Genetic analysis of a case of infant spinal muscular atrophy type 1c / 中国综合临床

Objective:To summarize the genetic characteristics of a case of spinal muscular atrophy type 1c.Methods:The case data of a child with spinal muscular atrophy type 1c was retrospectively analyzed, and the genetic analysis and literature review were carried out.Results:The patient, male, started at the age of 2 months, and showed gross motor development backwardness and low muscular tension. Multiplex connection probe amplification technique showed that the child had homozygous deletion mutation in exon 7-8 of SMN1 gene, and there was duplicate mutation in exon 7-8 of SMN2 gene. The number of copies of exon 7/8 was 3/3. His father was a heterozygous deletion carrier of SMN1 gene, and there was homozygous mutation in exon 8 of SMN2 gene. The number of copies of exon 7/8 was 2/3. His mother did not find abnormal exons of SMN1 gene, and the number of copies of exon 7/8 of SMN2 gene was 1/1.Conclusion:Spinal muscular atrophy lacks specific manifestations in the early stage, and the diagnosis mainly depends on genetic testing. Clinicians need to be vigilant, strengthen the early understanding of the disease, and improve the prognosis.

Cribado neonatal en atrofia muscular espinal: un desafío para cambiar la historia natural / Neonatal screening in spinal muscular atrophy: a challenge to change the natural history

Introducción: la atrofia muscular espinal (AME) es la primera causa de origen genético de muerte en la infancia. En los últimos 20 años han sido excepcionales los avances en el conocimiento de su base genética, de su historia natural y se han desarrollado estándares de cuidado y nuevas terapias. Este veloz aumento del conocimiento ha llevado al desarrollo de terapias eficaces para esta devastadora enfermedad, pero el tiempo son neuronas, y esa frase nos lleva a pensar la importancia del diagnóstico precoz y, por qué no, del diagnóstico presintomático mediante pesquisa neonatal. Métodos: revisión de la bibliografía disponible, a través de búsqueda en PubMed y Google para trabajos no indexados o publicaciones de organismos de Salud. Resultados: varios estudios clínicos han mostrado la mayor eficacia del tratamiento en pacientes presintomáticos, por lo que lograrlo en estos pacientes llevaría a cambiar radicalmente la historia de esta enfermedad. Conclusión: es importante analizar y promover el desarrollo de pilotos para pesquisa neonatal en vistas a lograr experiencia para, a partir de ello, pensar en la posibilidad de incorporarlo a programas nacionales. (AU)

Introduction: spinal muscular atrophy (SMA) is the first cause of genetic origin of death in childhood. Throughout the last 20 years, we have witnessed exceptional advances in the knowledge of its genetic base, the history of its nature and several standards of care and new therapies have been developed. This rapid increase in knowledge has led to the development of effective therapies for this devastating disease. However, time is neurons, and that phrase reminds us of the importance of early diagnosis, and, why not, of pre-symptomatic diagnosis by means of neonatal screening. Methods: review of scientific papers searching in Pubmed or Google for non-indexed articles or publications of Health organisms. Results: several clinical studies have shown the greatest effectiveness of treatment in pre-symptomatic patients, so achieving the same in these patients would result in radically changing the history of this disease. Discussion: it is important to analyze and promote the development of pilots for neonatal screening in order to gain experience, so from there on to be able to think about the possibility of incorporating it into national programs. (AU)

Natural history of spinal muscular atrophy in children: an analysis of 117 cases / 中国当代儿科杂志

OBJECTIVES@#To study the natural history of spinal muscular atrophy (SMA) in Chongqing and surrounding areas, China, and to provide a clinical basis for comprehensive management and gene modification therapy for SMA.@*METHODS@#A retrospective analysis was performed on the medical data and survival status of 117 children with SMA.@*RESULTS@#Of the 117 children, 62 (53.0%) had type 1 SMA, 45 (38.5%) had type 2 SMA, and 10 (8.5%) had type 3 SMA, with a median age of onset of 2 months, 10 months, and 15 months, respectively. Compared with the children with type 2 SMA or type 3 SMA, the children with type 1 SMA had significantly shorter time to onset, consultation, and confirmed diagnosis (@*CONCLUSIONS@#There are differences in clinical manifestations and survival rates among children with different types of SMA. The children with type 1 SMA have a low survival rate, and those with type 2 SMA may have non-linear regression of motor ability. Early identification and management of SMA should be performed in clinical practice.

