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1.
Ideggyogy Sz ; 74(3-4): 79-86, 2021 Mar 30.
Artigo em Húngaro | MEDLINE | ID: mdl-33938671

RESUMO

Background and purpose: Background - Spinal muscular atrophy (SMA) is an autosomal recessive, progressive neuromuscular disorder resulting in a loss of lower motoneurons. Recently, new disease-modifying treatments (two drugs for splicing modification of SMN2 and one for SMN1 gene replacement) have become available. Purpose - The new drugs change the progression of SMA with neonatal and childhood onset. Increasing amount of data are available about the effects of these drugs in adult patients with SMA. In this article, we summarize the available data of new SMA therapies in adult patients. Methods: Methods - Members of the Executive Committee of the Hungarian Clinical Neurogenetic Society surveyed the literature for palliative treatments, randomized controlled trials, and retrospective and prospective studies using disease modifying therapies in adult patients with SMA. Patients - We evaluated the outcomes of studies focused on treatments of adult patients mainly with SMA II and III. Results: In this paper, we present our consensus statement in nine points covering palliative care, technical, medical and safety considerations, patient selection, and long-term monitoring of adult patients with SMA. Conclusion: This consensus statement aims to support the most efficient management of adult patients with SMA, and provides information about treatment efficacy and safety to be considered during personalized therapy. It also highlights open questions needed to be answered in future. Using this recommendation in clinical practice can result in optimization of therapy.


Assuntos
Atrofia Muscular Espinal , Adulto , Criança , Consenso , Humanos , Hungria , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Estudos Prospectivos , Estudos Retrospectivos
2.
BMC Pediatr ; 21(1): 236, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001052

RESUMO

BACKGROUND: Spinal Muscular Atrophy (SMA), a leading genetic cause of death in infants, is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. While early diagnosis of SMA is critical to modifying disease progression and improving outcomes, serious diagnostic delays persist. There is a need to improve SMA awareness, screening, and referral patterns. METHODS: Two online surveys, developed by Cure SMA for general pediatricians, were distributed by Medscape Education via email (September 2018, n = 300, December 2019, n = 600). The surveys asked about adherence to the American Academy of Pediatrics (AAP) developmental screening and surveillance guidelines, comfort with identification of early signs of neuromuscular disease (NMD), familiarity with SMA, and barriers to timely referral. RESULTS: In 2018, 70.3% of survey respondents indicated comfort in identifying early signs of NMD and 67.3% noted familiarity with SMA. 52.7% correctly indicated the need for genetic testing to make a definitive diagnosis of SMA, 74.0% meet or exceed developmental screening recommendations, and 52.0% said they would immediately refer to a specialist. In 2019, with a larger sample, 73.0% adhere to developmental screening guidelines, and awareness of the genetic testing requirement for SMA was significantly lower by 7.7% (p < 0.03). Specialist wait times emerged as a barrier to referral, with 64.2% of respondents citing wait times of 1-6 months. CONCLUSIONS: Many pediatricians underutilize developmental screening tools and lack familiarity with diagnostic requirements for SMA. Continuing efforts to expand awareness and remove barriers to timely referral to SMA specialists, including reducing appointment wait times, are needed.


Assuntos
Atrofia Muscular Espinal , Pediatras , Criança , Testes Genéticos , Humanos , Lactente , Programas de Rastreamento , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Encaminhamento e Consulta , Estados Unidos
3.
Biochemistry (Mosc) ; 86(Suppl 1): S12-S23, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33827397

RESUMO

Aminoacyl-RNA synthetases (aaRSs) are among the key enzymes of protein biosynthesis. They are responsible for conducting the first step in the protein biosynthesis, namely attaching amino acids to the corresponding tRNA molecules both in cytoplasm and mitochondria. More and more research demonstrates that mutations in the genes encoding aaRSs lead to the development of various neurodegenerative diseases, such as incurable Charcot-Marie-Tooth disease (CMT) and distal spinal muscular atrophy. Some mutations result in the loss of tRNA aminoacylation activity, while other mutants retain their classical enzyme activity. In the latter case, disease manifestations are associated with additional neuron-specific functions of aaRSs. At present, seven aaRSs (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, MetRS, and LysRS) are known to be involved in the CMT etiology with glycyl-tRNA synthetase (GlyRS) being the most studied of them.


