.)

The underlying etiology of neonatal and infantile hypotonia can be divided into primary peripheral and central nervous system and acquired or genetic disorders. The approach to identifying the likeliest cause of hypotonia begins with a bedside assessment followed by a careful review of the birth history and early development and family pedigree and obtaining available genetic studies and age- and disease-appropriate laboratory investigations. Until about a decade ago, the main goal was to identify the clinical signs and a battery of basic investigations including electrophysiology to confirm or exclude a given neuromuscular disorder, however the availability of whole-exome sequencing and next generation sequencing and transcriptome sequencing has simplified the identification of specific underlying genetic defect and improved the accuracy of diagnosis in many related Mendelian disorders., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Hypotonia is considered a determinant factor in multiple developmental disorders and is associated with various characteristics and morbidities. It is necessary to perform a systematic review to know which characteristics are described as associated with hypotonia in children and which methods are used for its diagnosis., Methods: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used to develop the systematic review protocol. A search of databases (Pubmed, Cochrane, Web of Knowledge, among others) was performed in May 2021 to identify relevant studies. Those describing characteristics or tests of hypotonia assessment were included, excluding those that exclusively addressed peripheral hypotonia. Two reviewers evaluated the articles and collected the data in a table, noting the authors, date of publication, type of study, and characteristics or tests described in relation to hypotonia. The quality of the studies was also assessed, and data were extracted., Results: A total of 8778 studies were identified and analyzed, of which 45 met the inclusion criteria. Fifty-three characteristics associated with hypotonia and tests used for its evaluation were located, with pull to sit and vertical suspension being the most frequently referenced., Conclusions: The characteristics associated with hypotonia, more highly debated by authors are muscle strength, hypermobility, or the maintenance of antigravity postures. The most used test in the diagnosis of hypotonia is observation, followed by the pull-to-sit test, and adoption of frog posture. A unanimous understanding of the term hypotonia would favor further research., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome., Study Design: Twelve patients with Cohen syndrome aged 0.2-13.9 years from 8 families with a median follow-up of 7 years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses., Results: Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4 years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5 years, respectively. Eleven patients aged older than 5 years at their last examination had severe speech delay., Conclusions: A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9 years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is a leading predictor of Parkinson's disease (PD). Diagnosis is performed in the sleep laboratory by detecting pathological REM sleep without atonia (RSWA). The evidence on the overnight distribution of RSWA% is conflicting., Objective: To investigate the temporal distribution of the number of ocular movements per REM sleep minute (REM density), and RSWA% in people with PD and non-PD controls., Methods: All participants underwent a single overnight evaluation in a sleep laboratory. Clinical evaluation was performed on a separate day. REM density and RSWA% were compared between PD and controls both across four sleep periods and individual REM cycles., Results: A total of 51 participants with recorded RSWA in polysomnography laboratory were included, 28 with PD aged 64±9 years with a disease duration of 3.3±2.9 years, and 23 controls aged 55±8 years. People with PD had lower REM density and higher RSWA% compared to controls. As expected, REM density was higher towards the morning. In contrast, RSWA% was equally distributed across the night, for both PD and controls., Conclusions: PD pathology affects REM sleep features, but not the overnight distribution of those features. While REM density increased towards the end of the night, RSWA% was equally distributed across the night for both PD and controls. Our findings have clinical implications for diagnosing RBD, as quantification of RSWA% in any sleep cycle is sufficient for reliably evaluating total RSWA% and reduced REM density may be a marker of PD.