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile / Atrofia muscular espinal en Chile, resultados de un programa de atención médica nacional

ABSTRACT Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

La Atrofia Muscular Espinal (AME) ha concitado mucha atención en los últimos 2 años debido a la aprobación del primer tratamiento intratecal para esta enfermedad neurodegenerativa. América Latina necesita desarrollar la demografía de AME, un acceso oportuno al diagnóstico y un seguimiento apropiado de los pacientes que incorporen los estándares de atención recomendados por expertos. Estos son pasos esenciales para orientar las futuras políticas de salud en esta enfermedad. Métodos Este es un estudio descriptivo de una cohorte de pacientes con AME de todo el país. Se analizaron los datos clínicos, motores, funcionales, sociales y el estado nutricional, respiratorio y esquelético de los pacientes. También medimos el número de copias del gen SMN2 en esta población. Resultados se reclutaron 92 pacientes, 50 varones; 23 AME tipo 1, 36 AME tipo 2 y 33 AME tipo 3. La edad media al diagnóstico genético fue de 5, 24 y 132 meses respectivamente. Evaluamos el número de copias de SMN2 en 57 pacientes. Un 69,6% de los pacientes con AME tipo 1 estaban traqueostomízados y gastrostomizados , un 65% de los pacientes con AME tipo 2 usaban ventilación nocturna no invasiva y el 37% de toda la cohorte presentaba una cirugía de escoliosis. Conclusión Esta cohorte chilena de pacientes con AME tuvo acceso oportuno al diagnóstico genético, asistencia ventilatoria, apoyo nutricional y cirugía de escoliosis, sin embargo, la atención ventilatoria para AME tipo 1 continúa aun basándose principalmente en la traqueostomía. En esta serie, AME tipo 1 está subrepresentada, probablemente debido a las restricciones en el acceso al diagnóstico temprano y la tasa de mortalidad alta y temprana.

Supplementary value of denaturing high performance liquid chromatography for routine prenatal diagnosis of spinal muscular atrophy by multiple ligation-dependent probe amplification / 中华医学遗传学杂志

Objective@#To explore the feasibility of high performance liquid chromatography (DHPLC) combined with multiple ligation-dependent probe amplification (MLPA) for the prenatal diagnosis of spinal muscular atrophy (SMA).@*Methods@#Three families who had given birth to children with SMA type I were subjected to prenatal diagnosis. Peripheral blood samples were collected from the three couples, and 10 mL amniotic fluid was taken for each fetus through amniocentesis at 16-24 gestational week. Following DNA extraction, maternal contamination was excluded by STR analysis. Copy numbers of the SMN genes were detected by denaturing high performance liquid chromatography (DHPLC). Relative copy number of SMN1, SMN2 and reference genes was detected with a MLPA P021 assay kit.@*Results@#The three couples were all found to harbor heterozygous deletion of exon 7 of the SMN1 gene by DHPLC. MLPA analysis also suggested that the three couples were all carriers of SMA mutations. The fetus of family 1 harbored homozygous deletion of exons 7 and 8 of the SMN1 gene, in addition with heterozygous deletion of exons 7 and 8 of the SMN2 gene, suggesting that the fetus had SMA. The fetus of family 2 also harbored homozygous deletion of exons 7 and 8 of the SMN1 gene, while the copy number of SMN2 gene was normal, suggesting that the fetus was a SMA patient too. The fetus of family 3 harbored heterozygous deletion of exons 7 and 8 of the SMN1 gene, in addition with heterozygous deletion of exons 7 and 8 of the SMN2 gene, suggesting that the fetus was a carrier.@*Conclusion@#DHPLC can effectively screen carriers of SMA mutations. Combined DHPLC and MLPA can provide accurate diagnosis for fetuses with a high risk for SMA.

