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Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
ZOLGENSMA is a gene therapy product that has been developed using an AAV-based vector (AAV9) to treat spinal muscular atrophy in children. In this therapy, a wildtype copy of the survival motor neuron 1 (SMN1) gene is delivered systemically through intravenous injection. It was approved for use in the United States in 2019 (Dunbar et al. 2018; Li and Samulski 2020; Shahryari et al. 2019).
The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
Prior to the current era of expanded pan-ethnic screening, two other disorders where DNA screening was universally considered for screening by ACMG or ACOG were identified: spinal muscular atrophy (SMA) and fragile X syndrome (fragile X mental retardation [FMR1]). Heterozygote frequencies for autosomal recessive spinal muscular atrophy range from 1 in 40 to 1 in 60 in most populations but are lower in Hispanics (34). The causative gene is Survival Motor Neuron 1 (SMN1). ACMG has long recommended population screening (34), but ACOG recommends screening only for couples with a positive family history (28,29). Screening for SMN1 carriers is complex because, on each copy of chromosome 5, the SMN1 gene is present in duplicate as two individual and functional copies of the SMN1 gene, totaling four functional copies per individual. Confusion may arise if DNA analysis reports a single individual having two copies of the SMN1. This could be explained either by each homologous chromosome having one copy of the mutant allele (trans) or by a single chromosome having two (both) copies of the mutant allele (cis) but with zero copies on the homolog. In the latter situation, the chromosome with no copies could result in an affected embryo if the other partner likewise contributes a chromosome lacking a wild-type copy of the SMN1 gene.
Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
SMA is an autosomal recessive condition caused by a deletion of a segment of DNA in exon 7 and exon 8 in the SMN1 (survival motor neuron) gene located on chromosome 5. Rarely, SMA is caused by a point mutation in the SMN1 gene. There does not appear to be a correlation between the type of SMN1 pathogenic variant and disease severity. SMN2 generates small amounts of SMN protein. The number of copies of SMN2 does correlate with SMA phenotype. Individuals with fewer copies of SMN2 typically have more severe forms of SMA (type I or II). See Table 6.10.
Decision-making and challenges within the evolving treatment algorithm in spinal muscular atrophy: a clinical perspective
Published in Expert Review of Neurotherapeutics, 2023
Lakshmi Balaji, Michelle A Farrar, Arlene M D’Silva, Didu S Kariyawasam
SMN2 modulates disease severity in a dose-dependent manner, however this is not absolute and predictions of the clinical course vary. Current molecular genetic assays amplify specific gene segments and rely on single nucleotide differences between SMN1 and SMN2. These do not provide insight into whether the detected ‘SMN gene copies’ are intact, which may influence the onset and evolution of disease. Recent technological advances including long-read DNA and RNA sequencing methodologies allow for the increasingly detailed analysis of the structure, sequence and expression of the highly complex SMN locus. Combining these novel methods with a well-phenotyped cohort of patients in future studies will be required to obtain a complete picture of the genetic variability that underlies clinical variation in SMA. Whilst still in the research domain, the clinical relevance of elucidating genetic variability in the SMN locus has increased with the advent of genetically targeted therapeutics, based on SMN2 modulation, to further understand variabilities of therapeutic response.
Onasemnogene abeparvovec for the treatment of spinal muscular atrophy
Published in Expert Opinion on Biological Therapy, 2022
Hugh J. McMillan, Crystal M. Proud, Michelle A. Farrar, Ian E. Alexander, Francesco Muntoni, Laurent Servais
SMA is a neurodegenerative disease that results in motor neuron loss because of biallelic mutations of the survival motor neuron 1 (SMN1) gene, leading to severe muscle weakness and atrophy. SMN1 directs the production of the survival motor neuron (SMN) protein, which is essential for the development and maintenance of motor neurons [1,2]. SMA occurs in an estimated 1 in 10,000 live births and was, until recent advancements in treatment, a leading genetic cause of infant mortality [3–5]. The survival motor neuron 2 (SMN2) gene functions as a partial backup gene to SMN1, and the severity of SMA correlates inversely with the polymorphic number of SMN2 gene copies [6–8]. However, quantification of SMN2 copies, and the clinical significance of this quantification, still requires standardization [9].
An evaluation of onasemnogene abeparvovec for spinal muscular atrophy (SMN1)
Published in Expert Opinion on Orphan Drugs, 2021
Megan A. Waldrop, Anne M. Connolly, Jerry R. Mendell
SMA is a progressive neurodegenerative disease affecting the motor neurons in the brain stem and spinal cord with an incidence of approximately 1 in 10,000 [2]. SMA is caused by homozygous loss-of-function mutations in the SMN1 gene located on chromosome 5q13. SMN1 produces the survival motor neuron (SMN) protein, which is essential for health and function of motor neurons. The absence of SMN is not compatible with life. Individuals with SMA have varying copies of a back-up gene, SMN2, which has a single-nucleotide change in exon 7 resulting in altered splicing and production of a nonfunctional SMN protein (Figure 1). However, a small amount of nonspliced transcript (~10%), and thus a fully functional SMN protein, is made from each SMN2 copy [3]. SMA is categorized into five types based on disease severity, with Type 0 being the most severe and Type 4 the least severe. As expected, more copies of SMN2 leads to more functional SMN protein and a milder phenotype [Table 1[4,5]]. When untreated, most children with type 1 SMA (the most common form; typically, with two copies of SMN2) die by age 2 [6,7].