scholarly journals Mutation analysis of 419 family and prenatal diagnosis of 339 cases of spinal muscular atrophy in China

2020 ◽  
Author(s):  
Yingjie Sun ◽  
Xiangdong Kong ◽  
Zhenhua Zhao ◽  
Xuechao Zhao
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Point Mutations ◽  
Homozygous Deletion ◽  
Common Mutation ◽  
Type I ◽  
Copy Numbers ◽  
Smn2 Gene ◽  
The Impact

Abstract 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.

scholarly journals Mutation analysis of 419 family and prenatal diagnosis of 339 cases of spinal muscular atrophy in China

2020 ◽  
Author(s):  
Yingjie Sun ◽  
Xiangdong Kong ◽  
Zhenhua Zhao ◽  
Xuechao Zhao
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Point Mutations ◽  
Homozygous Deletion ◽  
Common Mutation ◽  
Type I ◽  
Copy Numbers ◽  
Smn2 Gene ◽  
The Impact

Abstract 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.

scholarly journals Mutation analysis and prenatal diagnosis of 419 cases of Spinal Muscular Atrophy in China

2020 ◽  
Author(s):  
YingJie Sun ◽  
Xiangdong Kong ◽  
Xuechao Zhao ◽  
Zhenhua Zhao
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Chorionic Villus ◽  
Genetic Diagnosis ◽  
Point Mutations ◽  
Homozygous Deletion ◽  
Compound Heterozygous ◽  
Prenatal Genetic Diagnosis ◽  
Compound Heterozygous Variants

Abstract Background Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. At present, the gene therapy medicine for SMA, i.e. , Spinraza (Nusinersen), has been approved by the FDA, bringing hope to SMA patients and families. In this study, we analyzed the deletion of SMN gene in patients suspected of SMA, and performed prenatal genetic diagnosis of SMA. Methods In this study, we collected the peripheral blood of 419 probands and their parents who were treated in the genetic counseling clinic at our hospital from January 2010 to September 2019, and extracted DNA from the blood samples for analysis. Patients who were diagnosed with SMA were first tested by MLPA. The patients with negative MLPA results were further analysed with long-range PCR combined with nest PCR and validated by Sanger sequencing to look for point mutations. In 293 families, pregnant women were subjected to chorionic villus or amniotic fluid sampling for prenatal genetic diagnosis depending on gestational weeks. In addition to the above methods used for genetic diagnosis, we also used QF-PCR in all prenatal diagnoses, which can help detect the presence of trisomy of chromosome while eliminating maternal contamination. Results 1. 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%). 2. In total, 10 point mutations were detected in the 15 pedigrees. Five of these variants have not been previously reported in the literature. 3. Among the 293 pedigrees that underwent one prenatal diagnosis, 118 foetuses were normal, 149 foetuses were carriers of heterozygous variants, and the remaining 72 foetuses harboured compound heterozygous variants or homozygous variants. 4. In all prenatal diagnoses, we found one 21-trisomy fetus by QF-PCR. Couples whose foetuses were normal or carriers continued the pregnancy, whereas couples whose foetuses harboured compound heterozygous variants or homozygous variants decided to terminate the pregnancy. The follow-up results were consistent with the prenatal diagnosis.

SMN1 gene point mutations in type I–IV proximal spinal muscular atrophy patients with a single copy of SMN1

2015 ◽  
Vol 51 (9) ◽  
pp. 925-931
Author(s):  
V. V. Zabnenkova ◽  
E. L. Dadali ◽  
S. B. Artemieva ◽  
I. V. Sharkova ◽  
G. E. Rudenskaya ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Point Mutations ◽  
Single Copy ◽  
Type I ◽  
Smn1 Gene ◽  
Proximal Spinal Muscular Atrophy

scholarly journals A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy

2003 ◽  
Vol 160 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Umrao R. Monani ◽  
Matthew T. Pastore ◽  
Tatiana O. Gavrilina ◽  
Sibylle Jablonka ◽  
Thanh T. Le ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Type I ◽  
Missense Mutations ◽  
Smn2 Gene ◽  
Smn Gene

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

scholarly journals Spinal muscular atrophy (5qSMA): best practice of diagnostics, newborn screening and therapy

2020 ◽  
Vol 32 (3) ◽  
pp. 263-272
Author(s):  
Katja Eggermann ◽  
Dieter Gläser ◽  
Angela Abicht ◽  
Brunhilde Wirth
Keyword(s):  
Spinal Muscular Atrophy ◽  
Newborn Screening ◽  
Best Practice ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Genetic Defect ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Compound Heterozygous ◽  
Common Mutation

