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Annals of Clinical and Translational... Dec 2023We explored various prognostic factors of motor outcomes in corticosteroid-naive boys with Duchenne Muscular Dystrophy (DMD).
OBJECTIVE
We explored various prognostic factors of motor outcomes in corticosteroid-naive boys with Duchenne Muscular Dystrophy (DMD).
METHODS
The associations between parent-reported neurodevelopmental concerns (speech delay, speech and language difficulties (SLD), and learning difficulties), DMD mutation location, and motor outcomes (6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA) total score, 10-meter walk/run velocity, and rise from floor velocity) were studied in 196 corticosteroid-naive boys from ages 4 to less than 8 years.
RESULTS
Participants with SLD walked 25.8 fewer meters in 6 minutes than those without SLD (p = 0.005) but did not demonstrate statistical differences in NSAA total score, 10-meter walk/run velocity, and rise from floor velocity. Participants with distal DMD mutations with learning difficulties walked 51.8 fewer meters in 6 minutes than those without learning difficulties (p = 0.0007). Participants with distal DMD mutations were slower on 10-meter walk/run velocity, and rise from floor velocity (p = 0.02) than those with proximal DMD mutations. Participants with distal DMD mutations, who reported speech delay or learning difficulties, were slower on rise from floor velocity (p = 0.04, p = 0.01) than those with proximal DMD mutations. The mean NSAA total score was lower in participants with learning difficulties than in those without (p = 0.004).
INTERPRETATION
Corticosteroid-naive boys with DMD with distal DMD mutations may perform worse on some timed function tests, and that those with learning difficulties may perform worse on the NSAA. Pending confirmatory studies, our data underscore the importance of considering co-existing neurodevelopmental symptoms on motor outcome measures.
Topics: Male; Humans; Muscular Dystrophy, Duchenne; Walking; Adrenal Cortex Hormones; Outcome Assessment, Health Care; Language Development Disorders
PubMed: 37804000
DOI: 10.1002/acn3.51914 -
BMC Medicine Aug 2023Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and...
BACKGROUND
Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and neurobehavioral developmental delays in children and the underlying biological mechanisms need to be further revealed. The "placenta-brain axis" (PBA) provides a new perspective for gene regulation and risk prediction of neurodevelopmental delays in MLPT children.
METHODS
The authors performed multivariate logistic regression models between MLPT and children's neurodevelopmental outcomes, using data from 129 MLPT infants and 3136 full-term controls from the Ma'anshan Birth Cohort (MABC). Furthermore, the authors identified the abnormally regulated PBA-related genes in MLPT placenta by bioinformatics analysis of RNA-seq data and RT-qPCR verification on independent samples. Finally, the authors established the prediction model of neurodevelopmental delay in children with MLPT using multiple machine learning models.
RESULTS
The authors found an increased risk of neurodevelopmental delay in children with MLPT at 6 months, 18 months, and 48 months, especially in boys. Further verification showed that APOE and CST3 genes were significantly correlated with the developmental levels of gross-motor domain, fine-motor domain, and personal social domain in 6-month-old male MLPT children.
CONCLUSIONS
These findings suggested that there was a sex-specific association between MLPT and neurodevelopmental delays. Moreover, APOE and CST3 were identified as placental biomarkers. The results provided guidance for the etiology investigation, risk prediction, and early intervention of neurodevelopmental delays in children with MLPT.
Topics: Pregnancy; Infant; Infant, Newborn; Humans; Child; Female; Male; Premature Birth; Placenta; Brain; Computational Biology; Apolipoproteins E
PubMed: 37633927
DOI: 10.1186/s12916-023-03023-1 -
Digestive and Liver Disease : Official... May 2024Achalasia is a rare disorder characterized by impaired esophageal motility and symptoms like dysphagia, regurgitation, chest pain, and weight loss. A timely diagnosis is...
BACKGROUND
Achalasia is a rare disorder characterized by impaired esophageal motility and symptoms like dysphagia, regurgitation, chest pain, and weight loss. A timely diagnosis is crucial to adequately manage this condition.