Clinical Characteristics of Spinal Muscular Atrophy in Korea Confirmed by Genetic Analysis

The objective of this study was to review the clinical characteristics of patients with spinal muscular atrophy and to emphasize the importance of performing genetic mutational analysis at initial patient assessment. This is a single center oriented, retrospective, and descriptive study conducted in Seoul, South Korea. Genetic mutational analysis to detect the deletion of exon 7 of the SMN1 gene on chromosome 5q13 was performed by multiplex ligation-dependent probe amplification. Clinical features, electrodiagnostic study results, muscle biopsy results, and laboratory test results were reviewed from patient medical records. Of all 28 patients (15 males and 13 females), all showed bilateral symmetric proximal dominant weakness. Among them, 3 patients were classified as type I, 14 patients as type II, and 11 patients as type III. Twenty-five patients had scoliosis and eight of these patients received surgical treatment for scoliosis with improvement in clinical outcomes. Ventilator support was used in 15 patients. In terms of the diagnostic process, 15 patients had completed an electrodiagnostic study and muscle biopsy before genetic testing, and six of these patients were initially misdiagnosed with myopathy. Owing to the similar clinical features of SMA and congenital myopathy, an electrodiagnostic study and muscle biopsy could create confusion in the correct diagnosis in some cases. Therefore, it is recommended that genetic mutation analysis should be conducted along with an electrodiagnostic study or muscle biopsy in the diagnostic process for spinal muscular atrophy.

НУГАС-БУЛЧИНГийН ХАТАНГИРАЛ ӨВЧНИЙ ГЕНЕТИК ОНОШЛОГОО / Шинэ санаа Шинэ нээлт

@#BACKGROUND. Spinal muscular atrophy (SMA MIM#253300) is a heterogeneous group of neuromuscular disorders caused by degeneration of anterior horn cells. Spinal muscular atrophy is the second most common autosomal recessive disorder. The first substantive descriptions of SMA occurred at the end of the 19th century when Werdnig and Hoffman characterized the features of autosomal recessive SMA. SMA is broadly classified into four major categories characterized by the age of onset as well as severity of the disease. Clinically proximal weakness, predominantly athropy, upper muscle athropy and other muscle weakness including of facial, scapula and respiratory were reported. SMA is inherited by X chromosomal, autosomal recessive and dominant mode. In our study, we recruited an individual diagnosed with SMA, without SMN1 gene mutation to investigate BICD2 mutation. Peripherial blood from the patient and his family members were taken to extract genomic DNA according to commercial protocol. Amplification of target gene was done by special primers. DNA sequencing was done to detect a mutation. As a result, we identified a mutation in location c.484 C>T of third exon of BICD2 gene. This mutation is was a heterozygous in mother’ and child’ DNA, SIFT and Polyphen program was used to detect its pathogenic effect. We also checked by Grantham matrix score is 180.0 representing it,s changing acid and alkaline feature in this amino acid. We diagnoses a suspected case with SMA by his clinical symptoms as a SMA type III, Kugelberg-Belander desease. We detected a mutation of BICD2 gene in a patient with SMA. This mutation altered acid and alkaline checked by Grantham matrix. This mutation has never reported before, showing 100% pathogenic effect on protein function, but because of highly penetrate feature of this disease makes its inheritance mode of autosomal dominant pattern.

Genotype-Phenotype Correlation of SMN1 and NAIP Deletions in Korean Patients with Spinal Muscular Atrophy

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients. METHODS: Thirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed. RESULTS: Deletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008). CONCLUSIONS: Homozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA.

Características clínicas de los pacientes menores de 18 años con atrofia muscular espinal en Medellín, 2008 - 2013 / Clinical characteristics of patients under 18 years-old with spinal muscular atrophy in Medellín, 2008 - 2013

Introducción: La atrofia muscular espinal (AME) es una enfermedad degenerativa que afecta las neuronas motoras del asta anterior de la médula espinal, se manifiesta por debilidad muscular progresiva de predominio proximal, hipotonía y arreflexia osteotendinosa, la etiología es una mutación en el gen de supervivencia neuronal SMN. Objetivo: determinar las características clínicas de los pacientes menores de 18 años con atrofia muscular espinal en de Medellín, durante el período 2008-2013. Materiales y métodos: se realizó un estudio descriptivo retrospectivo de los pacientes con AME que consultaron en el Hospital Universitario San Vicente Fundación y un consultorio privado de neuropediatría en Medellín durante el período 2008-2013, en total se recopilaron datos de 29 pacientes, se revisaron las características clínicas, las ayudas diagnósticas practicadas y los tratamientos realizados. Resultados: la AME tipo II resultó la forma clínica más frecuente (62%) seguida por la AME tipo I (24.13%), las principales manifestaciones fueron la hipotonía (100%) debilidad muscular (93.1%) y la arreflexia osteotendinosa (82.8%). Las fasciculaciones en la lengua se presentaron en el 48.3% de los pacientes. La prueba molecular fue realizada en 6 pacientes y en todos se encontró deleción del exón 7 del gen SMN1. Conclusión: la atrofia muscular espinal es una enfermedad degenerativa y de progresión variable de acuerdo a su clasificación. Clínicamente, se debe sospechar cuando exista síndrome motoneuronal y fasciculaciones linguales. El diagnóstico molecular es el método más acertado para confirmar la enfermedad.

