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1.
Yonsei Med J ; 61(4): 273-283, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32233169

RESUMO

The reduction of survival motor neuron (SMN) protein causes spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease. Nusinersen is an antisense oligonucleotide, approved by the FDA, which specifically binds to the repressor within SMN2 exon 7 to enhance exon 7 inclusion and augment production of functional SMN protein. Nusinersen is the first new oligonucleotide-based drug targeting the central nervous system for the treatment of SMA. This review of nusinersen will discuss its action mechanism, cellular uptake, trafficking mechanisms, and administration approaches to cross the blood-brain barrier. Furthermore, nusinersen clinical trials will be assessed in terms of pharmacokinetics, tolerability and safety, the clinical outcomes of multiple intrathecal doses, and a discussion on the primary and secondary endpoints.


Assuntos
Éxons/genética , Atrofia Muscular Espinal/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Barreira Hematoencefálica , Humanos , Atrofia Muscular Espinal/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 384-388, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219818

RESUMO

OBJECTIVE: To perform carrier screening for spinal muscular atrophy (SMA) among 3049 reproductive-age individuals from Yunnan region and determine the copy number of survival motor neuron (SMN) gene and carrier frequencies. METHODS: Multiplex ligation-dependent probe amplification (MLPA) was used to determine the copy number of exon 7 of SMN1 and SMN2 genes and identify those with a single copy of SMN1 gene. Prenatal diagnosis was performed for couples whom were both found to be SMA carriers. RESULTS: In total 62 SMA carriers were identified among the 3049 subjects, which yielded a carrier frequency of 1 in 49 (2.03%). No statistical difference was found in the carrier frequency between males and females (1.91% vs. 2.30%, P>0.05). Respectively, 1.3% (41/3049) and 0.69% (21/3049) of the carriers were caused by heterozygous deletion and conversion of the SMN1 gene. The average copy number for SMN1 alleles was 1.99. Two couples were found to be both as SMA carriers, for whom the birth of an affected fetus was avoided by prenatal diagnosis. CONCLUSION: No difference was found in the carrier frequency of SMA-related mutations between the two genders in Yunnan region, which was in keeping to an autosomal recessive inheritance pattern. Determination of the carrier frequency for SMA and SMN gene variants may provide a basis for genetic counseling and prenatal diagnosis for the disease.


Assuntos
Triagem de Portadores Genéticos , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , China , Feminino , Aconselhamento Genético , Variação Genética , Heterozigoto , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Proteína 2 de Sobrevivência do Neurônio Motor/genética
3.
Medicine (Baltimore) ; 99(5): e18975, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000428

RESUMO

INTRODUCTION: Spinal muscular atrophy (SMA) was the second most fatal autosomal recessive hereditary disease in clinic. There had been no detailed study to characterize the prevalence of SMA carrier among people in China. So, we conducted a systematic review and meta-analysis to obtain a reliable estimation of the prevalence of SMA carrier to characterize its epidemiology for the first time. METHODS: We systematically searched for articles in kinds of important electronic databases, including PubMed, Embase, Wanfang Database and China National Knowledge Infrastructure (CNKI) to identify all relevant literatures about carrier rates of SMA in China. The prevalence was performed by forest plot choosing random effect models. The publication bias was evaluated by means of funnel plots and Egger test. The sensitivity analysis was carried out by the method of omitting any literature at a time. Combined with the results of subgroup analysis, the source of heterogeneity was also discussed absolutely. RESULTS: A total of 10 studies published between 2005 and 2016 were included in our analysis at last. The sample size ranged from 264 to 107,611 in included studies. The random effect models of meta-analysis showed that the overall carrier rate of SMA was 2.0% (95% confidence interval [CI], 1.7%-2.3%) in a heterogeneous set of studies (I = 64%). There was a gradual rise trend observed in the SMA carrier rate during the study period. The funnel plots and Egger test (Coef = 0.02, t = -0.45, P = .667 > .05) showed no obvious potential risk of publication bias. CONCLUSION: The overall carrying rate of SMA was high as 2.0% and may be on a slow upward trend. So it was recommended that the countries should take active and effective measures to roll out routine prenatal screening and health genetic counseling for SMA as early as possible. What is more, further studies also need to be conducted to explore the etiology and epidemic factors of SMA to better control the risk of this common birth defect.


