Central Hypotonia Research Articles

Incidence of hip problems in developmental central hypotonia: A scoping review.

Incidence of hip problems in developmental central hypotonia: A scoping review.

Heterozygous de novo variants in HSPD1 cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation

IntroductionHypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity...

Incidence of hip problems in developmental central hypotonia: A scoping review.

To describe what is known about hip problems in individuals with developmental central hypotonia. Searches were conducted in five databases to October 2023. Down syndrome was excluded from this analysis of less well-known genetic diagnoses. At least two reviewers independently screened titles, abstracts, read full-text articles, and extracted data. Of 89 full-text articles, 79 met inclusion criteria. Studies included 544 individuals aged 1 month to 63 years with Kabuki, 49, XXXXY, Prader-Willi, PURA, Koolen de Vries, Emanuel, TRPM3, Wolf-Hirschhorn, and other rare syndromes. Most diagnoses may be associated with a combination of differences in hip structure or stability that are evident at birth, or develop in early infancy, with increasing hip dysplasia and subluxation over time. Joint or ligamentous laxity was most reported along with hypotonia and hypermobility as risk factors. Limited data were identified about conservative or surgical intervention and outcomes in these populations. Children with significant hypotonia, with or without a confirmed genetic diagnosis, are at increased risk of hip problems that may be missed with standard neonatal screening. Ultrasound is recommended between 6 weeks and 6 months, and annual orthopaedic review with regular radiographs for older children and adults with significant and persistent hypotonia.

The anesthetic management of a child with ohtahara syndrome and severe stridor: a case report

BackgroundOhtahara syndrome is a progressive developmental and epileptic encephalopathy that manifests in the early infantile period. This rare condition is characterized by intractable seizures, psychomotor retardation, and poor prognosis. To date, there are a handful of case reports regarding the anesthetic management of children with Ohtahara syndrome. However, limited reports exist of patients with Ohtahara syndrome who present with difficult airways. This report describes our airway findings and general anesthetic management of a pediatric patient with Ohtahara syndrome undergoing diagnostic bronchoscopy for severe inspiratory stridor.Case presentationA 14-month-old, 9 kg, male patient with Ohtahara syndrome presented with a year-long history of severe inspiratory stridor and was scheduled for bronchoscopy with lavage. On exam, the patient had noisy breathing, was non-verbal with developmental delay, and had poor head control with significant central hypotonia. The patient was induced with ketamine and general anesthesia was maintained with propofol. Bronchoscopic evaluation was completed uneventfully and revealed a diagnosis of laryngotracheomalacia. The patient’s breathing was maintained spontaneously throughout the procedure and no seizures were noted. In the post anesthesia care unit, the patient’s respiratory and cardiovascular function were stable.ConclusionsThis report documents the unusual finding of severe inspiratory stridor in a 14-month-old child diagnosed with Ohtahara syndrome and our anesthetic management during their diagnostic bronchoscopy. Currently, documentation of complex airway pathology present in patients with Ohtahara syndrome is limited and should be further evaluated. This will assist pediatric anesthesiologists as these patients may require careful preoperative assessment, thoughtful airway management, and surgical alternatives on standby.

Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders. Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs). Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amish Infantile Epilepsy in an Indian Child

AbstractConsanguineous marriages in India continue to give rise to a wide spectrum of recessively inherited disorders that require a broader base of knowledge. A 2-year-old boy presented with global development delay, persistent vomiting, drug refractory seizures, deafness, and central hypotonia. He had profound bilateral hearing loss, barium swallow showed severe reflux but magnetic resonance imaging brain was normal, leading to a diagnostic dilemma. A normal electromyogram with nerve conduction velocity ruled out disorders of muscle and nerve. Whole-exome sequencing showed salt and pepper development regression syndrome but phenotypically, he did not have the classic skin changes. He has shown mild improvement in cognition, mobility, and weight gain with citicoline, antireflux medications, antiseizure medications, and a protein diet. Accurate diagnosis based on cohort of symptoms and appropriate early intervention can help improve the quality of life in such children.

The phenotypic spectrum of PTCD3 deficiency.

