RESUMO
Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the CNS white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus-Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.
Assuntos
Doença de Pelizaeus-Merzbacher , Humanos , Doença de Pelizaeus-Merzbacher/genética , Mutação de Sentido Incorreto , Bainha de Mielina/metabolismo , Zinco/metabolismo , Proteínas de Membrana/genéticaRESUMO
PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.
Assuntos
Genômica , Doenças Raras , Criança , Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Doenças Raras/diagnóstico , Doenças Raras/genética , Análise de Sequência de DNARESUMO
BACKGROUND: Dopamine D2 receptor antagonists used to treat Tourette syndrome may have inadequate responses or intolerable side effects. We present results of a 4-week randomized, double-blind, placebo-controlled crossover study evaluating the safety, tolerability, and efficacy of the D1 receptor antagonist ecopipam in children and adolescents with Tourette syndrome. METHODS: Forty youth aged 7 to 17 years with Tourette syndrome and a Yale Global Tic Severity Scale - total tic score of ≥20 were enrolled and randomized to either ecopipam (50 mg/day for weight of <34 kg, 100 mg/day for weight of >34 kg) or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days. Stimulants and tic-suppressing medications were excluded. The primary outcome measure was the total tic score. Secondary outcomes included obsessive compulsive and attention deficit/hyperactivity disorder scales. RESULTS: Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days (mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033). There were no weight gain, drug-induced dyskinesias, or changes in laboratory tests, electrocardiograms, vital signs, or comorbid symptoms. Dropout rate was 5% (2 of 40). Adverse events reported for both treatments were rated predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo). CONCLUSIONS: Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Benzazepinas/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Síndrome de Tourette/tratamento farmacológico , Adolescente , Criança , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de DoençaRESUMO
STUDY OBJECTIVE: We seek to determine whether ropivacaine cervical paraspinal injections compared with normal saline solution injections provide headache relief to pediatric patients that is sufficient for emergency department (ED) discharge. METHODS: We enrolled children aged 7 to 17 years in a double-blinded, randomized, controlled trial of patients presenting to a pediatric ED with headache. Subjects were randomized into 1 of 3 groups: bilateral cervical paraspinal injections of either (1) 0.5% ropivacaine or (2) normal saline solution, or (3) a natural history group (not blinded) receiving no headache therapy for the first 30 minutes. Pain scores were assessed at enrollment and at 10-, 20-, and 30-minute intervals after the administration of the injections. After the intervention period of 30 minutes, additional therapy was provided as needed. Primary outcome was the proportion of children discharged with adequate pain relief at 30 minutes without additional therapy. Secondary outcomes included reduction in pain scores, reoccurrence of headache, and re-presentation to health care with headache. RESULTS: One hundred fifty-three children were enrolled. The proportion discharged with adequate pain relief 30 minutes after the injections did not differ between the 2 intervention groups (32% in the ropivacaine group versus 28% in the saline solution group; effect difference 4%; 95% confidence interval -14% to 21%). In contrast, only 4% percent of patients in the natural history group were discharged without additional therapy after the 30-minute assessment. Reduction of pain scores (2.0 and 2.2 in ropivacaine versus saline solution), headache reoccurrence, and return to care was similar between the 2 treatment groups. CONCLUSION: Cervical paraspinal injections of either ropivacaine or saline solution were effective for approximately one third of patients.
Assuntos
Amidas/administração & dosagem , Amidas/uso terapêutico , Anestésicos Locais/administração & dosagem , Anestésicos Locais/uso terapêutico , Serviço Hospitalar de Emergência , Cefaleia/tratamento farmacológico , Adolescente , Criança , Método Duplo-Cego , Feminino , Cefaleia/epidemiologia , Humanos , Injeções Intramusculares , Masculino , Medição da Dor , Recidiva , Ropivacaina , Resultado do TratamentoRESUMO
The cerebellum has a medial, cortico-nuclear zone consisting of the cerebellar vermis and the fastigial nucleus. Functionally, this zone is concerned with whole-body posture and locomotion. The vermis classically is thought to be included within the "spinocerebellum" and to receive somatic sensory input from ascending spinal pathways. In contrast, the lateral zone of the cerebellum is included in the "cerebro-cerebellum" because it is densely interconnected with the cerebral cortex. Here we report the surprising result that a portion of the vermis receives dense input from the cerebral cortex. We injected rabies virus into lobules VB-VIIIB of the vermis and used retrograde transneuronal transport of the virus to define disynaptic inputs to it. We found that large numbers of neurons in the primary motor cortex and in several motor areas on the medial wall of the hemisphere project to the vermis. Thus, our results challenge the classical view of the vermis and indicate that it no longer should be considered as entirely isolated from the cerebral cortex. Instead, lobules VB-VIIIB represent a site where the cortical motor areas can influence descending control systems involved in the regulation of whole-body posture and locomotion. We argue that the projection from the cerebral cortex to the vermis is part of the neural substrate for anticipatory postural adjustments and speculate that dysfunction of this system may underlie some forms of dystonia.
