RESUMO
INTRODUCTION: During the COVID-19 pandemic, an influx of adolescents presented worldwide with acute onset of functional tic-like behaviors (FTLBs). Our goal was to evaluate psychosocial factors around onset, to elucidate outcomes after pandemic isolation protocols were lifted, and to examine therapy and medication management. METHODS: A retrospective review was performed of 56 patients ages 10-18 years with new-onset FTLBs seen at Boston Children's Hospital beginning in March 2020. Demographic factors, medical history, and treatment were evaluated. Patient outcomes were determined retrospectively based on the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales from follow-up visits. CGI-I scores assessed the progression of FTLBs; CGI-S assessed overall function. RESULTS: Ninety-six percent of patients were female-assigned at birth with high rates of comorbid anxiety (93%) and depression (71%). Forty-five percent were gender-diverse. Based on scales that assessed FTLBs (CGI-I) and overall functioning (CGI-S), up to 79% of patients improved independent of comorbid diagnosis or treatment. Evidence-based tic-specific treatments were not more effective than other treatments. A subset of patients had improvement in their FTLBs but not in their general functioning and continued to have other psychosomatic presentations. CONCLUSION: While many patients' FTLBs improved, it is critical to remain alert to patients' overall function and to assess for other functional neurological disorders and mental health concerns. The tendency of FTLBs to improve in this population, independent of treatment, highlights the unique pathophysiology of FTLBs. Future research on contributing psychosocial factors and specific treatment protocols will allow optimal support for these patients.
Assuntos
COVID-19 , Mídias Sociais , Tiques , Síndrome de Tourette , Criança , Adolescente , Recém-Nascido , Humanos , Feminino , Masculino , Tiques/tratamento farmacológico , Seguimentos , Estudos Retrospectivos , PandemiasRESUMO
Benign paroxysmal vertigo of childhood (or recurrent vertigo of childhood) is the most common cause of vertigo in young children. It is considered a pediatric migraine variant or precursor disorder, and children with the condition have an increased likelihood of developing migraine later in life than the general population. Episodes are typically associated with room-spinning vertigo in conjunction with other migrainous symptoms (e.g. pallor, nausea, etc.), but it is rarely associated with headaches. Episodes typically only last for a few minutes and occur with a frequency of days to weeks without interictal symptoms or exam/test abnormalities. Treatment is rarely necessary, but migraine therapy may be beneficial in cases where episodes are particularly severe, frequent, and/or prolonged. An appreciation of the typical presentation and characteristics of this common condition is essential to any provider responsible for the care of children with migraine disorders and/or dizziness. This chapter will review the current literature on this condition, including its proposed pathophysiology, clinical presentation, and management. This chapter also includes a brief introduction to pediatric vestibular disorders, including relevant anatomy, physiology, embryology/development, history-taking, physical examination, testing, and a review of other common causes of pediatric dizziness/vertigo.
Assuntos
Transtornos de Enxaqueca , Doenças Vestibulares , Humanos , Criança , Pré-Escolar , Tontura/diagnóstico , Tontura/etiologia , Tontura/terapia , Vertigem/diagnóstico , Vertigem/terapia , Vertigem/epidemiologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapia , Cefaleia , Doenças Vestibulares/diagnóstico , Vertigem Posicional Paroxística Benigna/diagnóstico , Vertigem Posicional Paroxística Benigna/terapia , Vertigem Posicional Paroxística Benigna/complicaçõesRESUMO
Obsessive compulsive disorder (OCD) and chronic tic disorders (CTD) including Tourette Syndrome (TS) are often comorbid conditions. While some patients present with distinct symptoms of CTD and/or OCD, a subset of patients demonstrate a unique overlap of symptoms, known as Tourettic OCD (TOCD), in which tics, compulsions, and their preceding premonitory urges are overlapping and tightly intertwined. The specific behaviors seen in TOCD are typically complex tic-like behaviors although with a compulsive and partially anxious nature reminiscent of OCD. TOCD is not classified within the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) as an independent diagnostic entity, but mounting evidence suggests that TOCD is an intermediate neuropsychiatric disorder distinct from either TS or OCD alone and as such represents a unique phenomenology. In this review of TOCD we discuss clinical, genetic, environmental, neurodevelopmental, and neurocircuit-based research to better characterize our current understanding of this disorder. TOCD is characterized by earlier age of onset, male predominance, and specific symptom clusters such as lower tendency toward compulsions related to checking, cleaning, and reassurance seeking and higher tendency toward compulsions such as rubbing, tapping, or touching associated with symmetry concerns or thoughts of exactness. Functional magnetic resonance imaging (fMRI) imaging suggests that TOCD symptoms may arise from involvement of an intermediate neurocircuitry distinct from classic OCD or classic CTD. Small cumulative contributions from multiple genetic loci have been implicated, as have environmental factors such as infection and perinatal trauma. In addition, this review addresses the treatment of TOCD which is especially complex and often treatment resistant and requires pharmacology and behavioral therapy in multiple modalities. Given the distressing impact of TOCD on patients' functioning, the goal of this review is to raise awareness of this distinct entity toward the goal of improving standards of care.
