1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China, Yingjie Sun, Xiangdong Kong, Zhenhua Zhao & Xuechao Zhao, You can also search for this author in SMA type 3 can have similar respiratory problems, but it is more rare. All SMA cases met the diagnostic criteria established by the International SMA Consortium (Munsat and Davies, 1992). [9][8], The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into a number of types. Trends Mol Med. [33][34][35] In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests[36][37][38] and as of May 2020 it has been adopted in 36 US states. Whereas the least severe form (type 4/adult onset), individuals may not seek the certain aspects of care until later (decades) in life. [59][60], Risdiplam (Evrysdi) is a medication taken by mouth in liquid form. They are mainly distinguished by two loci on exon 7 and exon 8. Proximal muscles are always affected earlier and to a greater degree than distal. Accurate diagnosis is essential for treatment. The authors sincerely thank the SMA families for their help and willingness to participate in this study. This situation will lead to a false negative result, as the carrier status will not be correctly detected by a traditional genetic test. http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s12881-020-01069-z, Clinical-Molecular Genetics and Cytogenetics. In 11.1% (45/404) of the patients, homozygous deletion of only the 7th exon of the SMN1 gene was found. We suggest that detecting only the deletion of exon 7 of SMN1 can meet most of the screening needs. A survey of transcripts generated by spinal muscular atrophy genes. PLoS One. The specific information is listed in Table 3. [11][1], Usually, the mutation in the SMN1 gene is inherited from both parents in an autosomal recessive manner, although in around 2% of cases it occurs during early development (de novo). [50] [51] It was approved for use in the US in 2016, and for use in the EU in 2017. A total of 419 patients with SMA from the Genetics and Prenatal Diagnostic Center of the First Affiliated Hospital of Zhengzhou University from January 2010 to July 2019 were enrolled in the study. 2012 Jun 20;32(25):8703-15. doi: 10.1523/JNEUROSCI.0204-12.2012. Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life. Other complications are rare and life expectancy is unaffected. In addition to the above detection methods, we also used QF-PCR in prenatal diagnosis to reduce the impact of maternal contamination. [8] Loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles. There are a total of five nucleotide differences between the two genes. [medical citation needed], Nusinersen (Spinraza) is used to treat spinal muscular atrophy. In 2018, also Biogen announced working on a gene therapy product to treat SMA.[90]. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Therefore, we believe that the detection of exon 7 can meet the needs of carrier screening in most cases. In a well-diagnosed SMA family, the risk of recurrence for each child is 25% and is equal for males and females. [126], No compounds have been taken forward to the clinical stage. We also believe that SMN2 copy numbers can help infer the disease classification and provide some reference for future treatment options. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. Supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support.[10]. For “2 + 0” carriers, current technology cannot detect them. Cookies policy. The incidence of SMA is 1/10,000–1/6000, and the carrier rate is 1/50–1/38 [1]. 2020 Aug 5;28(8):1887-1901. doi: 10.1016/j.ymthe.2020.05.011. The Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Add: No. The villus samples were cut, and whole genomic DNA was extracted using a tissue extraction procedure of an Eppendorf epMotion 5075 m workstation (Eppendorf, Germany). The datasets generated and/or analysed during the current study are not publicly available because patient details were involved, the data needed to be kept confidential. We also detected the number of copies of SMN2. Arch Neurol. Aminoglycosides showed capability to increase SMN protein availability in two studies. The eponymous label Werdnig–Hoffmann disease (sometimes misspelled with a single n) refers to the earliest clinical descriptions of childhood SMA by Johann Hoffmann and Guido Werdnig. For one family, the three prenatal diagnoses corresponded to three singleton pregnancies. [75][76][77][78], Children with SMA do not differ from the general population in their behaviour; their cognitive development can be slightly faster, and certain aspects of their intelligence are above the average. Epub 2012 Dec 8. Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene is located on an autosome. eCollection 2019 Mar-Apr. There were 177 patients with SMAI, 126 patients with SMAII, 100 patients with SMAIII and 16 patients with SMAIV. [24] Once weakened, the muscles never fully recover the same functional capacity to help in breathing and coughing as well as other functions. