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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.
Chronic Denervation Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Spinal muscular atrophy (SMA) is an autosomal recessive inherited neuromuscular disease characterized by degeneration of spinal cord motor neurons. It is caused by homozygous mutations of survival motor neuron 1 (SMN1) gene on both copies of chromosome 5q. The presence of a human unique SMN2 as a backup gene provides partially functional SMN protein and affects the severity of the phenotype. SMA was originally described in two infant brothers by Guido Werdnig in 1891 and in seven additional cases by Johan Hoffmann from 1893 to 1900. The International Consortium on SPA sponsored by the Muscular Dystrophy Association in 1991 suggested phenotype classification of SMA based on the highest level of motor function and age of onset (Table 21.2). Subsequent modifications added a type I for adult-onset cases and included a type 0 for patients with prenatal onset and death within weeks.
Spinal Cord Disease
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
There is autosomal recessive loss of the SMN1 gene on chromosome 5q13. SMN has multiple copies in the normal human genome: one copy of SMN1 and varying copies of SMN2. The product of both SMN1 and SMN2 is a protein involved in ribonucleic acid (RNA) processing, which, although ubiquitous, is highly concentrated in motor neurons. SMN2 is rapidly degraded within the cell, thus the volume of protein produced by SMN2 is largely determined by the functional status of the SMN1 copy. SMA patients lose normal SMN1 function, but the amount of remaining SMN2 gene function can predict severity of disease phenotype. It is estimated that there are 2% de novo mutations where only one parent is identified as a carrier.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
SMA is a group of inheritable genetic disorders resulting from splicing defects leading to progressive loss of motor neuron function between the lower brainstem and spinal cord culminating in muscle atrophy [67]. The most common splicing defect is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene, leading to deficiency of SMN protein in motor neurons [68]. SMN plays an essential role in regulating cellular homeostasis by directing the assembly of the spliceosome machinery and playing a role in mRNA trafficking. Defects in SMN lead to aberrant mRNA splicing by failure to properly assemble the spliceosome complex, thus impeding intron removal from pre-mRNAs. In humans, SMN2 is a paralog of SMN1 that encodes an identical copy of SMN. However, the SMN2 pre-mRNA undergoes aberrant splicing leading to deletion of exon 7. As with FD, ASOs have been used to rectify the splicing defect of SMN2 pre-mRNA [69]. These ASOs have made their way to the clinic resulting in the first FDA-approved therapy to treat SMA, nusinersen, that targets SMN2 splicing truncation thus producing a full-length SMN protein [70].
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
Regarding the RNA components of the SPL, mutations of U1 and U2 snRNA are implicated in cancer (hepatocellular carcinoma, CCL, and medulloblastoma). These mutations are responsible for 5’ cryptic splicing and intron retention events. Additionally, mutations of U1 snRNA at the 5’SS induce spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease and the leading genetic cause of newborn lethality [26,27,71–73]. The mechanism underlying SMA onset is rather complex. SMA is caused by a homozygous deletion of the survival of motor neuron-1 gene (SMN1) in chromosome 5 encoding for the SMN protein, which plays a critical role in snRNP assembly [72–74]. In humans, two paralog SMN genes exist: SMN1 and SMN2 [75]. The SMN protein produced by the SMN2 gene cannot fully compensate for the loss of SMN1 in SMA patients.
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
Until relatively recently, most studies of SMA focused on symptom management [12–14]. The advent of an antisense oligonucleotide (nusinersen) and a small-molecule drug (risdiplam) that affect SMN2 gene splicing, as well as a gene replacement therapy (onasemnogene abeparvovec) that delivers a functional gene to restore expression of full-length SMN protein, has changed the model of SMA treatment [15]. Multidisciplinary care in combination with disease-modifying therapies remains imperative, necessitating an approach focused on each individual patient’s clinical status and current needs, to optimize motor, respiratory, and bulbar function. Although these treatments do not offer a cure for SMA, they do offer substantial gains in motor function achievements and life expectancy. With the introduction of disease-modifying treatments, SMA phenotypes are evolving, and classification is increasingly described according to functional status (e.g. non-sitter, sitter, walker) [12,13]. Age, SMN2 copy number, and baseline motor function are important determinants of outcomes [16,17].