Assuntos
Heterozigoto , Atrofia Muscular Espinal/epidemiologia , Atrofia Muscular Espinal/genética , China/epidemiologia , Humanos , Prevalência
4.
Medicine (Baltimore) ; 99(3): e18809, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011487

RESUMO

In this article, the correlation between the copy number of survival motor neuron 2 (SMN2) gene, neuronal apoptosis inhibitory protein (NAIP), and the phenotype of spinal muscular atrophy patients were analyzed.Forty patients with spinal muscular atrophy (SMA) were included in the study at the Department of Medical Genetics of the First People's Hospital and the Department of Neurology of the Second People's Hospital in Yunnan Province from January 2012 to September 2018. Multiplex ligation-dependent probe amplification assay was performed to determine the copy numbers of SMN2 and NAIP genes. Statistical analysis was performed to determine the correlation between copy numbers of the SMN2 and NAIP genes and the clinical phenotypes of SMA.Our results show that among the 40 SMA patients, there were 13 type I cases, 16 type II cases and 11 type III cases. A total of 37 patients possessed a homozygous deletion of SMN1 exons 7 and 8, while the other 3 SMA patients possessed a single copy of SMN1 exon 8. There was no correlation between SMA subtypes and the deletion types of SMN1 exon 7 and 8 (P = .611). The percentage of 2, 3, and 4 copies of SMN2 exon 7 was 25.0%, 62.5%, and 12.5%, respectively. The percentage of 0, 1, and 2 copies of NAIP exon 5 was 10%, 57.5%, and 32.5%, respectively. The distributions of SMN2 and NAIP copy numbers among various SMA types were significantly different (all P < .05). Five combined SMN1-SMN2-NAIP genotypes were detected, of which 0-3-1 genotype had the highest proportion than the others, accounting for 42.5%. The copy number of SMN2 and NAIP gene had synergistic effect on SMA phenotype. The combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age, higher mortality, and smaller average age at death in SMA patients.Therefore, we conclude that the copy number variance of SMN2 and NAIP is correlated with the SMA phenotype. Analysis of the copy number structure of the SMN1-SMN2-NAIP gene is helpful for SMA typing, disease prognosis prediction, and genetic counseling.


Assuntos
Dosagem de Genes , Atrofia Muscular Espinal/genética , Proteína Inibidora de Apoptose Neuronal/genética , Adolescente , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Adulto Jovem
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 116-122, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034734

RESUMO

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for 90 families affected with spinal muscular atrophy (SMA), and discuss the necessity for carrier screening. METHODS: All families were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis. Combined MLPA and allele-specific PCR (AS-PCR) was used for prenatal diagnosis of the pregnant women. RESULTS: Among the 90 couples, 84 (93%) had a negative family history, 85 (94%) had given birth to an affected child before. Eighty-five husbands and 88 wives carried heterozygous deletion of exon 7 of the SMN1 gene. Two wives had homozygous deletion of exon 7 of the SMN1 gene and were affected. Prenatal diagnosis showed that 19 fetuses were SMA patients, 48 fetuses were carriers, and 23 fetuses were normal. Of note, eighteen affected fetuses were conceived by couples without a family history, which accounted for 20% of all pregnancies and 95% of all affected fetuses. CONCLUSION: To screen SMA carriers using MLPA and carry out prenatal diagnosis using combined MLPA and AS-PCR can ensure accurate diagnosis, which has a significant value for the prevention of SMA affected births.