Introduction: Spinal muscular atrophy (SMA) is a degenerative disease that affects motor neurons in the anterior horn of the spinal cord, it is manifested by progressive muscle weakness predominantly proximal, hypotonia andosteotendinous arreflexia, the cause is a mutation in neuronal survival gene SMN1 Objective: Establish the clinical, electromyographics and genetics characteristics of patients younger than 18 years with spinal muscular atrophy in the Medellín city, during the period 2008-2013. Materials and methods: A retrospective study of patients with SMA seen in the Hospital Universitario San Vicente Foundation and private center of Neuro- pediatric of Medellín during the period 2008-2013 was performed. Data from 29 patientes were available, were reviewed clinical feature, diagnostic aids and treatments practiced. Results: SMA type II resulted the most frequent clinical presentation (62%) followed by SMA type I (24.13%), the main manifestations were hypotonia (100 %), muscle weakness (93.1%) and osteotendinous arreflexia (82.8%), tongue fasciculations occurred in 48.3% of patients. The molecular test was performed in 6 patients and in all the deletion of exon 7 of the SMN1 gene was found. Conclusion: spinal muscular atrophy is a degenerative and progressive disease according to their clinical classification. It should be suspected when there are motoneuronal syndrome and lingual twitches. Molecular diagnosis is the most accurate to confirm the disease.

Spinal Muscular Atrophy: Review of a Child Onset Disease.

Spinal Muscular Atrophy (SMA) is a group of inherited disorders that involve mainly bulbar and spinal motor neurons; causing muscle weakness and atrophy of proximal and symmetrical predominantly in lower extremities, without affecting the facial muscles and the intellectual ability. It is also unclear if SMA is a developmental or a neurodegenerative disease and occurs predominantly in childhood. The continuous clinical spectrum of SMA has been divided into 3 types based on the age at onset and highest motor milestones achieved. SMA type I was described by Hoffman in 1894 and in 1900 was reported as a disease characterized by hypotonia during the first 3 months of life, as well, is considered as the leading cause of death in children under two years of age among genetic diseases worldwide. SMA type II patients can achieve sitting but not walking. While SMA type III patients achieve full milestones with a progressive loss of walking ability. Deterioration in muscle strength and motor function eventually occurs in SMA type II and III. SMA occurs due to depletion of SMN, a ubiquitously expressed protein, which in all cells regulates RNA biogenesis and splicing through its role in the assembly of small nuclear ribonucleoprotein (snRNP) complexes.

Sequencing Technology in Molecular Diagnosis of Spinal Muscular Atrophy Caused by SMN1 Deletion / 天津医药

Objective To investigate the feasibility of DNA sequencing analysis in molecular diagnosis for spinal muscular atrophy (SMA). Methods Two pairs of primers were utilized to amplify the region including 5 different bases in SMA-causative gene SMN1 and its homologue copy SMN2 by polymerase chain reaction (PCR). The first primer amplified a fragment 501 bp long spanning from SMN intron 6 to intron 7 targeting four different bases (g.31957, 32006, 32154 and 32269). The second primer reversely amplified a 189 bp long fragment within SMN exon 8 including one base-pair differ-ence (g.32734). PCR procedure was followed by Sanger sequencing technique to identify the 5 different bases. SMA patients caused by SMN1 homozygous deletion were distinguished from carriers or normal controls by absence of SMN1 specific bas-es in sequence chromatograms. This assay was performed in 7 SMA suspected patients and their parents. The specimens were also detected by PCR- restriction fragment length polymorphism (RFLP) method. Results It was found that 6 of 7 SMA suspected patients showed only SMN2 specific bases at the 5 different base positions among the region from intron 6 to exon 8, which meant the patient displaying only SMN2-specific nucleotide a, T, g, g and A at g.31957, 32006, 32154, 32269 and 32734, while their parents (carriers) showed a/g, T/C, g/a, g/a and A/G at the same sites. SMN1 gene was deleted in the patient, and the deletion region was inferred from intron 6 to exon 8. Because carriers had both SMN1 and SMN2 genes, they can be discriminated from the SMN1 deleted patient. One of 7 patients yield an unique sequence chromatogram of a, T, g, g and A/G, indicating that exon 8 of SMN1 was not deleted in this patient. Conclusion DNA sequencing analysis is an alter-native simple method for detecting SMA caused by homozygous deletion of SMN1. We recommend to replace the widely used PCR-RFLP method with DNA sequencing assay.