Assuntos
Glicina-tRNA Ligase/genética , Mutação , Doenças do Sistema Nervoso/enzimologia , Doença de Charcot-Marie-Tooth/enzimologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Feminino , Humanos , Masculino , Atrofia Muscular Espinal/enzimologia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/fisiopatologia , Neurônios/enzimologia , Neurônios/fisiologia
4.
J Med Chem ; 64(8): 4744-4761, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822618

RESUMO

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.


Assuntos
Desenho de Fármacos , Splicing de RNA , Tiadiazóis/química , Animais , Meia-Vida , Halogênios/química , Humanos , Masculino , Camundongos , Conformação Molecular , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Oxigênio/química , Piridazinas/química , Splicing de RNA/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Enxofre/química , 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 , Tiadiazóis/metabolismo , Tiadiazóis/farmacologia
5.
Yi Chuan ; 43(2): 160-168, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33724218

RESUMO

Spinal muscular atrophy (SMA) is a common childhood neuromuscular disease inherited in an autosomal recessive pattern. The majority of SMA patients have a homozygous deletion of survival motor neuron 1 (SMN1) gene. As a special SMA carrier, the (2+0) genotype ofSMN1 poses a great challenge for carrier screening and family genetic counseling. A previous study showed that polymorphisms of g.27134 T>G and g.27706_27707delAT had a predictive effect on (2+0) carriers in the Ashkenazi Jewish population. To further explore whether these two polymorphisms are specific to the Chinese population, the present study recruited 44 family members and 204 controls with knownSMN1copy number. These 44 family members were from nine unrelated SMA families withSMN1 homozygous deletion, and one of the proband parents was suspected to be a (2+0) carrier. Multiplex ligation-dependent probe amplification (MLPA) and short tandem repeat (STR) linkage analyses were used to determine the (2+0) genotype and polymorphism screening. Finally, by analyzing theSMN copies and haplotype from three generations of family members and two generations of multi-child families, ten individuals in nine families were confirmed as (2+0) carriers. Moreover, only one individual with three copies ofSMN1 carried the two polymorphisms of g.27134 T>G and g.27706_27707delAT. Therefore, we provided precise genetic counseling for these SMA families after confirming the (2+0) carriers. The association between the polymorphisms of g.27134T>G and g.27706_27707delAT and Chinese (2+0) carriers might be weak. Hence, it is necessary to find specific polymorphisms in the Chinese population to improve the detection rate of (2+0) carriers.


Assuntos
Atrofia Muscular Espinal , Criança , Dosagem de Genes , Genótipo , Homozigoto , Humanos , Neurônios Motores , Atrofia Muscular Espinal/genética , Deleção de Sequência , Proteína 1 de Sobrevivência do Neurônio Motor/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 214-218, 2021 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-33751527

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for families with high risk for spinal muscular atrophy (SMA) by using multiplex ligation-dependent probe amplification (MLPA). METHODS: Twenty-one families were enrolled. MLPA was used to detect copy numbers of SMN1 and SMN2 genes. Maternal contamination was excluded by using a short tandem repeat method. RESULTS: For 23 fetuses from the 21 families, 14 were identified as carriers, 1 as SMA patient, and 8 as normal. By linkage analysis of parental samples, three individuals were determined as silent (2+0) carriers. CONCLUSION: MLPA can determine the carrier status of SMA. The identification of three silent (2+0) carriers among the 44 parental samples indicated a risk for such families, for which genetic counseling and reproduction guidance should be provided.


Assuntos
Aconselhamento Genético , Atrofia Muscular Espinal , Diagnóstico Pré-Natal , Feminino , Heterozigoto , Humanos , Reação em Cadeia da Polimerase Multiplex , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Gravidez , Proteína 1 de Sobrevivência do Neurônio Motor/genética
8.
Nat Commun ; 12(1): 428, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462199

RESUMO

The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.


Assuntos
Motivo de Reconhecimento de RNA/genética , Sítios de Splice de RNA/genética , Splicing de RNA , Fatores de Processamento de Serina-Arginina/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Substituição de Aminoácidos , Asparagina/genética , Biologia Computacional , Éxons/genética , Ácido Glutâmico/genética , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Ressonância Magnética Nuclear Biomolecular , Engenharia de Proteínas , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/isolamento & purificação , Fatores de Processamento de Serina-Arginina/ultraestrutura , Uridina/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-33010453

RESUMO

Lipid droplets (LDs) are ubiquitous fat storage organelles composed of a neutral lipid core, comprising triacylglycerols (TAG) and sterol esters (SEs), surrounded by a phospholipid monolayer membrane with several decorating proteins. Recently, LD biology has come to the foreground of research due to their importance for energy homeostasis and cellular stress response. As aberrant LD accumulation and lipid depletion are hallmarks of numerous diseases, addressing LD biogenesis and turnover provides a new framework for understanding disease-related mechanisms. Here we discuss the potential role of LDs in neurodegeneration, while making some predictions on how LD imbalance can contribute to pathophysiology in the brain.