The PTCD3 gene product (protein PTCD3 or MRPS39) forms the entry channel of the mitochondrial small ribosomal subunit and binds to single-stranded mRNA. Here, we expand on the clinical manifestations of PTCD3 pathogenic variants by describing an early-onset patient with Leigh-like syndrome and two patients with milder form of disease, with combined oxidative phosphorylation deficiency. A 34-year-old male and his 33-year-old sister both have horizontal nystagmus, pronounced rough tremor, truncal ataxia, dysmetria, spasticity and hyperreflexia. The basal respiration rate decreased significantly for the male patient and his mother (p < 0.0001) compared to the controls. The whole genome sequencing analysis revealed two heterozygous variants in the PTCD3: c.1182T>A, p.(Tyr394Ter) and c.805C>T, p.(His269Tyr). Tyr394Ter variant ablates the C-terminal half of the protein, including a significant portion of the central fold. In silico modelling for the variant His269Tyr shows that the inclusion of the slightly larger tyrosine sidechain is well tolerated, with no significant change in either the position or the movement of the surrounding area. The third case is a 9-year-old boy, who has a global developmental delay, central hypotonia, hyperreflexia and abnormal MRI. PTCD3 pathogenic variant c.538+4A>G was identified by whole exome sequencing. To test the variant's effect on splicing, an RT-PCR experiment was performed, which revealed skipping of an out-of-frame exon 7.

Familial genetic study in a patient with global maturational delay and central hypotonia

Familial genetic study in a patient with global maturational delay and central hypotonia

Identifying and Evaluating Young Children with Developmental Central Hypotonia: An Overview of Systematic Reviews and Tools.

Children with developmental central hypotonia have reduced muscle tone secondary to non-progressive damage to the brain or brainstem. Children may have transient delays, mild or global functional impairments, and the lack of a clear understanding of this diagnosis makes evaluating appropriate interventions challenging. This overview aimed to systematically describe the best available evidence for tools to identify and evaluate children with developmental central hypotonia aged 2 months to 6 years. A systematic review of systematic reviews or syntheses was conducted with electronic searches in PubMed, Medline, CINAHL, Scopus, Cochrane Database of Systematic Reviews, Google Scholar, and PEDro and supplemented with hand-searching. Methodological quality and risk-of-bias were evaluated, and included reviews and tools were compared and contrasted. Three systematic reviews, an evidence-based clinical assessment algorithm, three measurement protocols, and two additional measurement tools were identified. For children aged 2 months to 2 years, the Hammersmith Infant Neurological Examination has the strongest measurement properties and contains a subset of items that may be useful for quantifying the severity of hypotonia. For children aged 2-6 years, a clinical algorithm and individual tools provide guidance. Further research is required to develop and validate all evaluative tools for children with developmental central hypotonia.

Manifestações neurológicas da Síndrome de Ogden: relato de caso

INTRODUCTION: The syndrome related to a mutation in the N-alpha-acetyltransferase 10 (NAA10) gene, an X-linked recessive disorder, Ogden Syndrome, presents in boys with severe developmental delay, central hypotonia, dysmorphic features, cardiac malformations, and early death in the first months of life. CASE REPORT: Male infant with hypotonia and craniofacial dysmorphisms: prominent forehead, triangular facies, bilateral microphthalmia, superior oblique palpebral fissure and epicanthus, increased nasolabial filter, tapered upper lip, sparse blond hair, long and light eyelashes. Delay in neuropsychomotor development, brief episodes of oromasticatory movements, sialorrhea, horizontal nystagmus, excessive sleepiness, and hypo-responsiveness, with oxygen saturation drop and bradycardia. Electroencephalogram: bursts of diffuse slow waves. Echocardiogram and electrocardiogram without alterations. Cranial resonance: cortical thickening in the right frontal lobe, small encephalomalacic area; signs of previous ischemic insult in the territory of the right posterior cerebral artery; areas of signal alteration in the central and deep white matter adjacent to the lateral ventricles with mild compensatory dilation of the same; and diffuse thinning of the corpus callosum of undetermined nature, treatment initiated. Genome identified a likely pathogenic variant in the NAA10 gene. Under treatment with phenobarbital and oxcarbazepine, and multiprofessional follow-up. DISCUSSION/CONCLUSION: Many patients present neuroimaging alterations, mainly: corpus callosum hypoplasia and microcephaly. Epilepsy around 69%, generalized, described eyelid myoclonias or spasms, or as identified in this patient: oromasticatory automatism. There is a need to include Ogden Syndrome in differential diagnoses and investigate the NAA10 gene in epilepsy and intellectual disability panels, even without multisystemic manifestations.

Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder

PurposeSLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness. MethodsUtilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles. ResultsThe families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants. ConclusionWe provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice.

Genotype–phenotype correlation and treatment effects in young patients with GNAO1-associated disorders

BackgroundPatients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement...

Semilobar Holoprosencephaly Caused by a Novel and De Novo ZIC2 Pathogenic Variant.