Study Objectives: Rapid eye movement (REM) sleep without atonia (RWA) is essential for diagnosing REM sleep behavior disorder (RBD). Manual and automatic quantifications of RWA that use different criteria have been validated. This study compared the RWA quantification methods for diagnosing RBD., Methods: The PubMed, EMBASE, Web of Science, and Cochrane Library databases were systemically searched for studies published from inception to December 2021. The inclusion criteria were cohort, cross-sectional, and case-control studies assessing the sensitivity and specificity of RWA quantification methods. Pooled estimates of the sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were determined. Risk of bias and certainty of evidence was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool and the Grading of Recommendations, Assessment, Development, and Evaluations framework, respectively., Results: Fourteen articles including 402 patients with RBD met the inclusion criteria. Manual methods evaluating any chin and phasic flexor digitorum superficialis (FDS) activity had the highest DOR (138.8, 95% CI = 21.8% to 881.7%) and AUC (0.9686). The automatic REM atonia index (RAI) showed similar or higher sensitivity (89.1%, 95% CI = 84.6% to 92.7%) but a lower specificity (73.5%), DOR (43.1), and AUC (0.9369) than the manual techniques., Conclusions: In this meta-analysis, manual RWA quantification that employed chin or phasic FDS activity had the best RBD diagnostic performance. The automatic RAI method may be useful for screening patients with RBD. The results should be interpreted carefully because of the high risk of bias in patient selection and significant heterogeneity among the studies., Prospero Registration Number: CRD42021276445., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypotonia of the newborn or infant is defined as decreased resistance to passive movement and is a frequent diagnostic challenge in pediatric practice. The hypotonic syndrome is a working diagnosis and its etiology must be identified to determine associated morbidities, prognosis, and management. Rapid advances in bioinformatics and molecular genetic testing allow for early accurate diagnoses in the diagnostic process. Therefore, it is necessary to carry out an updated review on this topic. The objective of this non-systematic narrative review is to describe the diagnostic approach to hypotonic syndrome and its main etiologies. A review of the literature from PubMed and Scielo databases was carried out, including relevant articles in English and Spanish published in the last 15 years. We emphasize the value of the clinical examination and history in locating the cause of hypotonia (cen tral or peripheral) as the first step toward the etiological diagnosis. Systemic diseases such as sepsis, hypoxic-ischemic encephalopathy, heart failure, and metabolic and electrolyte abnormalities are still common causes of central hypotonia. Peripheral hypotonia involves disorders of the anterior horn of the spinal cord, peripheral nerve, neuromuscular junction and muscle, of inherited and acquired origin. The use of images of the central nervous system and muscle and genetic panels and exome, constitute the most recent contributions to the diagnosis of hypotonic syndrome. This article propo ses an initial approach based on the main clinical clues leading to a certain diagnosis. Its therapy is supportive, except for some conditions that require specific treatment.

Our aim was to develop a new module for assessing the floppy infant, to describe the application of the module in a cohort of low-risk newborns and piloting the module in a cohort of floppy infants. The module was applied to a cohort of 143 low-risk newborns and piloted in in a cohort of 24 floppy infants. The new add-on module includes a neurological section and provides a section for recording information obtained by physical examination and antenatal history. For each item, column 1 reports abnormal findings, column 3 normal findings, and column 2 intermediate signs to be followed. Consistent with previous studies, in low-risk infants, none had definitely abnormal or mildly abnormal signs, with the exception of tendon reflexes that were not easily elicitable in 17.14% of term-born infants., Conclusion: Our study suggest that the module can be easily used in a clinical setting as an add-on to the regular neonatal neurological examination in newborns identified as hypotonic on routine examination. Larger cohorts are needed to establish the accuracy of the prognostic value of the module in the differential diagnosis of floppy infant., What Is Known: • Hypotonia is one of the key signs in newborns with neuromuscular disorders and can be associated with a wide range of other conditions (central nervous system involvement, genetic and metabolic diseases). • Weakness or/and contractures can identify infants with a neuromuscular disorder and help in the differential diagnosis of floppy infants., What Is New: • To date, this is the first attempt to develop and apply a specific neurological module for the assessment of the floppy infant. • The module can be used in a routine clinical setting as an add-on to the regular neurological examination and has potential to differentiate the floppy infants from the low-risk infants., (© 2022. The Author(s).)

Fumaric aciduria resulting from fumarate hydratase deficiency is a rare inherited disorder of the Krebs tricarboxylic acid cycle that is characterized by neurologic manifestations, a spectrum of brain abnormalities, and the excretion of fumaric acid in urine. We describe a 3 year old Sri Lankan boy who was referred at age 10 months with poor weight gain and hypotonia for further laboratory investigations. In addition to global developmental delay, there were noticeable dysmorphic features with a prominent forehead, low-set ears, micrognathia, and hypertelorism with persistent neutropenia. Urine organic acid assay revealed a massive elevation of fumaric acid on 2 occasions. Molecular analysis revealed a homozygous likely pathogenic missense variant, NM000143.3:c.1048C>T p. (Arg350Trp), in the FH gene, confirming the biochemical diagnosis. Our patient was the first patient in Sri Lanka molecularly diagnosed with fumaric aciduria. This case study highlights the importance of performing organic acid assays in children presenting with neurologic manifestations especially when these are suspected to have a metabolic basis., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease., Observations: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations., Conclusions and Relevance: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.

