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The Pan African Medical Journal 2021Vitamin B12 deficiency in early childhood is an important cause of neurodevelopmental delay and regression. Most of these cases occur in exclusively breast-fed infants... (Review)
Review
Vitamin B12 deficiency in early childhood is an important cause of neurodevelopmental delay and regression. Most of these cases occur in exclusively breast-fed infants of deficient mothers. Symptoms and signs of vitamin B12 deficiency appear between the ages of 2 to 12 months and include vomiting, lethargy, failure to thrive, hypotonia, and arrest or regression of developmental skills. Approximately one half of this cases exhibit abnormal movements, variously described as tremors, twitches, chorea, or myoclonus. Urinary concentrations of methylmalonic acid and homocysteine are characteristically elevated in vitamin B12 deficiency. Hyperglycinuria is sometimes present. The early diagnosis and treatment of vitamin B12 deficiency is crucial for significant neurological impairment and long-term prognosis. Treatment with vitamin B12 corrects these metabolic abnormalities very rapidly (within a few days). Vitamin B12 supplementation of pregnant women may prevent neurological and neuroradiological findings of the infants. Because of the importance of vitamin B12 in the development of the foetal and neonatal brain, vegetarian and vegan mothers should be aware of the severe and not fully-reversible damages caused by insufficient nutritional intake of vitamin B12 during pregnancy and lactation. Therefore, efforts should be directed to prevent its deficiency in pregnant and breastfeeding women on vegan diets and their infants. It is also important to take the nutritional history of both infants and their mothers for the early prevention and treatment. Here an interesting case of vitamin B12 deficiency in a 10-month-old boy presented with psychomotor regression, hypotonia and lethargy.
Topics: Breast Feeding; Dietary Supplements; Female; Humans; Infant; Male; Muscle Hypotonia; Pregnancy; Prenatal Care; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 34046142
DOI: 10.11604/pamj.2021.38.237.20967 -
JAMA Neurology Apr 2022Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide... (Review)
Review
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.
Topics: Child; Consensus; Genetic Testing; Humans; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Multicenter Studies as Topic; Muscle Hypotonia; Exome Sequencing
PubMed: 35254387
DOI: 10.1001/jamaneurol.2022.0067 -
European Journal of Pediatrics Jul 2022Our 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...
UNLABELLED
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.
Topics: Female; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Muscle Hypotonia; Muscular Diseases; Neurologic Examination; Neuromuscular Diseases; Pregnancy
PubMed: 35504981
DOI: 10.1007/s00431-022-04476-x -
Advances in Clinical and Experimental... Nov 2019Down syndrome (DS) is the most often diagnosed chromosomal disorder in newborns. The incidence is 1:792 live births. The article describes the irregularities and...
Down syndrome (DS) is the most often diagnosed chromosomal disorder in newborns. The incidence is 1:792 live births. The article describes the irregularities and characteristics found in trisomy 21, which greatly affect the functioning of the stomatognathic system. The most significant disorders include the following: false macroglossia, muscular hypotonia and gothic palate. These abnormalities affect articulation, breathing, food intake, and swallowing. We analyzed the morphological characteristics of the craniofacial region in children with DS based on the current literature review. The following databases were used for the analysis: MEDLINE (via PubMed), Scopus, Infona, and Dentistry & Oral Sciences Source. In the course of the study, 199 pieces of literature were analyzed; the analysis also included 18 articles on children and adults with DS. It also took into account the structure of the palate, dental and skeletal defects, size of the tongue, muscular hypotonia, and temporomandibular joint dysfunction. Down syndrome is still a current subject of research. Although macroglossia, hypotonia, malocclusion, and temporomandibular joint abnormalities are not features exclusive to DS, numerous dysfunctions and parafunctions as well as retarded psychomotor development greatly complicate the treatment. Therefore, interdisciplinary treatment of patients with trisomy 21 and early treatment in the first months of life with the use of the Castillo-Morales plate are very important, as they ensure better adaptation to the subsequently used apparatus and reduce the risk of disorders of the stomatognathic system.