Assuntos
Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Córtex Motor/fisiologia , Vias Neurais/fisiologia , Animais , Transporte Biológico , Mapeamento Encefálico , Córtex Cerebelar/anatomia & histologia , Córtex Cerebelar/fisiologia , Núcleos Cerebelares/anatomia & histologia , Núcleos Cerebelares/fisiologia , Cerebelo/anatomia & histologia , Córtex Cerebral/anatomia & histologia , Toxina da Cólera/metabolismo , Feminino , Macaca fascicularis , Macaca mulatta , Masculino , Modelos Anatômicos , Córtex Motor/anatomia & histologia , Vias Neurais/anatomia & histologia , Vírus da Raiva/metabolismoRESUMO
Over the past 3 years, a global phenomenon has emerged characterized by the sudden onset and frequently rapid escalation of tics and tic-like movements and phonations. These symptoms have occurred not only in youth known to have tics or Tourette syndrome (TS), but also, and more notably, in youth with no prior history of tics. The Tourette Association of America (TAA) convened an international, multidisciplinary working group to better understand this apparent presentation of functional neurological disorder (FND) and its relationship to TS. Here, we review and summarize the literature relevant to distinguish the two, with recommendations to clinicians for diagnosis and management. Finally, we highlight areas for future emphasis and research.
RESUMO
Deep brain stimulation (DBS) is an established intervention for use in pediatric movement disorders, especially dystonia. Although multiple publications have provided guidelines for deep brain stimulation patient selection and programming in adults, there are no evidence-based or consensus statements published for pediatrics. The result is lack of standardized care and underutilization of this effective treatment. To this end, we assembled a focus group of 13 pediatric movement disorder specialists and 1 neurosurgeon experienced in pediatric deep brain stimulation to review recent literature and current practices and propose a standardized approach to candidate selection, implantation target site selection, and programming algorithms. For pediatric dystonia, we provide algorithms for (1) programming for initial session and follow-up sessions, and (2) troubleshooting side effects encountered during programming. We discuss common side effects, how they present, and recommendations for management. This topical review serves as a resource for movement disorders specialists interested in using deep brain stimulation for pediatric dystonia.
Assuntos
Estimulação Encefálica Profunda , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Adulto , Algoritmos , Criança , Distonia/etiologia , Distonia/terapia , Distúrbios Distônicos/terapia , Humanos , Transtornos dos Movimentos/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role. METHODS AND RESULTS: By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences. CONCLUSION: We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.
Assuntos
Coreia/genética , Sequências Reguladoras de Ácido Nucleico , Fator Nuclear 1 de Tireoide/genética , Adolescente , Criança , Coreia/patologia , Cromossomos Humanos Par 14/genética , Sequência Conservada , Feminino , Humanos , Masculino , Linhagem , Deleção de SequênciaRESUMO
Tourette syndrome (TS) is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics. Once thought to be rare, TS affects 0.3-1% of the population. Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities. The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown. However, clinical experience gained from treating TS has helped us better understand its pathogenesis and, as a result, derive treatment options. The strongest data exist for the antipsychotic agents, both typical and atypical, although their use is often limited in children and adolescents due to their side-effect profiles. There are agents in a variety of other pharmacologic categories that have evidence for the treatment of TS and whose side-effect profiles are more tolerable than the antipsychotics; these include clonidine, guanfacine, baclofen, topiramate, botulinum toxin A, tetrabenazine, and deutetrabenazine. A number of new agents are being developed and tested as potential treatments for TS. These include valbenazine, delta-9-tetrahydrocannabidiol, and ecopipam. Additionally, there are agents with insufficient data for efficacy, as well as agents that have been shown to be ineffective. Those without sufficient data for efficacy include clonazepam, ningdong granule, 5-ling granule, omega-3 fatty acids, and n-acetylcysteine. The agents that have been shown to be ineffective include pramipexole and metoclopramide. We will review all of the established pharmacologic treatments, and discuss those presently in development.