AIMS
This study aimed to assess the diagnostic delay from symptom onset to a definite diagnosis of achalasia, and to identify associated factors.
METHODS
This retrospective, single-center study included patients diagnosed with achalasia between January 2013 and September 2023. Demographic data, symptoms, manometric, endoscopic, and radiological findings were collected. We also considered socio-economic deprivation. Early diagnosis was defined as occurring within 12 months of symptom onset, while late diagnosis was defined as occurring more than 12 months.
RESULTS
We included 278 patients (142 males, median age 58 years). Dysphagia was the most common symptom (96 %), followed by regurgitation (70.1 %). The median diagnostic delay was 24 months (IQR 12-72, range 0-720), with 213 patients (76.6 %) experiencing late diagnosis. Early diagnosis was more common in patients with weight loss (63.1% vs. 42.0 %, p = 0.003). Lower material deprivation correlated with shorter diagnostic delay (24 months, IQR 10-60 vs. 60 months, IQR 18-300, p = 0.001).
CONCLUSIONS
Achalasia diagnosis is often delayed. Weight loss along with socio-economic factors, influence the timeliness of diagnosis. Improving awareness of disease and relevance of initial symptoms may facilitate earlier diagnosis and treatment.
PubMed: 38762352
DOI: 10.1016/j.dld.2024.05.001 -
Medicine Jul 2023As a multifactorial degenerative disease, Parkinson disease (PD) causes tremor, gait rigidity, and hypokinesia, which interfere with normal life. Because the disease is... (Review)
Review
As a multifactorial degenerative disease, Parkinson disease (PD) causes tremor, gait rigidity, and hypokinesia, which interfere with normal life. Because the disease is usually discovered in the late stage of complete degeneration of neurons, it can greatly delay treatment and even eventually lead to death. Therefore, the diagnosis of this disease is very challenging, and it is gratifying that substantial progress has been made in the development of optical coherence tomography (OCT) as a diagnostic biomarker for this disease, and genetic and imaging tests have become part of routine protocols in clinical practice. In the cognition of traditional Chinese medicine (TCM), this disease belongs to deficiency in origin and excess in superficiality, which is always caused by deficiency of liver and kidney, deficiency of qi and blood, and is closely related to wind, fire, phlegm and blood stasis. A large number of studies have shown that TCM can effectively treat motor and non-motor symptoms of PD, combat oxidative stress and reduce inflammatory response, and improve the quality of life of patients. Based on the pathophysiological mechanism of PD, this paper discusses the treatment of PD by TCM acupuncture combined with medicine based on syndrome differentiation.
Topics: Humans; Parkinson Disease; Quality of Life; Medicine, Chinese Traditional; Acupuncture Therapy; Syndrome
PubMed: 37505150
DOI: 10.1097/MD.0000000000034278 -
Molecular Cytogenetics Mar 2024Potocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The...
BACKGROUND
Potocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging.
CASE PRESENTATION
We report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region.
CONCLUSIONS
Children with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.
PubMed: 38519962
DOI: 10.1186/s13039-024-00673-5 -
The Journal of Comparative Neurology Jan 2024Betz cells, named in honor of Volodymyr Betz (1834-1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are... (Review)
Review
Betz cells, named in honor of Volodymyr Betz (1834-1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α-motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type-specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders.
Topics: Adult; Humans; Animals; Motor Cortex; Amyotrophic Lateral Sclerosis; Pyramidal Cells; Motor Neurons; Primates; Mammals
PubMed: 38289193
DOI: 10.1002/cne.25567 -
Molecular Neurobiology Dec 2023Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle...