Holoprosencephaly (HPE) is the most common embryonic forebrain developmental anomaly. It involves incomplete or absent division of the prosencephalon into two distinct cerebral hemispheres during the early stages of organogenesis. HPE is etiologically heterogeneous, and its clinical presentation is very variable. We report a case of a 7 month old female infant, diagnosed with non-syndromic semilobar holoprosencephaly, caused by a novel, de novo pathogenic variant in ZIC2 - one of the most commonly mutated genes in non-syndromic HPE coding for the ZIC2 transcription factor. The patient presented with microcephaly, mild facial dysmorphic features, central hypotonia and spasticity on all four extremities. Ultrasound imaging demonstrated the absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna and brain MRI with confirmed the diagnosis of HPE. Early diagnosis and management are important for the prevention and treatment of complications associated with this condition.

Degree of implementation in Spain of the therapeutic recommendations for hypotonia of central origin according to the consensus of experts of the American Academy for Cerebral Palsy and Developmental Medicine

In early childhood, there are a number of different neurological conditions and syndromes that present with hypotonia of central origin. In 2019, the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) drew up a set of guidelines on therapeutic recommendations for the population aged from 0 to 6 years, based on the consensus of experts and on scientific evidence. The aim of this study is to determine how those therapeutic recommendations are being implemented in Spain. A survey of paediatric physiotherapists treating 0-6-year-old children with central hypotonia was carried out by means of a questionnaire consisting of 31 questions: 10 questions on sociodemographic and practice-related data, and the remaining 21 related to the use of the therapeutic recommendations based on the AACPDM guidelines for children with hypotonia of central origin. From a sample of 199 physiotherapists, it was found that familiarity with the AACPDM guidelines was significantly associated with the number of years of clinical experience, level of qualification and the community in which the professionals practise. These guidelines can serve to raise awareness and unify criteria regarding the therapeutic approach to children with central hypotonia. The results indicate that, with the exception of a few techniques, in our country most of the therapeutic strategies are being implemented within the framework of early care.

O papel do pediatra na investigação de doenças neuromusculares da infancia

OBJECTIVE: Help the pediatrician in the suspicion of neuromuscular diseases when the child has complaints or altered findings in neuropsychomotor development, presenting one review on the topic. METHODOLOGY: Non-systematic literature review using articles published between 2015 and 2021 obtained with the terms “neuromuscular disorders” and “children”; “neuromuscular disorders” and “pediatric”; “milestones” and “delay”; “motor development” and “delay”; “development”and “neuromuscular disorders”; “neuromuscular disorder” and “evaluation”; “neuromuscular disorders” and “examination” in the Lilacs, Medline, Paho, Wholis and Scielo research bases. RESULTS: Data found in the review were compiled and divided into three topics: (1) Warning signs for neuromuscular diseases: how history and physical examination help define hypotonia and signs of muscle weakness; (2) Differential Etiological Diagnoses: most common clinical presentations and brief description of the main diseases with available therapies; and (3) Investigation of Neuromuscular Diseases: examples of situations divided between those with central or peripheral hypotonia, the use of creatine phosphokinase dosage in cases of muscle weakness and motor delay and examples of confirmatory tests of neuromuscular diseases with therapeutic possibilities. CONCLUSION: Although neuromuscular diseases are individually rare, they may have specific treatment that modifies their natural history, then the important differential diagnosis when there is a delay in neuropsychomotor development. It is imperative that the pediatrician, as a reference professional for families, have a high degree of suspicion and knowledge that allows initial assessment and referral to a specialized service.

O PAPEL DO PEDIATRA NA INVESTIGAÇÃO DE DOENÇAS NEUROMUSCULARES DA INFANCIA

Objective: Help the pediatrician in the suspicion of neuromuscular diseases when the child has complaints or altered findings in neuropsychomotor development, presenting one review on the topic. Methodology: Non-systematic literature review using articles published between 2015 and 2021 obtained with the terms "neuromuscular disorders" and "children"; "neuromuscular disorders" and "pediatric"; "milestones" and "delay"; "motor development" and "delay"; "development"and "neuromuscular disorders"; "neuromuscular disorder" and "evaluation"; "neuromuscular disorders" and "examination" in the Lilacs, Medline, Paho, Wholis and Scielo research bases. Results: Data found in the review were compiled and divided into three topics: (1) Warning signs for neuromuscular diseases: how history and physical examination help define hypotonia and signs of muscle weakness; (2) Differential Etiological Diagnoses: most common clinical presentations and brief description of the main diseases with available therapies; and (3) Investigation of Neuromuscular Diseases: examples of situations divided between those with central or peripheral hypotonia, the use of creatine phosphokinase dosage in cases of muscle weakness and motor delay and examples of confirmatory tests of neuromuscular diseases with therapeutic possibilities.