Assuntos
Doença de Alzheimer/metabolismo , Autofagia/genética , Demência Frontotemporal/metabolismo , Gotículas Lipídicas/metabolismo , Lipólise/genética , Atrofia Muscular Espinal/metabolismo , Sistema Nervoso/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Ésteres do Colesterol/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Regulação da Expressão Gênica , Humanos , Lisossomos/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fosfolipídeos/metabolismo , Triglicerídeos/metabolismo
10.
Nutrients ; 12(12)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339220

RESUMO

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.


Assuntos
Atrofia Muscular Espinal/metabolismo , Terapia Nutricional/métodos , Fenômenos Fisiológicos da Nutrição/genética , Proteínas do Complexo SMN/deficiência , Proteína 1 de Sobrevivência do Neurônio Motor , Biomarcadores/metabolismo , Humanos , Metaboloma , Metabolômica/métodos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Avaliação Nutricional
11.
Nat Commun ; 11(1): 5608, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154379

RESUMO

The minor spliceosome is evolutionarily conserved in higher eukaryotes, but its biological significance remains poorly understood. Here, by precise CRISPR/Cas9-mediated disruption of the U12 and U6atac snRNAs, we report that a defective minor spliceosome is responsible for spinal muscular atrophy (SMA) associated phenotypes in Drosophila. Using a newly developed bioinformatic approach, we identified a large set of minor spliceosome-sensitive splicing events and demonstrate that three sensitive intron-containing neural genes, Pcyt2, Zmynd10, and Fas3, directly contribute to disease development as evidenced by the ability of their cDNAs to rescue the SMA-associated phenotypes in muscle development, neuromuscular junctions, and locomotion. Interestingly, many splice sites in sensitive introns are recognizable by both minor and major spliceosomes, suggesting a new mechanism of splicing regulation through competition between minor and major spliceosomes. These findings reveal a vital contribution of the minor spliceosome to SMA and to regulated splicing in animals.


Assuntos
Proteínas de Drosophila/genética , Íntrons , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Spliceossomos/patologia , Animais , Modelos Animais de Doenças , Drosophila , Atrofia Muscular Espinal/patologia , Mutação , Fenótipo , Sítios de Splice de RNA , Splicing de RNA/genética , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Spliceossomos/genética
12.
J Pharmacol Sci ; 144(4): 204-211, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070839

RESUMO

The deficiency of survival motor neuron (SMN) protein can result in the onset of spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by a progressive loss of motor neurons and skeletal muscle atrophy. The mechanism underlying SMA pathology remains unclear. Here, we demonstrate that SMN protein regulates oxidative stress and inflammatory response in microglia. Antisense oligonucleotide, which increases SMN protein expression (SMN-ASO), attenuated SMA model mice phenotypes and suppressed the activation of microglia in the spinal cord. The expression of oxidative stress marker in microglia was decreased by SMN-ASO injection in SMA model mice. Increased reactive oxygen species production and subsequent antioxidative stress reaction was observed in SMN protein-depleted RAW264.7. Furthermore, nuclear factor kappa B (NFκB) and c-Jun amino terminal kinase (JNK) signaling, which mainly mediate the inflammatory response, are activated in SMN protein-depleted RAW264.7. Tumor necrosis factor-α (TNF-α) production is also increased in SMN protein-depleted RAW264.7. These findings suggest that SMN protein regulates oxidative stress and inflammatory response in microglia, supporting current claims that microglia can be an effective target for SMA therapy.


Assuntos
Inflamação/genética , Microglia/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Estresse Oxidativo/genética , Medula Espinal/citologia , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/fisiologia , Animais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Atrofia Muscular Espinal/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Am J Hum Genet ; 107(4): 763-777, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937143

RESUMO

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.