Assuntos
Atrofia Muscular Espinal , Feminino , Testes Genéticos , Homozigoto , Humanos , Atrofia Muscular Espinal/genética , Gravidez , Diagnóstico Pré-Natal , Deleção de Sequência , Proteína 1 de Sobrevivência do Neurônio Motor
6.
Medicina (B Aires) ; 79(Spec 6/1): 582-586, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31864230

RESUMO

Alternative splicing of the messenger RNA plays a fundamental role in the flow of genetic information from DNA to proteins by expanding the coding capacity of the genome. The regulation of alternative splicing is as important as the regulation of transcription to determine the specific characteristics of cells and tissues, the normal functioning of cells and the responses of eukaryotic cells to external signals. Basic knowledge of the pre-mRNA sequences and splicing factors that recognize them has allowed scientists to design a therapeutic synthetic oligonucleotide for spinal muscular atrophy. This is an autosomal recessive inherited disease in which the SMN1 gene is mutated and affects one in 10,000 births. By blocking the binding of a negative splicing factor to the mRNA of a paralogue of the SMN1 gene, called SMN2, the Spinraza oligonucleotide corrects an abnormal alternative splicing event of the SMN2 gene and allows the synthesis of high levels of the SMN protein, constituting the first successful case of cure of a neurodegenerative disease.


Assuntos
Processamento Alternativo/genética , Atrofia Muscular Espinal/terapia , Processamento de RNA/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Transcrição Genética/genética , Humanos , Atrofia Muscular Espinal/genética , RNA Mensageiro/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
8.
J Hum Genet ; 64(11): 1141-1144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420593

RESUMO

Distal hereditary motor neuronopathies (dHMN) are a genetically heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and progressive distal muscle weakness. A heterozygous missense variant in FBXO38 has been previously described in two families affected by autosomal-dominant dHMN. In this paper, we describe a homozygous missense variant in FBXO38 (c.1577G>A; p.(Arg526Gln)) in a young Turkish female, offspring of consanguineous parents, with a congenital mild neuronopathy with idiopathic toe walking, normal sensory examination, and hearing loss. This work is the first to describe a novel homozygous variant and a suggested loss of function mechanism in FBXO38, expanding the dHMN type IID phenotype.


Assuntos
Proteínas F-Box/genética , Atrofia Muscular Espinal/genética , Adulto , Feminino , Heterogeneidade Genética , Heterozigoto , Homozigoto , Humanos , Atrofia Muscular Espinal/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-31323435

RESUMO

Role of RNA structure in pre-mRNA splicing has been implicated for several critical exons associated with genetic disorders. However, much of the structural studies linked to pre-mRNA splicing regulation are limited to terminal stem-loop structures (hairpins) sequestering splice sites. In few instances, role of long-distance interactions is implicated as the major determinant of splicing regulation. With the recent surge of reports of circular RNA (circRNAs) generated by backsplicing, role of Alu-associated RNA structures formed by long-range interactions are taking central stage. Humans contain two nearly identical copies of Survival Motor Neuron (SMN) genes, SMN1 and SMN2. Deletion or mutation of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1 due to exon 7 skipping causes spinal muscular atrophy (SMA), one of the leading genetic diseases of children. In this review, we describe how structural elements formed by both local and long-distance interactions are being exploited to modulate SMN2 exon 7 splicing as a potential therapy for SMA. We also discuss how Alu-associated secondary structure modulates generation of a vast repertoire of SMN circRNAs. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.