A KCNC1-related neurological disorder due to gain of Kv3.1 function.

To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage-gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole-cell voltage clamp electrophysiological recording of wild-type versus variants in a heterologous mammalian expression system. We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3-expressing high frequency- firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical-genetic syndrome within the spectrum of KCNC1-related neurological disorders.

Electromyographic Patterns in Children presented as Floppy Baby: Experience in a Neurophysiology Laboratory of a Tertiary care hospital in Bangladesh

Introduction: Electromyography (EMG) is an invaluable diagnostic tool to reach a diagnosis in patients with hypotonia. The objective of this study was to observe the EMG patterns in children presented as floppy baby. Methods: It was a cross-sectional study conducted in the neurophysiology department of the National Institute of Neurosciences and hospital over 4 years. Floppy children, aged 1 month to 5 years, referred to the laboratory for EMG were enrolled in the study. Hypotonia due to acute flaccid paralysis or children having drugs that could cause decreased muscle tone were excluded from the study. Thereafter, children were categorized into groups of central, peripheral, and uncategorized/mixed hypotonia. EMG was done in all patients and an electro-diagnostic impression was made. Results: Out of 72 patients, 54.17% were male and 45.83% were female. Their average age of performing EMG was 26.81±18.12 months. Clinically it was observed that central and peripheral hypotonia were present in 18.05% and 70.83% of cases respectively and in 11.11% of cases, hypotonia could not be differentiated. EMG revealed Spinal muscular atrophy (SMA) in 38.89% of cases, followed by myopathy (26.39%), peripheral neuropathy (9.72%), and neuromuscular disorder (2.78%). In 19.44% of cases, EMG findings remained normal. Conclusion: Hypotonia of peripheral origin was the most common EMG finding in floppy children. SMA is the commonest electro-diagnostic impression followed by myopathy. J Bangladesh Coll Phys Surg 2022; 40: 240-245

Vojta Therapy Affects Trunk Control and Postural Sway in Children with Central Hypotonia: A Randomized Controlled Trial.

(1) Background: Decreased trunk stability is accompanied by delay in motor development in children with central hypotonia. We investigated the effect of Vojta therapy on trunk control in the sitting position in children with central hypotonia. (2) Methods: In 20 children with central hypotonia, Vojta therapy was applied to the experimental group (n = 10) and general physical therapy to the control group (n = 10). The intervention was applied for 30 min per session, three times a week, for a total of six weeks. We assessed abdominal muscle thickness, trunk control (segmental assessment of trunk control), trunk angle and trunk sway in a sitting position, and gross motor function measure-88. (3) Results: In the experimental group, the thicknesses of internal oblique and transversus abdominis were significantly increased (p < 0.05). The segmental assessment of trunk control score was significantly increased (p < 0.05), and the trunk sway significantly decreased (p < 0.05). Gross motor function measure-88 was significantly increased (p < 0.05). (4) Conclusions: Vojta therapy can be suggested as an effective intervention method for improving trunk control and gross motor function in children with central hypotonia.

Neonatal Sotos Syndrome: A Novel Frameshift Mutation of the NSD1 Gene Associated with Neonatal Encephalopathy Presenting without Overgrowth

AbstractSotos syndrome type I is one of the more common genetic overgrowth disorders. It presents classically with macrocephaly, distinctive facial gestalt, and acromegalic features, along with neonatal complications including hypotonia, feeding difficulties, and hypoglycemia with other minor feature inconstancies. The phenotypical overlap of features of this syndrome, more so in neonatal age, thwarts an easy diagnosis. In this case report, a neonate of a nonconsanguineous marriage to a multigravida mother with insignificant obstetric history, presented primarily with respiratory difficulty, central hypotonia, and hypoglycemia. Sparse hair, tall forehead, pointed chin, and lax skin were accompanied by persistent encephalopathy and refractory myoclonic jerks. However, the quintessential features of pre- and postnatal overgrowth were lacking, making the line of diagnosis difficult. On neuroimaging, atypical diffuse pachygyria was found. Clinical exome sequencing revealed heterozygous single base pair deletion in exon 21 of the NSD1 gene on chromosome 5q35, resulting in an unreported frameshift and premature truncation of the protein 19 amino acids downstream to codon 2065, confirming the genetic diagnosis of autosomal dominant Sotos syndrome 1. The neonate later succumbed to death after withdrawal of ventilatory support.