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1.
JAMA ; 327(15): 1456-1468, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35381069

RESUMO

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.


Assuntos
Glucocorticoides , Distrofia Muscular de Duchenne , Prednisona , Criança , Pré-Escolar , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Pregnenodionas/efeitos adversos
2.
EBioMedicine ; 98: 104855, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38251463

RESUMO

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. FINDINGS: Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.


Assuntos
Ataxia , Neurônios , Humanos , Animais , Camundongos , Ataxia/diagnóstico , Ataxia/genética , Códon sem Sentido , Bloqueadores dos Canais de Sódio , Canal de Sódio Disparado por Voltagem NAV1.6/genética
3.
Epilepsia Open ; 3(1): 103-108, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29588995

RESUMO

Focal status epilepticus in POLG-related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re-emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full-time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.

5.
Arch Dis Child ; 99(12): 1074-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25187493

RESUMO

BACKGROUND: Over the last 30 years, there has been little improvement in the age of diagnosis of Duchenne muscular dystrophy (DMD) (mean age of 4.5-4.11 years). AIM: To review the diagnostic process for DMD in boys without a family history in order to identify where delays occur and suggest areas for improvement. DESIGN: A retrospective case note review. SETTING: A tertiary centre for neuromuscular diseases in England. PATIENTS: All boys without family history diagnosed with DMD in the last 10 years (n=20). OUTCOME MEASURES: Mean age at four key steps in the diagnostic pathway of DMD. RESULTS: (1) Age at first reported symptoms of DMD was 32.5 (8-72) months (2.7 years). (2) First engagement of a healthcare professional was at 42.9 (10-90) months. (3) Creatine kinase (CK) levels were checked at 50.1 (14-91) months. (4) Diagnosis of DMD was confirmed at 51.7 (16-91) months (4.3 years). The total delay from parental concern to diagnosis was 19.2 (4-50) months (1.6 years). CONCLUSIONS: Our study shows an improvement in the age of diagnosis of DMD although there continues to be a delay in presentation to a health professional and a delay in obtaining a CK test. To reduce these delays, we propose screening for DMD as part of the Child Health Surveillance Programme, in addition to lowering the threshold for CK testing in primary care by promoting a new DMD mnemonic MUSCLE. An earlier diagnosis of DMD will allow timely access to genetic counselling, standards of care and clinical trials.


Assuntos
Distrofia Muscular de Duchenne/diagnóstico , Fatores Etários , Criança , Pré-Escolar , Creatina Quinase/sangue , Diagnóstico Precoce , Inglaterra , Humanos , Lactente , Masculino , Distrofia Muscular de Duchenne/enzimologia , Estudos Retrospectivos , Centros de Atenção Terciária
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