Assuntos
Atrofia Muscular Espinal/genética , Processamento de RNA , RNA Mensageiro/química , Elementos Alu , Éxons , Regulação da Expressão Gênica , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico , RNA Mensageiro/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/química , Proteína 2 de Sobrevivência do Neurônio Motor/genética
10.
J Phys Chem Lett ; 10(15): 4362-4367, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306018

RESUMO

Dynein adaptors such as Bicaudal D2 (BicD2) recognize cargo for dynein-dependent transport, and cargo-bound adaptors are required to activate dynein for processive transport, but the mechanism of action is unknown. Here we report the X-ray structure of the cargo-binding domain of human BicD2 and investigate the structural dynamics of the coiled-coil. Our molecular dynamics simulations support the fact that BicD2 can switch from a homotypic coiled-coil registry, in which both helices of the homodimer are aligned, to an asymmetric registry, where a portion of one helix is vertically shifted, as both states are similarly stable and defined by distinct conformations of F743. The F743I variant increases dynein recruitment in the Drosophila homologue, whereas the human R747C variant causes spinal muscular atrophy. We report spontaneous registry shifts for both variants, which may be the cause for BicD2 hyperactivation and disease. We propose that a registry shift upon cargo binding may activate autoinhibited BicD2 for dynein recruitment.


Assuntos
Dineínas/química , Proteínas Associadas aos Microtúbulos/química , Animais , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Humanos , Simulação de Dinâmica Molecular , Atrofia Muscular Espinal/genética , Mutação , Fenilalanina/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios Proteicos
11.
Drugs ; 79(11): 1255-1262, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31270752

RESUMO

Onasemnogene abeparvovec (onasemnogene abeparvovec-xioi; formerly AVXS-101; ZOLGENSMA®) is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the human survival motor neuron (SMN) gene to the motor neuron cells of patients with spinal muscular atrophy (SMA). It has been developed by AveXis, a Novartis company, and was approved in May 2019 in the USA for the treatment of paediatric patients aged < 2 years with SMA and bi-allelic mutations in the SMN1 gene (the primary gene encoding survival motor neuron protein). Onasemnogene abeparvovec is the first gene therapy to be approved for SMA in the USA. The recommended dose is 1.1 × 1014 vector genomes per kg of bodyweight, administered as a single intravenous infusion over 60 min. Regulatory assessments for this formulation of onasemnogene abeparvovec are underway in the EU and Japan; an intrathecal formulation is currently undergoing clinical development in the USA. This article summarizes the milestones in the development of onasemnogene abeparvovec leading to this first approval for the treatment of paediatric patients aged < 2 years with SMA and bi-allelic mutations in SMN1.


Assuntos
Atrofia Muscular Espinal/terapia , Proteínas do Complexo SMN/metabolismo , Dependovirus/genética , Aprovação de Drogas , Terapia Genética , Vetores Genéticos , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Mutação , Proteínas do Complexo SMN/genética , Estados Unidos , United States Food and Drug Administration
12.
Int J Neurosci ; 129(11): 1103-1118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271088

RESUMO

Spinal Muscular Atrophy (SMA) is a pan-ethnic disorder and generally characterized as prevalent lethal genetic disease of infants. It is an autosomal recessive neuromuscular disease caused by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Due to the high carrier frequency (1:50), the burden of this genetic disorder is very heavy in developing countries. Till date no absolute cure or effective treatment of the disease is available in clinical practice, whereas minor enhancement of SMN protein levels can be beneficial. It can be achieved by augmenting SMN2 transcription, stimulating exon 7 splicing and protein stabilization. Due to its low prevalence among population, costly screening and diagnosis, the disease is still lacking proper management. SMN is expressed almost in all tissues of body, still the reason why only lower motor neurons are affected in SMA is unknown. Research is still going on and with advancement of innovative therapies and gene modification, improved outcome may come in near future. Presently, supportive care including respiratory, nutritional, psychiatric and orthopaedic management can ameliorate clinical symptoms and improve survival rates if SMA is diagnosed early in life. Routine prenatal and new-born screening can help with potential benefits and timely management. In this review, the concept of newer methodological system and recent advances for molecular diagnosis of SMA with the variability in the clinical features is stressed. The public health community should remain alert to the rapidly changing developments in early detection and treatment of SMA.