RESUMO
Torticollis refers to a twisting of the head and neck caused by a shortened sternocleidomastoid muscle, tipping the head toward the shortened muscle, while rotating the chin in the opposite direction. Torticollis is seen at all ages, from newborns to adults. It can be congenital or postnatally acquired. In this review, we offer a new classification of torticollis, based on its dynamic qualities and pathogenesis. All torticollis can be classified as either nonparoxysmal (nondynamic) or paroxysmal (dynamic). Causes of nonparoxysmal torticollis include congenital muscular; osseous; central nervous system/peripheral nervous system; ocular; and nonmuscular, soft tissue. Causes of paroxysmal torticollis are benign paroxysmal; spasmodic (cervical dystonia); Sandifer syndrome; drugs; increased intracranial pressure; and conversion disorder. The description, epidemiology, clinical presentation, evaluation, treatment, and prognosis of the most clinically significant types of torticollis follow.
Assuntos
Músculos do Pescoço/patologia , Pescoço/patologia , Torcicolo/diagnóstico , Torcicolo/terapia , Humanos , Torcicolo/etiologiaRESUMO
Muscle contraction relies on a highly organized intracellular network of membrane organelles and cytoskeleton proteins. Among the latter are the intermediate filaments (IFs), a large family of proteins mutated in more than 30 human diseases. For example, mutations in the DES gene, which encodes the IF desmin, lead to desmin-related myopathy and cardiomyopathy. Here, we demonstrate that myotubularin (MTM1), which is mutated in individuals with X-linked centronuclear myopathy (XLCNM; also known as myotubular myopathy), is a desmin-binding protein and provide evidence for direct regulation of desmin by MTM1 in vitro and in vivo. XLCNM-causing mutations in MTM1 disrupted the MTM1-desmin complex, resulting in abnormal IF assembly and architecture in muscle cells and both mouse and human skeletal muscles. Adeno-associated virus-mediated ectopic expression of WT MTM1 in Mtm1-KO muscle reestablished normal desmin expression and localization. In addition, decreased MTM1 expression and XLCNM-causing mutations induced abnormal mitochondrial positioning, shape, dynamics, and function. We therefore conclude that MTM1 is a major regulator of both the desmin cytoskeleton and mitochondria homeostasis, specifically in skeletal muscle. Defects in IF stabilization and mitochondrial dynamics appear as common physiopathological features of centronuclear myopathies and desmin-related myopathies.
Assuntos
Desmina/fisiologia , Músculo Esquelético/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/fisiologia , Animais , Linhagem Celular , Desmina/genética , Humanos , Técnicas In Vitro , Filamentos Intermediários/fisiologia , Filamentos Intermediários/ultraestrutura , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias Musculares/fisiologia , Mitocôndrias Musculares/ultraestrutura , Modelos Moleculares , Músculo Esquelético/ultraestrutura , Mutação , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/fisiopatologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Tirosina Fosfatases não Receptoras/deficiência , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Nemaline myopathy (NM) is a congenital myopathy characterized by muscle weakness and nemaline bodies in affected myofibers. Five NM genes, all encoding components of the sarcomeric thin filament, are known. We report identification of a sixth gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy. The proband's muscle contained characteristic nemaline bodies, as well as occasional fibers with minicores, concentric laminated bodies, and areas of F-actin accumulation. Her affected sister's muscle was reported to exhibit nonspecific myopathic changes. Cofilin-2 levels were significantly lower in the proband's muscle, and the mutant protein was less soluble when expressed in Escherichia coli, suggesting that deficiency of cofilin-2 may result in reduced depolymerization of actin filaments, causing their accumulation in nemaline bodies, minicores, and, possibly, concentric laminated bodies.
Assuntos
Cofilina 2/genética , Predisposição Genética para Doença , Proteínas dos Microfilamentos/genética , Miofibrilas/patologia , Miopatias da Nemalina/genética , Actinas/metabolismo , Criança , Pré-Escolar , Cofilina 2/fisiologia , Escherichia coli/metabolismo , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos/fisiologia , Modelos Moleculares , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Miofibrilas/metabolismo , Miopatias da Nemalina/patologia , Linhagem , FosforilaçãoRESUMO
Myoblast fusion is a highly regulated process that is important during muscle development and myofiber repair and is also likely to play a key role in the incorporation of donor cells in myofibers for cell-based therapy. Although several proteins involved in muscle cell fusion in Drosophila are known, less information is available on the regulation of this process in vertebrates, including humans. To identify proteins that are regulated during fusion of human myoblasts, microarray studies were performed on samples obtained from human fetal skeletal muscle of seven individuals. Primary muscle cells were isolated, expanded, induced to fuse in vitro, and gene expression comparisons were performed between myoblasts and early or late myotubes. Among the regulated genes, melanoma cell adhesion molecule (M-CAM) was found to be significantly downregulated during human fetal muscle cell fusion. M-CAM expression was confirmed on activated myoblasts, both in vitro and in vivo, and on myoendothelial cells (M-CAM(+) CD31(+)), which were positive for the myogenic markers desmin and MyoD. Lastly, in vitro functional studies using M-CAM RNA knockdown demonstrated that inhibition of M-CAM expression enhances myoblast fusion. These studies identify M-CAM as a novel marker for myogenic progenitors in human fetal muscle and confirm that downregulation of this protein promotes myoblast fusion.