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay. MicroRNA (miRNA) expression levels have been proposed as ALS biomarkers, and altered function has been reported in ALS pathogenesis. The aim of this study was to assess the differential expression of plasma miRNAs in ALS patients and two control populations (healthy controls and ALS-mimic disorders). For that, 16 samples from each group were pooled, and then 1008 miRNAs were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). From these, ten candidate miRNAs were selected and validated in 35 ALS patients, 16 ALS-mimic disorders controls and 15 healthy controls. We also assessed the same miRNAs in two different time points of disease progression. Although we were unable to determine a miRNA signature to use as disease or condition marker, we found that miR-7-2-3p, miR-26a-1-3p, miR-224-5p and miR-206 are good study candidates to understand the pathophysiology of ALS.
Topics: Humans; MicroRNAs; Amyotrophic Lateral Sclerosis; Delayed Diagnosis; Brain; Disease Progression
PubMed: 37531027
DOI: 10.1007/s12035-023-03520-7 -
Frontiers in Genetics 2024The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities... (Review)
Review
The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities for research and treatment development, and a few genetic disorders (e.g., spinal muscular atrophy) have recently been treated with gene-based therapies. is found on the X chromosome and regulates the transcription of thousands of genes. Loss of gene product leads to Rett Syndrome, a disease found primarily in females, and is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfunction, epilepsy, scoliosis, and autistic-like behavior. Duplication of causes MECP2 Duplication Syndrome (MDS). MDS is found mostly in males and presents with developmental delay, hypotonia, autistic features, refractory epilepsy, and recurrent respiratory infections. While these two disorders share several characteristics, their differences (e.g., affected sex, age of onset, genotype/phenotype correlations) are important to distinguish in the light of gene-based therapy because they require opposite solutions. This review explores the clinical features of both disorders and highlights these important clinical differences.
PubMed: 38410154
DOI: 10.3389/fgene.2024.1332469 -
Frontiers in Neuroscience 2023Chromatin Modifying Disorders (CMD) have emerged as one of the most rapidly expanding genetic disorders associated with autism spectrum disorders (ASD). Motor...
BACKGROUND
Chromatin Modifying Disorders (CMD) have emerged as one of the most rapidly expanding genetic disorders associated with autism spectrum disorders (ASD). Motor impairments are also prevalent in CMD and may play a role in the neurodevelopmental phenotype. Evidence indicates that neurodevelopmental outcomes in CMD may be treatable postnatally; thus deep phenotyping of these conditions can improve clinical screening while improving the development of treatment targets for pharmacology and for clinical trials. Here, we present developmental phenotyping data on individuals with Bohring-Optiz Syndrome (BOS - ASXL1) and Bainbridge-Ropers Syndrome (BRS - ASXL3) related disorders, two CMDs highly penetrant for motor and developmental delays.
OBJECTIVES
To phenotype the motor and neurodevelopmental profile of individuals with ASXL1 and ASXL3 related disorders (BOS and BRS). To provide a preliminary report on the association of motor impairments and ASD.
METHODS
Neurodevelopmental and motor phenotyping was conducted on eight individuals with pathogenic ASXL1 variants and seven individuals with pathogenic ASXL3 variants, including medical and developmental background intake, movement and development questionnaires, neurological examination, and quantitative gait analysis.
RESULTS
Average age of first developmental concerns was 4 months for individuals with BOS and 9 months in BRS. 100% of individuals who underwent the development questionnaire met a diagnosis of developmental coordination disorder. 71% of children with BOS and 0% of children with BRS noted movement difficulty greatly affected classroom learning. Participants with BRS and presumed diagnoses of ASD were reported to have more severe motor impairments in recreational activities compared to those without ASD. This was not the case for the individuals with BOS.
CONCLUSION
Motor impairments are prevalent and pervasive across the ASXL disorders with and without ASD, and these impairments negatively impact engagement in school-based activities. Unique neurodevelopmental and motor findings in our data include a mixed presentation of hypo and hypertonia in individuals with BOS across a lifespan. Individuals with BRS exhibited hypotonia and greater variability in motor skills. This deep phenotyping can aid in appropriate clinical diagnosis, referral to interventions, and serve as meaningful treatment targets in clinical trials.
PubMed: 38027485
DOI: 10.3389/fnins.2023.1244176