Assuntos
Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Humanos
13.
Zhonghua Er Ke Za Zhi ; 57(6): 458-464, 2019 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-31216804

RESUMO

Objective: To identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy (PME). Methods: In this cross-sectional study, 26 PME children (11 boys and 15 girls) sent to neurological outpatient clinics and admitted to wards of the Department of Pediatrics, Peking University First Hospital were enrolled prospectively from January 2014 to October 2018. The pathogenic gene variants of PME children and their parents were identified by Sanger sequencing, next generation sequencing panels of epilepsy or trio-based whole exome sequencing and so on. The genotypes and phenotypes of the PME children were anaylzed. Results: The clinical features of 26 children include myoclonus, multiple types of seizures and progressive neurological regression. Their onset ages ranged from 3 months to 15 years. Several pathogenic gene variants were identified in the 15 patients, including TPP1 gene variantions in 3 patients; NEU1, GBA, TBC1D24 and KCNC1 gene variantions in 2 patients respectively; CLN6, MFSD8, ASAH1 and ATN1 gene variantions in 1 patient respectively. Several variants of uncertain significance were identified in 4 patients, including GOSR2 gene compound heterozygous variants in 2 patients, KCTD7 gene compound heterozygous variants in 1 patient, and compound heterozygous variants of an unreported TARS gene in 1 patient. No pathogenic gene variant was identified in 7 patients. In 15 children with the identified pathogenic gene variants, 5 patients were diagnosed with neuronal ceroid lipofuscinoses (NCL), 2 patients with sialidosis, 2 patients with neuronopathic Gaucher disease, 1 patient with dentatorubral-pallidoluysian atrophy (DRPLA), and 1 patient with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME). Conclusions: PME include a group of diseases with genetic heterogeneity. Identification of the pathogenic gene variants of PME could help to predict the prognosis and guide the genetic counseling.


Assuntos
Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Epilepsias Mioclônicas Progressivas/genética , Adolescente , Idade de Início , Proteínas de Transporte , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana , Atrofia Muscular Espinal/fisiopatologia , Mutação , Epilepsias Mioclônicas Progressivas/diagnóstico , Proteínas do Tecido Nervoso , Fenótipo , Canais de Potássio , Canais de Potássio Shaw
14.
Nucleic Acids Res ; 47(14): 7618-7632, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31127278

RESUMO

Spinal Muscular Atrophy results from loss-of-function mutations in SMN1 but correcting aberrant splicing of SMN2 offers hope of a cure. However, current splice therapy requires repeated infusions and is expensive. We previously rescued SMA mice by promoting the inclusion of a defective exon in SMN2 with germline expression of Exon-Specific U1 snRNAs (ExspeU1). Here we tested viral delivery of SMN2 ExspeU1s encoded by adeno-associated virus AAV9. Strikingly the virus increased SMN2 exon 7 inclusion and SMN protein levels and rescued the phenotype of mild and severe SMA mice. In the severe mouse, the treatment improved the neuromuscular function and increased the life span from 10 to 219 days. ExspeU1 expression persisted for 1 month and was effective at around one five-hundredth of the concentration of the endogenous U1snRNA. RNA-seq analysis revealed our potential drug rescues aberrant SMA expression and splicing profiles, which are mostly related to DNA damage, cell-cycle control and acute phase response. Vastly overexpressing ExspeU1 more than 100-fold above the therapeutic level in human cells did not significantly alter global gene expression or splicing. These results indicate that AAV-mediated delivery of a modified U1snRNP particle may be a novel therapeutic option against SMA.