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Biomarcadores/metabolismo , Antígeno CD146/metabolismo , Fusão Celular , Feto/anatomia & histologia , Músculo Esquelético , Mioblastos/fisiologia , Adulto , Animais , Antígeno CD146/genética , Fracionamento Celular , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Músculo Esquelético/citologia , Músculo Esquelético/embriologia , Músculo Esquelético/fisiologia , Mioblastos/citologia , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Interferência de RNARESUMO
Recent work has significantly enhanced our understanding of the centronuclear myopathies and, in particular, myotubular myopathy. These myopathies share similar morphologic appearances with other diseases, namely the presence of hypotrophic myofibers with prominent internalized or centrally placed nuclei. Early workers suggested that this alteration represented an arrest in myofiber maturation, while other hypotheses implicated either failure in myofiber maturation or neurogenic causes. Despite similarities in morphology, distinct patterns of inheritance and some differences in clinical features have been recognized among cases. A severe form, known as X-linked myotubular myopathy (XLMTM), presents at or near birth. Affected males have profound global hypotonia and weakness, accompanied by respiratory difficulties that often require ventilation. Most of these patients die in infancy or early childhood, but some survive into later childhood or even adulthood. The responsible gene (MTM1) has been cloned; it encodes a phosphoinositide lipid phosphatase known as myotubularin that appears to be important in muscle maintenance. In autosomal recessive centronuclear myopathy (AR CNM), the onset of weakness typically occurs in infancy or early childhood. Some investigators have divided AR CNM into 3 subgroups: 1) an early-onset form with ophthalmoparesis, 2) an early-onset form without ophthalmoparesis, and 3) a late-onset form without ophthalmoparesis. Clinically, autosomal dominant CNM (AD CNM) is relatively mild and usually presents in adults with a diffuse weakness that is slowly progressive and may be accompanied by muscle hypertrophy. Overall, the autosomal disorders are not as clinically uniform as XLMTM, which has made their genetic characterization more difficult. Currently the responsible gene(s) remain unknown. This review will explore the historical evolution in understanding of these myopathies and give an update on their histopathologic features, genetics and pathogenesis.
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Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Adulto , Diagnóstico Diferencial , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/fisiopatologia , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases não ReceptorasRESUMO
Nemaline myopathy (NM) is the most common of several congenital myopathies that present with skeletal muscle weakness and hypotonia. It is clinically heterogeneous and the diagnosis is confirmed by identification of nemaline bodies in affected muscles. The skeletal muscle alpha-actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM. We have screened the ACTA1 gene in a cohort of 109 unrelated patients with NM. Here, we describe clinical and pathological features associated with 29 ACTA1 mutations found in 38 individuals from 28 families. Although ACTA1 mutations cause a remarkably heterogeneous range of phenotypes, they were preferentially associated with severe clinical presentations (p < 0.0001). Most pathogenic ACTA1 mutations were missense changes with two instances of single base pair deletions. Most patients with ACTA1 mutations had no prior family history of neuromuscular disease (24/28). One severe case, caused by compound heterozygous recessive ACTA1 mutations, demonstrated increased alpha-cardiac actin expression, suggesting that cardiac actin might partially compensate for ACTA1 abnormalities in the fetal/neonatal period. This cohort also includes the first instance of an ACTA1 mutation manifesting with adult-onset disease and two pedigrees exhibiting potential incomplete penetrance. Overall, ACTA1 mutations are a common cause of NM, accounting for more than half of severe cases and 26% of all NM cases in this series.
Assuntos
Actinas/genética , Músculo Esquelético/fisiologia , Mutação , Miopatias da Nemalina/genética , Actinina/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biópsia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Miopatias da Nemalina/diagnóstico , Miopatias da Nemalina/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Skeletal muscle differentiation is a complex, highly coordinated process that relies on precise temporal gene expression patterns. To better understand this cascade of transcriptional events, we used expression profiling to analyze gene expression in a 12-day time course of differentiating C2C12 myoblasts. Cluster analysis specific for time-ordered microarray experiments classified 2895 genes and ESTs with variable expression levels between proliferating and differentiating cells into 22 clusters with distinct expression patterns during myogenesis. Expression patterns for several known and novel genes were independently confirmed by real-time quantitative RT-PCR and/or Western blotting and immunofluorescence. MyoD and MEF family members exhibited unique expression kinetics that were highly coordinated with cell-cycle withdrawal regulators. Among genes with peak expression levels during cell cycle withdrawal were Vcam1, Itgb3, Itga5, Vcl, as well as Ptger4, a gene not previously associated with the process of myogenesis. One interesting uncharacterized transcript that is highly induced during myogenesis encodes several immunoglobulin repeats with sequence similarity to titin, a large sarcomeric protein. These data sets identify many additional uncharacterized transcripts that may play important functions in muscle cell proliferation and differentiation and provide a baseline for comparison with C2C12 cells expressing various mutant genes involved in myopathic disorders.