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The Genetics of Spinal Muscular Atrophy: Progress and Challenges. Laird AS, Mackovski N, Rinkwitz S, Becker TS, Giacomotto J. Hum Mol Genet. [8] Another gene, SMN2, is considered a disease modifying gene, since usually the more the SMN2 copies, the milder is the disease course. The onset of weakness is usually noticed some time between 6 and 18 months of life. Among them, 252 families underwent one prenatal diagnosis, 38 families underwent two prenatal diagnoses, and 3 families underwent three prenatal diagnoses. At the same time, MLPA can also detect the copy number of SMN2, which is helpful to determine the subsequent treatment plan [8]. 2015;12(2):290–302. The eponymous term Kugelberg–Welander disease is after Erik Klas Hendrik Kugelberg (1913–1983) and Lisa Welander (1909–2001), who distinguished SMA from muscular dystrophy. In the most severe forms (types 0/1), individuals have the greatest muscle weakness requiring prompt intervention. Each SMN1 exon product was purified using the QIAquick PCR Purification Kit (Qiagen) and sequenced on the ABI 3130 Genetic Analyzer (Applied Biosystems) using the BigDye Terminator v3.1 Cycle Sequencing Kit. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. The juvenile form usually manifests after 12 months of age and describes people who have been able to walk without support at least for some time in their lives, even if they later lost this ability. In the long run, however, reduced availability of the SMN protein results in gradual death of motor neuron cells in the anterior horn of spinal cord and the brain. [61], The respiratory system is the most common system to be affected and the complications are the leading cause of death in SMA types 0/1 and 2. [68][medical citation needed] Therein, it could be necessary in SMA type I and people with more severe type II to have a feeding tube or gastrostomy. Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. Since the SMN1 and SMN2 genes are highly homologous, the conventional NGS panel cannot distinguish whether the mutation is derived from the SMN1 gene or the SMN2 gene. A person may learn carrier status only if one's child is affected by SMA or by having the SMN1 gene sequenced. In 2017, the American College of Obstetricians and Gynecologists (ACOG) required all women who had children to be screened for SMA carriers. Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Correspondence to SMA is a serious disease with a high carrier rate and a high incidence of disability and death, and its early symptoms are not obvious. This work was supported by the National Key Research and Development Program of China (Grant No. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. HHS Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Burlet P, et al. Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels of SMN protein. The basic principle is to use multiple probes to target DNA sequences combined with capillary electrophoresis separation technology to achieve the diagnosis of SMA pathogenic genes. 2019;61(1):19–24. The deletion rate of the SMN1 E7 allele was 98.21%, and the point mutation rate was 1.79%. After informed consent was obtained, 5 ml of amniotic fluid was taken from each pregnant woman by amniocentesis under B-ultrasound at 16 to 20 weeks of gestation. Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip dislocations, spinal deformity, osteopenia, an increase risk of fractures and pain. Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, Xu X, Davis C, Wooley J, Goldhamer DJ, Lutz CM, Rich MM, Sumner CJ. Studies have shown that 95% of SMA cases are caused by homozygous deletion of the 7th and 8th exons or only the 7th exon of the SMN1 gene, and approximately 5% of SMA cases are caused by complex heterozygous mutation of the SMN1 gene. Muscles that depend on these motor neurons for neural input now have decreased innervation (also called denervation), and therefore have decreased input from the central nervous system (CNS). [31] 2015;62(3):743–66. In healthy individuals, the SMN1 gene codes the survival of motor neuron protein (SMN) which, as its name says, plays a crucial role in survival of motor neurons. Neurol Clin. . California Privacy Statement, In untreated SMA type II, the course of the disease is slower to progress and life expectancy is less than the healthy population. neuron; therapeutics. Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. #2018YFC1002203). Gavrilov DK, Shi XY, Das K, et al. [8] The introduction of causative treatments in 2016 has significantly improved the outcomes. Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among ethnic groups. [85] Long-term survival in SMA type I is not sufficiently evidenced; however, recent advances in respiratory support seem to have brought down mortality.[86].