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1.
N Engl J Med ; 390(5): 421-431, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294974

RESUMO

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).


Assuntos
Fármacos do Sistema Nervoso Central , Doença de Niemann-Pick Tipo C , Humanos , Coleta de Dados , Método Duplo-Cego , Leucina/análogos & derivados , Leucina/uso terapêutico , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , Resultado do Tratamento , Estudos Cross-Over , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/uso terapêutico
2.
J Neurol ; 271(10): 6888-6902, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39225743

RESUMO

OBJECTIVE: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. METHODS: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator's, Caregiver's, and Patient's Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. RESULTS: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator's, Caregiver's, and Patient's CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient's everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. CONCLUSION: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.


Assuntos
Ataxia , Humanos , Reprodutibilidade dos Testes , Masculino , Feminino , Ataxia/diagnóstico , Ataxia/fisiopatologia , Ataxia/etiologia , Índice de Gravidade de Doença , Adulto , Doenças por Armazenamento dos Lisossomos/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/normas , Adolescente , Criança , Adulto Jovem , Estudos de Coortes , Pré-Escolar , Pessoa de Meia-Idade
3.
J Neurol ; 269(3): 1651-1662, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34387740

RESUMO

OBJECTIVE: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients. METHODS: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. RESULTS: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. CONCLUSIONS: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS. GOV IDENTIFIER: NCT03759639.


Assuntos
Doença de Niemann-Pick Tipo C , Adolescente , Adulto , Criança , Método Duplo-Cego , Humanos , Leucina/análogos & derivados , Leucina/uso terapêutico , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
4.
Epilepsy Res ; 176: 106699, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229227

RESUMO

CDKL5 deficiency disorder (CDD) is an independent clinical entity associated with early-onset encephalopathy, which is often considered the type of epileptic encephalopathy with CDKL5 mutation also found in children diagnosed with early-onset seizure (Hanefeld) type of Rett syndrome, epileptic spasms, West syndrome, Lennox-Gastaut syndrome, or autism. Since early seizure onset is a prominent feature, in this study, a cohort of 54 unrelated patients consisting of 26 males and 28 females was selected for CDKL5 screening, with seizures presented before 12 months of age being the only clinical criterion. Five patients were found to have pathogenic or likely pathogenic variants in CDKL5 while 1 was found to have a variant of uncertain significance (p.L522V). Although CDKL5 variants are more frequently identified in female patients, we identified three male and three female patients (11.1 %, 6/54) in this study. Missense variant with unknown inheritance (p.L522V), de novo missense variant (p.E60 K), two de novo splicing (IVS15 + 1G > A, IVS16 + 2 T > A), and one de novo nonsense variant p.W125* were identified using Sanger sequencing. Whole exome analysis approach revealed de novo frameshift variant c.1247_1248delAG in a mosaic form in one of the males. Patient clinical features are reviewed and compared to those previously described in related literature. Variable clinical features were presented in CDKL5 positive patients characterised in this study. In addition to more common features, such as early epileptic seizures, severe intellectual disability, and gross motor impairment, inappropriate laughing/screaming spells and hypotonia appeared at the age of 1 year in all patients, regardless of the type of CDKL5 mutation or sex. All three CDKL5 positive males from our cohort were initially diagnosed with West syndrome, which suggests that the CDKL5 gene mutations are a significant cause of West syndrome phenotype, and also indicate the overlapping characteristics of these two clinical entities.


Assuntos
Síndromes Epilépticas , Proteínas Serina-Treonina Quinases , Espasmos Infantis , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Feminino , Humanos , Lactente , Masculino , Mutação , Proteínas Serina-Treonina Quinases/genética , Eslováquia , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética
5.
Sci Rep ; 10(1): 10288, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581296

RESUMO

Mutations in the voltage-gated sodium channel Nav1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant Nav1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients' treatment, and finally indicate misdiagnosis of SCN1A related epilepsies.


Assuntos
Epilepsia/genética , Potenciais da Membrana/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Idade de Início , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Erros de Diagnóstico/prevenção & controle , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutagênese , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Técnicas de Patch-Clamp , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sódio/metabolismo , Transfecção
6.
J Mol Neurosci ; 67(4): 559-563, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30632081

RESUMO

Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the PSAP gene. Only ten pathogenic variants were described in the PSAP gene in MLD patients to date. We report on two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A-D) or whole prosaposin. The patient's phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.


Assuntos
Leucodistrofia Metacromática/genética , Mutação com Perda de Função , Saposinas/genética , Éxons , Humanos , Lactente , Leucodistrofia Metacromática/patologia , Masculino , Fenótipo
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