Assuntos
Axônios/metabolismo , Doença de Charcot-Marie-Tooth/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Debilidade Muscular/genética , Atrofia Muscular Espinal/genética , Anormalidades Musculoesqueléticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Axônios/patologia , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/patologia , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Expressão Gênica , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Heterozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/metabolismo , Anormalidades Musculoesqueléticas/patologia , Mutação , Linhagem , Cultura Primária de Células , Medula Espinal/anormalidades , Medula Espinal/metabolismo
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 828-832, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761588

RESUMO

OBJECTIVE: To explore the genetic basis for a child with concomitant spinal muscular atrophy (SMA) and Citrin protein deficiency. METHODS: The child was subjected to whole exome sequencing by using target sequence capture high-throughput sequencing. Candidate variants were verified by Sanger sequencing. The SMN genes of the patient were also analyzed through multiplex ligation-dependent probe amplification (MLPA). RESULTS: The patient was found to carry homozygous deletion of exons 7 and 8 of the SMN1 gene, for which his parents were both carriers. The patient also carried compound heterozygous variants c.1737G>A and IVS16ins3kbof the SLA25A13 gene, in addition with compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene, for which his parents were carriers, too. CONCLUSION: Variants of the SLC25A13 gene probably underlay the deficiency of Citrin protein, which may lead to neonatal intrahepatic cholestasis (NICCD). The patient also had SMA. The compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene are likely to cause mitochondrial DNA deletion syndrome type 4A, though other types of mitochondrial disease cannot be excluded.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Atrofia Muscular Espinal/genética , Transportadores de Ânions Orgânicos/genética , Deficiência de Proteína/genética , Proteínas de Ligação ao Cálcio/deficiência , Criança , DNA Polimerase gama/genética , Homozigoto , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Transportadores de Ânions Orgânicos/deficiência , Deleção de Sequência , Proteína 1 de Sobrevivência do Neurônio Motor/genética
18.
Neurol Clin ; 38(3): 505-518, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32703464

RESUMO

Spinal muscular atrophy is an autosomal-recessive degenerative neuromuscular disease that has historically been categorized into 5 types based on the individual's best functional ability. Two rather remarkable treatments have recently been approved for commercial use, and both have markedly changed the natural history of this disease. Here the authors report several cases of individuals, ranging from infants to adults, to highlight diagnostic considerations, along with initial and long-term treatment considerations in these individuals who now have the potential for stabilization to significant improvement in functional outcomes.


Assuntos
Técnicas de Transferência de Genes , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/terapia , Oligonucleotídeos/uso terapêutico , Atividades Cotidianas , Adolescente , Adulto , Feminino , Técnicas de Transferência de Genes/tendências , Humanos , Lactente , Recém-Nascido , Masculino , Atrofia Muscular Espinal/genética , Triagem Neonatal/métodos , Triagem Neonatal/tendências
20.
BMC Med Genet ; 21(1): 133, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552676

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. At present, gene therapy medicine for SMA, i.e., Spinraza (Nusinersen), has been approved by the FDA, bringing hope to SMA patients and families. Accurate diagnosis is essential for treatment. Our goal was to detect genetic mutations in SMA patients in China and to show the results of the prenatal diagnosis of SMA. METHODS: In this study, we examined 419 patients in our hospital from January 2010 to September 2019. Multiplex ligation-dependent probe amplification analysis was used to determine the copy numbers of SMN1 and SMN2. Long-range PCR combined with nested PCR was used to detect point mutations in SMN1. In addition to the above detection methods, we also used QF-PCR in prenatal diagnosis to reduce the impact of maternal contamination. We conducted a total of 339 prenatal diagnoses from January 2010 to September 2019. RESULTS: Homozygous deletion of SMN1 exon 7 was detected in 96.40% (404/419) of patients. Homozygous deletion of SMN1 exon 7 alone was detected in 15 patients (3.60%). In total, 10 point mutations were detected in the 15 pedigrees. Most patients with SMA Type I have 1 ~ 2 copies of the SMN2 gene. Patients with SMA Type II have 2 or 3 copies of the SMN2 gene. The results of prenatal diagnoses showed that 118 fetuses were normal, 149 fetuses were carriers of heterozygous variants, and the remaining 72 fetuses harbored compound heterozygous variants or homozygous variants. CONCLUSIONS: Our study found that the most common mutation in SMA was homozygous deletion of SMN1 exon 7 in our study. We suggest that detecting only the deletion of exon 7 of SMN1 can meet most of the screening needs. We also believe that SMN2 copy numbers can help infer the disease classification and provide some reference for future treatment options.


Assuntos
Análise Mutacional de DNA , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Diagnóstico Pré-Natal , China , Deleção de Genes , Dosagem de Genes , Homozigoto , Humanos , Fenótipo , Proteína 1 de Sobrevivência do Neurônio Motor/genética
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