Assuntos
Desenho de Fármacos , Desenvolvimento de Medicamentos/métodos , Síndrome de Tourette/tratamento farmacológico , Adolescente , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Criança , Humanos , Síndrome de Tourette/fisiopatologiaRESUMO
The acute development of a movement disorder is often a dramatic and frightening experience for patients and families, often requiring urgent or emergent evaluation by a neurologist. In the assessment of these patients, one relies on the history, physical and neurologic examination to determine the etiology of the condition. We aim to demonstrate that a thorough medication history is an incredibly critical part of this evaluation as iatrogenic movement disorders can arise from exposure not only to psychoactive medications, but from drugs prescribed for a variety of nonneurologic disorders. This comprehensive review is organized by movement disorder semiology so that the reader can more readily develop a differential diagnosis when evaluating a patient with a movement disorder.
Assuntos
Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Criança , Humanos , Doença Iatrogênica , Transtornos dos Movimentos/terapiaRESUMO
BACKGROUND: It is not convenient or always possible to address parent requests for prescription refills after hours. The primary objective of this quality improvement study was to decrease the number of refill requests received outside of regular business hours. A secondary objective was to reduce the negative effects of call fatigue and related exhaustion for physicians taking calls. METHODS: Voluntary participation in this quality improvement project was solicited from the Child Neurology Division at a single academic, tertiary, metropolitan children's hospital. Study design was developed from a project charter, fishbone diagram, process map, driver diagram, and plan-do-study-act worksheet. A peer-reviewed letter was mailed to all clinic patient families and signs were displayed in the clinic space as notification of a policy change. A peer-reviewed script was provided to the Children's Mercy Contact Center triage personnel addressing after-hours refill requests. The number of refill requests received during each after-hours call shift was recorded from April 1, 2015, to March 31, 2016, with a primary outcome measure of the monthly number of refill requests. RESULTS: Postintervention, the average number of refill requests after hours decreased by 39% from 21 to 11 per month (p = 0.0055). CONCLUSIONS: This simple intervention has promise to limit prescription refill requests made after hours and improve physician quality of life. Continued data collection will help establish the sustainability of the effect made by this intervention.
RESUMO
BACKGROUND: Moyamoya disease is a rare cerebrovascular disease characterized by progressive stenosis of the bilateral distal internal carotid arteries and their proximal branches. Both chorea and dystonia have been reported as the initial presentation of moyamoya disease. OBJECTIVE: The objective was to define the clinical presentation and describe the disease course following pial synangiosis of 3 patients with dyskinesias. METHODS: A retrospective chart review of 3 cases of patients presenting with movement disorders and ultimately diagnosed with moyamoya disease was performed. RESULTS: The authors present a case series of 1 patient with dystonia and 2 patients with chorea, all diagnosed with moyamoya disease. All patients experienced resolution of their movement disorders following pial synangiosis. Magnetic resonance imaging disclosed moyamoya disease-related basal ganglia anomalies in all patients. CONCLUSIONS: Moyamoya disease is an important and surgically treatable cause of movement disorders.
Assuntos
Transtornos dos Movimentos/etiologia , Doença de Moyamoya/complicações , Pia-Máter/diagnóstico por imagem , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologia , Angiografia Cerebral , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Transtornos dos Movimentos/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive metabolic disease that results in the decreased production of catecholamines. Standard treatment relies on combinations of levodopa and carbidopa, anticholinergic agents, serotonergic agonists, and monamine oxidase B inhibitors. Unfortunately, severely affected children often require escalating doses of medication and suffer from dyskinesias as well as significant on/off symptomatology. The authors present a case of medically intractable dopa-responsive dystonia in a 6-year-old boy whose condition significantly improved with bilateral subthalamic nucleus deep brain stimulation. This case is unique in its novel approach to tyrosine hydroxylase deficiency and the young age of the patient.