Topics: Down Syndrome; Facial Muscles; Humans; Infant; Infant, Newborn; Macroglossia; Muscle Hypotonia; Tongue; Trisomy
PubMed: 31778604
DOI: 10.17219/acem/112785 -
Genome Medicine Feb 2019Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum...
De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.
BACKGROUND
Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).
METHODS
Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.
RESULTS
We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.
CONCLUSIONS
TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.
Topics: Adolescent; Child; Child, Preschool; Craniofacial Abnormalities; Developmental Disabilities; Female; Humans; INDEL Mutation; Infant; Intellectual Disability; Male; Muscle Hypotonia; Smith-Magenis Syndrome; Transcription Factors; Young Adult
PubMed: 30819258
DOI: 10.1186/s13073-019-0623-0 -
Andes Pediatrica : Revista Chilena de... Aug 2022Hypotonia of the newborn or infant is defined as decreased resistance to passive movement and is a frequent diagnostic challenge in pediatric practice. The hypotonic... (Review)
Review
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.
Topics: Humans; Infant; Infant, Newborn; Muscle Hypotonia; Prognosis
PubMed: 37906843
DOI: 10.32641/andespediatr.v93i4.4050 -
American Journal of Medical Genetics.... Nov 2021The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene....
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
Topics: Adolescent; Adult; Child; Child, Preschool; Developmental Disabilities; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertelorism; Intellectual Disability; Male; Muscle Hypotonia; Mutation; Neurodevelopmental Disorders; Phenotype; Transcription Factors; Young Adult
PubMed: 34436830
DOI: 10.1002/ajmg.a.62465 -
Developmental Medicine and Child... Jan 2022
Topics: Counseling; Humans; Infant; Muscle Hypotonia; Prognosis
PubMed: 34897666
DOI: 10.1111/dmcn.15085 -
Minerva Anestesiologica Aug 2021Children with symptoms of hypotonia (reduction of postural tone of lower limbs and trunk with or without changes in phasic tone) are frequently anesthetized for... (Review)
Review
Children with symptoms of hypotonia (reduction of postural tone of lower limbs and trunk with or without changes in phasic tone) are frequently anesthetized for diagnostic and therapeutic interventions. This review outlines the underlying causes and classifications, and the anesthesiologic pre- and peri-operative management of hypotonic children. Hypotonia may have a large range of etiologies that are categorized into central and peripheral hypotonia. A multidisciplinary approach towards the (differential) diagnosis of the underlying cause of the symptoms in cooperation with a pediatrician and/or pediatric neurologist is emphasized. Anesthetic management involves the anticipation of an increased risk in difficult airway management because of macroglossia, reduced mouth opening, obesity and limited neck mobility, which increases with age. There are no specific restrictions towards the use of intravenous or inhalational anesthetics. Short acting opioids and hypnotics, avoiding neuromuscular blockade, and locoregional techniques are preferred. Most patients are sensitive to the cardiac and depressive effects of anesthetics and all dystrophic myopathies are considered at risk of malignant hyperthermia. Depolarizing neuromuscular blockers are contraindicated. The use of a peripheral nerve stimulator is recommended to detect the severity of muscle relaxation before extubating. Accurate control and management of IV fluids, electrolytes and temperature is mandatory. Adequate postoperative pain treatment is essential to limit stress and metabolic alteration. Preferably a locoregional technique is used to reduce the increased risk of respiratory depression. A multidisciplinary preoperative approach taking into account the differential diagnosis of the underlying disease of the floppy child is recommended.
Topics: Anesthetics, Inhalation; Child; Electric Stimulation Therapy; Humans; Muscle Hypotonia; Obesity; Pain, Postoperative
PubMed: 33432795
DOI: 10.23736/S0375-9393.20.15011-9 -
European Journal of Human Genetics :... Jan 2009Prader-Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor...
Prader-Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.
Topics: Adolescent; Adult; Child; Child Behavior Disorders; Child, Preschool; Chromosomes, Human, Pair 15; Developmental Disabilities; Female; Genetic Counseling; Human Growth Hormone; Humans; Hypogonadism; Infant; Male; Muscle Hypotonia; Obesity; Phenotype; Prader-Willi Syndrome; Psychotic Disorders; Young Adult
PubMed: 18781185
DOI: 10.1038/ejhg.2008.165