Análisis genético molecular en atrofia muscular espinal / Molecular evaluation in infantile spinal muscular atrophy

Introducción: La atrofia muscular espinal de la infancia (AMEi) es una enfermedad neurodegenerativa, causada principalmente por deleciones del gen SMN 1 en su locus 5q11.1-13.3. La severidad va desde el tipo I, que compromete la vida en edades tempranas, hasta el tipo IV. Objetivos: Se describen hallazgos moleculares en pacientes con AME, nacionalmente remitidos al Instituto de Neurología y Neurocirugía así como se reporta la frecuencia por 100.000 habitantes en cada una de las provincias de la isla. Pacientes y Métodos: 105 pacientes fueron estudiados, remitidos entre 1997 y 2011. Para la detección de las deleciones se utilizó la técnica de reacción en cadena de la polimerasa (PCR) con cebadores correspondientes a los exones 7 y 8 del gen SMN 1, y digestión con enzimas DraI y DdeI respectivamente y analizados en gel de agarosa al 2 por ciento. Resultados y Discusión: Se encontró un 59 por ciento diagnosticados como AME I, 28,6 por ciento AME II, 12,4 por ciento AME III. Del total de casos 36,2 por ciento resultaron tener deleción de los exones 7 y 8, 35,2 por ciento deleción del exón 7 solamente y 28,2 por ciento no presentaron deleción de los exones correspondientes. Se discuten dichos resultados de acuerdo a la literatura internacional. Se presentan los resultados de frecuencias por 100.000 habitantes en cada provincia del país y discuten dichas frecuencias de acuerdo a la diversidad ancestral de la población cubana. Se concluye lo novedoso del estudio que constituye el primer reporte en una población caribeña.

Introduction: Infantile Spinal Muscular Atrophy (infantile SMA) is a neurodegenerative disease caused primarily by the deletion of the SMN1 gene at 5q11.1 - 13.3. Its severity ranges from type I, in early childhood, to type IV. Objectives: To describe molecular findings in patients with SMA, who were nationally referred to the Institute of Neurology and Neurosurgery and to describe the frequency per 100,000 people in each province of the island. Patients and Methods: 105 patients, referred between 1997 and 2011, were studied. The polymerase chain reaction (PCR) technique was used to detect the deletions of exons 7 and 8 of the SMN1 gene, and DraI and DdeI enzymes, in 2 percent agarose gel, were used for digestion. Results: 59 percent of the patients were diagnosed with SMA I, 28.6 percent with SMA II and 12.4 percent with SMA III. 36.2 percent of total patients presented deletions of exons 7, 8, 35.2 percent only deletion of exon 7 and 28.2 percentdid not present deletion of exons. Conclusion: These results are discussed according to the international literature. The frequency per 100,000 inhabitants in each province is presented and discussed according to ancestral diversity of the Cuban population. Also, the originality of the study is mentioned as it is the first report of this type in a Caribbean population.

Clinical and Molecular Characterization of Patients with Gross Hypotonia and Impaired Lower Motor Neuron Function.

Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. The aim was to study the clinical and molecular characteristics of patients suspected with SMA. It was a cross sectional study of 105 cases from January 2008 to August 2012. Patients’ demographic and presenting features and PCR findings were noted. 65 (62%) cases had a confirmed diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 34 (52.3%) children. Molecular analysis demonstrated deletion of both exon 7 and 8 of SMN1 gene in 83.1% of cases.

Allele-specific PCR for a cost-effective & time-efficient diagnostic screening of spinal muscular atrophy.

