#SPINE NUMBERS HOW TO#
Our approach is independent of the method used to estimate SMN2 copy number and focuses on the manifestations of the patient to decide how to proceed in each case. 8, 9 We propose a practical guide for the management of discordant SMA cases based on systematic specified actions once SMN2 copy number has been determined for a given patient. 4 Thus, accurate estimation of SMN2 copy number is essential in the present scenario of therapeutic advances with 3 specific SMA therapies already approved-nusinersen, onasemnogene abeparvovec, and risdiplam-and with the perspective of SMA neonatal screening and early diagnosis to initiate treatment. However, this correlation is not absolute, and some patients with 2 copies of SMN2 have mild SMA phenotypes, whereas some with 4 or more copies of the gene have been described as type I or II (reviewed in Calucho et al., 2018). Numerous studies have shown that the higher the number of copies of SMN2, the larger the amount of FL-SMN protein produced, and thus the milder the associated SMA phenotype. 7 Furthermore, intrinsic biological factors are also a source of discrepancies and add complexity to understanding how a specific SMN2 genotype influences the final phenotype in a given patient. 4 Along these lines, around 40% of samples recently studied by the same methodology in different laboratories yielded discordant results. Issues of DNA sample quality, calibration controls, and expertise to resolve ambiguous cases have been previously discussed. Indeed, whereas genetic confirmation of SMA is relatively straightforward (95% of the patients can be diagnosed with a simple qualitative test), the assessment of SMN2 copy number requires a quantitative methodology that is not easily implemented in most laboratories.
However, recent advances in SMA therapeutics have strengthened the importance of estimating as accurately as possible the number of SMN2 copies for all patients with SMA.
In previous years, this figure was mainly informative and mostly used to elaborate genotype-phenotype correlations rather than to predict a particular phenotype. On confirmation of biallelic deletion or pathogenic variants of the SMN1 gene in a given patient, the number of SMN2 copies is usually determined and reported. 6 Thus, the SMA phenotype is ultimately due to insufficient levels of full-length SMN (FL-SMN) protein. 5 The SMN-del7 protein is functionally compromised and unstable and therefore rapidly degraded by the ubiquitin-proteasome system. However, a single C→T transition in exon 7 disrupts an exon splicing enhancer and/or creates a splicing silencer, and as a consequence, SMN2 works as a hypomorphic allele that produces mainly transcripts lacking exon 7 (SMN-del7). 4 In fact, both SMN1 and SMN2 encode, in principle, the same survival motor neuron (SMN) protein.
2, 3 The number of copies of SMN2, the highly homologous paralog of SMN1, is currently the most important modifier of disease phenotype in most patients with SMA, this number varies between 1 and 5. Independent of the clinical severity, all forms of SMA are caused by loss or homozygous loss-of-function pathogenic variants of the SMN1 gene, located at 5q13. 1 According to age at onset and achieved motor abilities, patients with SMA are usually classified into type I (never sit), II (never walk unaided), or III (achieve independent walking abilities). Spinal muscular atrophy (SMA) is a neuromuscular disorder with a global incidence of approximately 1:11,000 live births and a worldwide carrier frequency of 1:51. Glossary FL-SMN = full-length SMN MLPA = multiplex ligation-dependent probe amplification NGS = next-generation sequencing SMA = spinal muscular atrophy SMN = survival motor neuron SMN-del7 = SMN2 transcripts lacking exon 7 SNV = single nucleotide variant
0 kommentar(er)