Assuntos
Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Distrofia Muscular Animal/terapia , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Animais , Dependovirus/genética , Modelos Animais de Doenças , Éxons/genética , Células HEK293 , Humanos , Camundongos Knockout , Atrofia Muscular Espinal/genética , Distrofia Muscular Animal/genética , Mutação , Processamento de RNA , Ribonucleoproteína Nuclear Pequena U1/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
15.
Fetal Pediatr Pathol ; 38(3): 226-238, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060440

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive destructive motor neuron disease which is characterized primarily by the degeneration of α-motor neurons in the ventral gray horn of the spinal cord. It mainly affects children and represents the most common reason of inherited infant mortality. MATERIAL AND METHODS: We provide an overview of the recent therapeutic strategies for the treatment of SMA together with available and developing therapeutic strategies. For this purpose, Google Scholar and PubMed databases were searched for literature on SMA, therapy and treatment. Titles were reviewed and 96 were selected and assessed in this paper. RESULT: Over the last two decades, different therapeutic strategies have been proposed for SMA. Some methods are in the pre-clinical, others the clinical phase. CONCLUSION: By emergence of the new approaches, especially in gene therapy, effective treatment in the close future is probable.


Assuntos
Terapia Genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Medula Espinal/patologia , Criança , Terapia Genética/métodos , Humanos , Lactente , Atrofia Muscular Espinal/patologia , Proteínas do Tecido Nervoso/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética
16.
Neurol Sci ; 40(8): 1729-1732, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004230

RESUMO

Spinal muscular atrophy (SMA) is one of the leading causes of death in infants and young children from heritable diseases. Patients diagnosed with SMA develop symmetrical progressive muscle weakness and atrophy from degeneration of alpha motor neurons. Approximately 95% of patients have a homozygous deletion of survival motor neuron 1 (SMN1) gene in exon 7 and inherited in autosomal recessive pattern. Considering the high prevalence of SMA carrier in many population, it is possible that SMA is one of the most common autosomal recessive disorders in Thailand and Southeast Asia. In this study, we analyzed DNA from peripheral blood of 505 healthy Thai adults using quantitative PCR-based for SMN1 gene exon 7 copy number analysis. Individual samples with heterozygous deletion of SMN1 gene were confirmed with MLPA. The result identified 9 samples (1.78%) with heterozygous deletion and 39 samples as more than 2 copies of SMN1. No homozygous deletion was detected in the samples. In conclusion, we established carrier frequency of SMA in selected Thai population at 1.8% from 505 participants. The prevalence coincides with prevalence in East Asia and Caucasian population. The result could be implemented for SMA carrier screening in couples at risk in the region.


Assuntos
Heterozigoto , Atrofia Muscular Espinal/epidemiologia , Atrofia Muscular Espinal/genética , Triagem de Portadores Genéticos , Humanos , Prevalência , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Tailândia/epidemiologia
17.
J Korean Med Sci ; 34(9): e54, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30863264

RESUMO

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive disorder caused by a defect in the immunoglobulin mu binding protein 2 (IGHMBP2) gene, leading to motor neuron degeneration. We identified an infant with SMARD1 by targeted exome sequencing from a consanguineous Syrian family having a history of recurrent infant deaths. The patient initially presented intrauterine growth retardation, poor sucking, failure to thrive, and respiratory failure at the age of two months, and an inborn error of metabolism was suspected at first. Over a period of one month, the infant showed rapid progression of distal muscular weakness with hand and foot contractures, which were suggestive of neuromuscular disease. Using targeted exome sequencing, the mutation in IGHMBP2 was confirmed, although the first report was normal. Targeted exome sequencing enabled identification of the genetic cause of recurrent mysterious deaths in the consanguineous family. Additionally, it is suggested that a detailed phenotypic description and communication between bioinformaticians and clinicians is important to reduce false negative results in exome sequencing.