This retrospective cohort study was designed to determine the yield of genetic tests in hypotonic infants and develop a diagnostic algorithm. Out of 496 patients identified by International Classification of Diseases (ICD) 9/10 coding, 324 patients met the inclusion criteria. Diagnostic yields were 32% for karyotype, 19% for microarray, 30% for targeted genetic tests, 38% for gene panels, and 31% for exome sequencing. In addition, we considered the diagnostic contribution of ancillary tests, including neuroimaging, metabolic tests, and so forth. The combination of microarray and exome sequencing gave the highest diagnostic yield. None of the other tests added significant value in arriving at a diagnosis. Based on these results we propose that the vast majority of infants with congenital hypotonia should start with a microarray and proceed with exome sequencing, with the notable exception of infants with clearly syndromic features in whom karyotyping or targeted testing may be more appropriate., (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Abstract: FOXG1, located at chromosome 14q12, is critical for brain development, and patients with FOXG1 mutation exhibit developmental encephalopathy with high phenotypic variability, known as FOXG1 syndrome. Here, we report 3 cases of FOXG1 syndrome that presented with infantile hypotonia and microcephaly.A total of 145 children with developmental delay and/or hypotonia were evaluated by whole-exome sequencing (WES) in the pediatric neurology clinic and medical genetics center at Asan Medical Center Children's Hospital, from 2017 to 2019. Each FOXG1 mutation was confirmed by Sanger sequencing. The clinical findings of each patient with FOXG1 mutation were reviewed.WES identified de-novo, pathogenic, and heterozygous FOXG1 mutations in 3 of 145 patients in our patient cohort with developmental delay and/or hypotonia. The characteristics of brain magnetic resonance imaging (MRI) were reported as callosal anomaly, decrease in frontal volume, fornix thickening, and hypoplastic olfactory bulbs. A phenotype-genotype correlation was demonstrated as a patient with a novel missense mutation, c.761A > C (p.Tyr254Ser), in the forkhead domain had better outcome and milder brain abnormalities than the other 2 patients with truncating mutation in the Groucho binding domain site, c.958delC (p.Arg320Alafs), or N-terminal domain, c.506dup (p.Lys170GlnfsThe). Importantly, all 3 patients had hypoplastic olfactory bulbs on their brain MRI, which is a distinct and previously unrecognized feature of FOXG1 syndrome.This is the first report of FOXG1 syndrome in a Korean population; this condition accounts for 2% (3 of 145 patients) of our patient cohort with developmental delays and/or hypotonia. Our report contributes to understanding this extremely rare genetic condition in the clinical and genetic perspectives., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2-10) and PREPL (deletion of exons 2-14). The molecular findings were consistent with the hypotonia-cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The HECT, C2, and WW domain containing E3 ubiquitin protein ligase 2 gene (HECW2) is involved in protein ubiquitination. Several genes associated with protein ubiquitination have been linked to neurodevelopmental disorders. HECW2-related disorder has been established through the identification of de novo variants in HECW2 in patients with neurodevelopmental disorders with hypotonia, seizures, and absent language. Recently, we identified novel HECW2 variants in four Japanese patients with neurodevelopmental disorders. Regarding motor development, two of the patients cannot walk, whereas the other two can walk with an unsteady gait, owing to hypotonia. All HECW2 variants, including those that were previously reported, are missense, and no loss-of-function variants have been identified. Most of the identified variants are located around the HECT domain. These findings suggest that the dominant negative effects of missense variants around the HECT domain may be the mechanism underlying HECW2-related disorder., (© 2021 Wiley Periodicals LLC.)

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca 2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca 2+ -dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy., (© 2021. The Author(s).)

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4-5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap ( p  < 0.0001). Conclusions: rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.