Background & objectives: Genetic diagnosis of spinal muscular atrophy (SMA) is complicated by the presence of SMN2 gene as majority of SMA patients show absence or deletion of SMN1 gene. PCR may amplify both the genes non selectively in presence of high amount of DNA. We evaluated whether allelespecific PCR for diagnostic screening of SMA is reliable in the presence of high amount of genomic DNA, which is commonly used when performing diagnostic screening using restriction enzymes. Methods: A total of 126 blood DNA samples were tested in amounts ranging 80-200 ng, referred for the genetic diagnosis of SMA using both conventional PCR-RFLP and allele-specific PCR. Results: The results from both methods showed agreement. Further, allele-specific PCR was found to be a time-efficient and cost-effective method. Interpretation & conclusions: Our study demonstrated the accuracy of our allele-specific PCR and the results were comparable compatible with that of PCR-RFLP, indicating its practical application in SMA diagnostic screening.

Homozygous SMN2 Deletion is a Major Risk Factor among Twenty-Five Korean Sporadic Amyotrophic Lateral Sclerosis Patients

PURPOSE: The association between survivor motor neuron (SMN) gene deletion and spinal muscular atrophy suggests that sporadic amyotrophic lateral sclerosis (sALS) may be related to SMN deletion. We examined the association between the SMN genotype and susceptibility to and severity of sALS. MATERIALS AND METHODS: We genotyped the copy number of SMN1 and SMN2 in 25 patients diagnosed with sporadic ALS and 100 healthy subjects in a Korean population. Onset age and medical research council (MRC) scale were compared among patients according to SMN1 : SMN2 genotypes. RESULTS: There was a significantly higher incidence of homozygous deletion of SMN2 (SMN1 : SMN2 genotype, 2 : 0) in sALS patients (20%) than in the normal controls (2%) (p<0.001). The onset age for patients with homozygous deletion of SMN2 (2 : 0) was significantly younger (34+/-15.38 years) than that of patients with 2 : 1, 2 : 2 and 2 : 3 of the SMN1 : SMN2 genotype (59.5+/-5.09; 52.69+/-16.46 and 50+/-0.00 years) (p=0.049). The ratio of patients with an MRC scale above G4- was smaller in the 2 : 0 genotype (40%) than in the 2 : 1, 2 : 2 and 2 : 3 genotypes (83.3%, 100% and 100%) (p=0.02). CONCLUSION: The homozygous SMN2 deletion (2 : 0) was statistically more frequent and associated with earlier onset age and lower MRC scale in Korean sALS patients. These suggest that SMN2 deletion may be one of the factors associated with susceptibility to and severity of sALS in a Korean population.

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras / Spinal muscular atrophy: diagnosis, treatment and future prospects

OBJETIVO: Relatar as recentes descobertas genéticas e moleculares, juntamente com as perspectivas futuras, para o tratamento da atrofia muscular espinhal, auxiliando, dessa forma, os profissionais da área da saúde a fazerem um rápido diagnóstico e proporcionarem um suporte terapêutico correto e precoce. FONTES DOS DADOS: As informações foram coletadas a partir de artigos científicos publicados nas duas últimas décadas, pesquisados nas bases de dados SciELO, PubMed e MEDLINE. SÍNTESE DOS DADOS: A atrofia muscular espinhal é uma doença neurodegenerativa com herança genética autossômica recessiva. É causada por uma deleção homozigótica do gene de sobrevivência do motoneurônio. Essa alteração genética resulta na redução dos níveis da proteína de sobrevivência do motoneurônio, levando à degeneração de motoneurônios alfa da medula espinhal, o que resulta em fraqueza e paralisia muscular proximal progressiva simétrica. Sabe-se que alguns cuidados básicos referentes à nutrição, respiração e fisioterapia podem ser importantes para retardar o progresso da doença e prolongar a vida dos pacientes. Vários medicamentos estão sendo testados, alguns novos, outros já conhecidos, como o ácido valproico, sendo que a paralisia pode ser estacionada, mas não revertida. CONCLUSÕES: A atrofia muscular espinhal é uma desordem de difícil diagnóstico, por ser pouco conhecida, e de tratamento ainda incerto. Os tratamentos farmacológicos e as terapias de suporte existentes ainda não são capazes de recuperar os motoneurônios ou as células musculares que já foram perdidos, mas têm o objetivo de retardar o progresso da doença e melhorar a função muscular residual dos pacientes, bem como oferecer uma melhor qualidade e expectativa de vida.