Abstract Proximal spinal muscular atrophy (SMA) is an autosomal-recessive inherited neuromuscular disorder caused by the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Patients show hypotonia, muscular atrophy and weakness of voluntary proximal muscles. SMA is one of the most common genetic diseases, with a frequency of about 1 in 7,000 newborns in Germany. The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1. The severity of the disease is mainly influenced by the copy number of the highly homologous SMN2. Since the discovery of the underlying genetic defect 25 years ago, both the diagnostics of SMA and its treatment have undergone constant and in recent times rapid improvements. SMA has become one of the first neuromuscular disorders with effective therapies based on gene targeted strategies such as splice correction of SMN2 via antisense oligonucleotides or small molecules or gene replacement therapy with a self-complementary adeno-associated virus 9 expressing the SMN1-cDNA. With the availability of treatment options, which are most effective when therapy starts at a pre-symptomatic stage, a newborn screening is indispensable and about to be introduced in Germany. New challenges for diagnostic labs as well as for genetic counsellors are inevitable. This article aims at summarising the current state of SMA diagnostics, treatment and perspectives for this disorder and offering best practice testing guidelines to diagnostic labs.

scholarly journals The Cure SMA Membership Surveys: Highlights of Key Demographic and Clinical Characteristics of Individuals with Spinal Muscular Atrophy

2021 ◽  
Vol 8 (1) ◽  
pp. 109-123
Author(s):  
Lisa Belter ◽  
Jill Jarecki ◽  
Sandra P. Reyna ◽  
Rosangel Cruz ◽  
Cynthia C. Jones ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Burden Of Disease ◽  
Large Scale ◽  
Muscular Atrophy ◽  
Healthcare Services ◽  
Age At Diagnosis ◽  
Gene Copy ◽  
Type I ◽  
Patient Reported ◽  
The Impact

Background: Cure SMA maintains the largest patient-reported database for people affected with spinal muscular atrophy (SMA). In 2017, Cure SMA initiated annual surveys with their membership to collect demographic and disease characteristics, healthcare, and burden of disease information from patients and caregivers. Objective: To summarize results from two large-scale Cure SMA surveys in 2017 and 2018. Methods: Cure SMA database members were invited to complete surveys; these were completed by caregivers for living or deceased individuals with SMA and/or affected adults. Results: In 2017, 726 surveys were completed for 695 individuals with SMA; in 2018, 796 surveys were completed for 760 individuals with SMA. Data from both survey years are available for 313 affected individuals. Age at symptom onset, distribution of SMN2 gene copy number, and representation of each SMA type in the surveys were consistent with that expected in the SMA population. In the 2018 survey, the average age at diagnosis was 5.2 months for SMA type I and the reported mean age at death for this subgroup was 27.8 months. Between survey years, there was consistency in responses for factors that should not change within individuals over time (e.g., reported age at diagnosis). Conclusions: Results from the Cure SMA surveys advance the understanding of SMA and facilitate advocacy efforts and healthcare services planning. Longitudinal surveys are important for evaluating the impact of effective treatments on changing phenotypes, and burden of disease and care in individuals with SMA.

Hydrocephalus in Spinal Muscular Atrophy: A Case Report and Review of the Literature

2020 ◽  
Author(s):  
Jeetendra P. Sah ◽  
Aaron W. Abrams ◽  
Geetha Chari ◽  
Craig Linden ◽  
Yaacov Anziska
Keyword(s):  
Spinal Muscular Atrophy ◽  
Clinical Characteristics ◽  
Clinical Presentation ◽  
Muscular Atrophy ◽  
Communicating Hydrocephalus ◽  
Type I ◽  
Review Of The Literature ◽  
Radiographic Findings ◽  
Comprehensive Review ◽  
The Relationship

AbstractIn this article, we reported a case of spinal muscular atrophy (SMA) type I noted to have tetraventricular hydrocephalus with Blake's pouch cyst at 8 months of age following intrathecal nusinersen therapy. The association of hydrocephalus with SMA is rarely reported in the literature. Development of hydrocephalus after intrathecal nusinersen therapy is also reported in some cases, but a cause–effect relationship is not yet established. The aim of this study was to describe the clinical characteristics of a patient with SMA type I and hydrocephalus, to review similar cases reported in the literature, and to explore the relationship between nusinersen therapy and development of hydrocephalus. The clinical presentation and radiographic findings of the patient are described and a comprehensive review of the literature was conducted. The adverse effect of communicating hydrocephalus related to nusinersen therapy is being reported and the authors suggest carefully monitoring for features of hydrocephalus developing during the course of nusinersen therapy.

First-trimester prenatal diagnosis of spinal muscular atrophy using microsatellite markers

1994 ◽  
Vol 14 (6) ◽  
pp. 459-462 ◽  
Author(s):  
S. Lo Cicero ◽  
F. Capon ◽  
S. Melchionda ◽  
M. Gennarelli ◽  
G. Novelli ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Microsatellite Markers ◽  
Muscular Atrophy ◽  
First Trimester
Sign in / Sign up

Export Citation Format

Share Document