Assuntos
Proteínas de Ligação a DNA/genética , Atrofia Muscular Espinal/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Fatores de Transcrição/genética , Sequência de Bases , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Éxons , Feminino , Humanos , Lactente , Morte do Lactente , Atrofia Muscular Espinal/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Síria , Sequenciamento Completo do Exoma
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(3): 239-243, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30907347

RESUMO

OBJECTIVE: To study the association of copy number of SMN1 and SMN2 with clinical phenotypes in children with spinal muscular atrophy (SMA). METHODS: A total of 45 children with SMA were enrolled. Multiplex ligation-dependent probe amplification was used to measure the gene copy numbers of SMN1 and SMN2. The association of copy number of SMN1 and SMN2 with clinical phenotypes was analyzed. RESULTS: Of the 45 children with SMA, 42 (93%) had a homozygous deletion of SMN1 exons 7 and 8, and 3 (7%) had a deletion of SMN1 exon 7 alone. No association was found between SMA clinical types and the deletion types of SMN1 exons 7 and 8 (P>0.05). There was a significant difference in the distribution of SMN2 gene copy numbers between the children with SMA and the healthy children (P<0.05). The children with SMA usually had two or three copies of SMN2 gene, while the healthy children usually had one or two copies of SMN2 gene. There was a significant difference in the distribution of SMN2 copy numbers among the children with different SMA clinical types (P<0.05). The children with two copies of SMN2 gene had a significantly lower age of onset than those with three or four copies. Most of the children with type I SMA had two or three copies of SMN2 gene. Most of the children with type II SMA had three copies of SMN2 gene. Most of the children with type III SMA had three or four copies of SMN2 gene. Children with a higher copy number of SMN2 gene tended to have an older age of onset and better motor function and clinical outcome, and there was a significant association between SMN2 gene copy number and clinical outcome (P<0.05). CONCLUSIONS: The SMN2 gene can reduce the severity of SMA via the dosage compensation effect. SMN2 copy number is associated with the phenotype of SMA, and therefore, it can be used to predict disease severity.


Assuntos
Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Criança , Humanos , Fenótipo , Proteína 2 de Sobrevivência do Neurônio Motor/genética
19.
Ann Clin Transl Neurol ; 6(2): 401-405, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30847374

RESUMO

Vaccinia-related kinase 1 (VRK1) mutations can cause motor phenotypes including axonal sensorimotor neuropathy, distal hereditary motor neuropathy (dHMN), spinal muscular atrophy, and amyotrophic lateral sclerosis. Here, we identify a novel homozygous VRK1 p.W375X mutation causing recessive dHMN. The proband presented with juvenile onset of weakness in the distal lower extremities, slowly progressing to the distal upper limbs, with bilateral pes cavus and no upper motor or sensory neuron involvement. Nerve conduction studies showed a pure motor axonal neuropathy. Our findings extend the ethnic distribution of VRK1 mutations, indicating that these mutations should be included in genetic diagnostic testing for dHMN.


Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Atrofia Muscular Espinal/genética , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Masculino , Atrofia Muscular Espinal/diagnóstico , Linhagem , Fenótipo
20.
Life Sci Alliance ; 2(2)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30910806

RESUMO

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by reduced levels of functional survival motor neuron (SMN) protein. To identify therapeutic agents for SMA, we established a versatile SMN2-GFP reporter line by targeting the human SMN2 gene. We then screened a compound library and identified Z-FA-FMK as a potent candidate. Z-FA-FMK, a cysteine protease inhibitor, increased functional SMN through inhibiting the protease-mediated degradation of both full-length and exon 7-deleted forms of SMN. Further studies reveal that CAPN1, CAPN7, CTSB, and CTSL mediate the degradation of SMN proteins, providing novel targets for SMA. Notably, Z-FA-FMK mitigated mitochondriopathy and neuropathy in SMA patient-derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood-brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human SMN2 reporter for future drug discovery and identified the potential therapeutic value of cysteine protease inhibitors in treating SMA via stabilizing SMN proteins.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Genes Reporter/genética , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Estabilidade Proteica/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Cetonas/farmacologia , Leucina/análogos & derivados , Leucina/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Substâncias Protetoras/farmacologia , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Transfecção , Resultado do Tratamento
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