OBJECTIVE: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. SOURCES: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SUMMARY OF THE FINDINGS: SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. CONCLUSIONS: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

Advances in the genetics of spinal muscular atrophy in childhood / 国际儿科学杂志

Spinal muscular atrophy in childhood is one of the most common neuromuscular disorders with an autosomal recessive mode of inheritance. The main pathogenesis is homozygous loss and small intragenic mutations of the SMN1. SMN2 ,as a very identical copy of SMN1, modulates the disease severity. The functional difference between both genes is a variance of single nucleotide within the coding region, causing silent mutation obviously to decrease SMN2 transcripts. Histone deacetylase inhibitors have been shown better perspective in clinical trials.

Detection of homozygous and heterozygous SMN deletions of spinal muscular atrophy in a single assay with multiplex ligation-dependent probe amplification / 北京大学学报(医学版)

Objective: Spinal muscular atrophy(SMA), an autosomal recessive neuromuscular degeneration of the anterior horn cells of the spinal cord and brain stem, results in one of the most common diseases with muscle fatigue and atrophy. Most SMA cases including all the types are due to the homozygous deletion of at least exon 7 within the survival motor neuron 1 (SMN-1) gene. Although a "golden standard" assay (PCR with mismatch primer followed by enzyme digestion) is very reliable for the identification of homozygous SMN-1 deletion, the carrier detection of heterozygous SMN-1 deletion remains a challenge. Methods: Some PCR-based gene dosage assays or multiplex PCR allow for the determination of the copy number of SMN-1 gene to identify heterozygous deletion, but these procedures are often time consuming and available on a limited clinical basis. Recently developed MLPA (multiplex ligation-dependent probe amplification) is an efficient procedure that can accurately analyze relative quantification to establish the copy number of the SMN gene. We performed a validation for simultaneous detection of homozygous SMN-1 deletions of SMA patients and heterozygous SMN-1 deletions of SMA carriers in a simple assay using a MLPA-SMA assay specific reagent. Results: Six out of 20 patients with SMA were found to have homozygous SMN-1 deletion, confirmed by the PCR/digestion assay. All 4 parents of the children with SMA had heterozygous SMN-1 deletion, confirmed by an independent relative quantitative analysis. Conclusion: MLPA provides a simple, rapid and accurate method of simultaneously detecting homozygous deletions and heterozygous deletions in a single assay for both SMN-1 and SMN-2 genes.

Genotype-Phenotype correlation of SMN locus genes in spinal muscular atrophy patients from India

Spinal muscular atrophy has been classified into four groups based on the age of onset and clinical severity of the disease. Homozygous deletion in SMN1 gene causes the disease but the clinical severity may be modified by copy number of homologous gene SMN2 as well as the extent of deletion at SMN locus. In the view of scarcity of genotype and phenotype correlation data from India, this study has been undertaken to determine that correlation in SMA patients by using the SMN and NAIP genes and two polymorphic markers C212 and C272 located in this region. Two to four alleles of the markers C212 and C272 were observed in normal individuals. However, majority of Type I patients showed only one allele from both markers whereas in Type II and III patients, 2-3 alleles were observed. The SMN2 copy number in our type III patients showed that patients carry 3-5 copies of SMN2 gene. Our results suggest that extent of deletions encompassing H4F5, SMN1, NAIP and copy number of SMN2 gene can modify the SMA phenotype, thus accounting for the different clinical subtypes of the disease.

Quantitative Analysis of SMN1 Gene and Estimation of SMN1 Deletion Carrier Frequency in Korean Population based on Real-Time PCR

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, caused by homozygous absence of the survival motor neuron gene (SMN1) in approximately 94% of patients. Since most carriers have only one SMN1 gene copy, several SMN1 quantitative analyses have been used for the SMA carrier detection. We developed a reliable quantitative real-time PCR with SYBR Green I dye and studied 13 patients with SMA and their 24 parents, as well as 326 healthy normal individuals. The copy number of the SMN1 gene was determined by the comparative threshold cycle (Ct) method and albumin was used as a reference gene. The homozygous SMN1 deletion ratio of patients was 0.00 and the hemizygous SMN1 deletion ratio of parents ranged from 0.39 to 0.59. The delta delta Ct ratios of 7 persons among 326 normal individuals were within the carrier range, 0.41-0.57. According to these data, we estimated the carrier and disease prevalence of SMA at 1/47 and 1/8,496 in Korean population, respectively. These data indicated that there would be no much difference in disease prevalence of SMA compared with western countries. Since the prevalence of SMA is higher than other autosomal recessive disorders, the carrier detection method using real-time PCR could be a useful tool for genetic counseling.