Highlights • SMA has evolving phenotypes due to improved standard of care and new treatments • The clinician should be alert to identify new patterns of motor development in SMA • Other organ systems ...may develop signs of dysfunction as these patients live longer • Early diagnosis, including newborn screening, warrants consideration • Strategies targeting the CNS and peripheral tissues are warrant consideration
•The largest series of SMA patients for which SMN2 copy number has been determined.•All relevant studies published on the correlation SMN2 copy-SMA phenotype have been reviewed.•Discussion of ...biological factors and technical pitfalls accounting for discrepancies in correlations.•Correlations for predicting the likely evolution of SMA patients would have an impact on early therapy.
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype–phenotype correlations, predict disease evolution, and to stratify patients for clinical trials. We have determined SMN2 copy numbers in 625 unrelated Spanish SMA patients with loss or mutation of both copies of SMN1 and a clear assignation of the SMA type by clinical criteria. Furthermore, we compiled data from relevant worldwide reports that link SMN2 copy number with SMA severity published from 1999 to date (2834 patients with different ethnic and geographic backgrounds). Altogether, we have assembled a database with a total of 3459 patients to delineate more universal prognostic rules regarding the influence of SMN2 copy number on SMA phenotype. This issue is crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatments.
Severe spinal muscular atrophy is an autosomal recessive motor neuron disorder characterized by rapidly progressive hypotonia and weakness with respiratory complications and fatal outcome. It is ...caused by absence or pathogenic variants in the SMN1 gene. Knowledge and advances of the genetics of the disease allowed the development of tailored therapies that has changed clinical trajectories with evolving phenotypes. Several clinical investigations demonstrate that early diagnosis and intervention are essential for improved response to treatment and better prognosis. Therapeutic interventions that are effective at pre-symptomatic or early stages of the disease creates the need for awareness, expedite diagnosis and consideration of newborn screening programs.
With the recent advances in spinal muscular atrophy therapies, the complete scenario of standard of care and following up is changing not only in the clinical field with new phenotypes emerging but ...also with new expectations for patients, caregivers and health providers. The actual evidence indicates that early intervention and treatment is crucial for better response and prognosis. Knowledge of the prenatal and pre-symptomatic postnatal stages of the disease are becoming essential to consider the opportunities of timely diagnosis and to decide the earliest therapeutic intervention.
•With recent therapeutic advances, the landscape of spinal muscular atrophy has changed.•Early intervention and treatment is crucial for better response and prognosis.•Knowledge of the prenatal and pre-symptomatic SMA is essential.•Early diagnosis by newborn screening imply moving towards pre-symptomatic intervention.•Ethical issues are considered on decision making by the families.
Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder representing a continuous spectrum of muscular weakness ranging from compromised neonates to adults with minimal ...manifestations. Patients show homozygous absence or disease-causing variants of the SMN1 gene (-/- or 0/0) and in carriers only one copy is absent or mutated (1/0). Genetic diagnosis and counseling in SMA present several challenges, including the existence of carriers (2/0) that are undistinguishable of non-carriers (1/1) with current genetic testing methods and the report of patients (0/0) with very mild manifestations and even asymptomatic that are discovered when a full symptomatic case appears in the family. Younger asymptomatic siblings of symptomatic SMA patients are usually never tested until adolescence or adult life. However, following regulatory approval of the first tailored treatment for SMA, the prospects for care of these patients have changed. Early testing, including pre-symptomatic newborn screening and confirmation of diagnosis would change proactive measures and opportunities for therapy based in the actual landscape of new treatments. This review discusses the challenges and new perspectives of genetic counseling in SMA.
After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already ...approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.
•Efficacy of new treatments in SMA is better in pre than in post-symptomatic patients.•NBS is complementary of carrier screening, with different false negatives.•Pilot projects of SMA NBS have ...started or are planned to start in several countries.•Questions remain on SMN2 quantification and management of patients with 4 copies.•A strategy is proposed to launch an evidence-based approach for these patients.
Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results ...are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring.
•Onasemnogene abeparvovec (Zolgensma®) is the first approved gene therapy for a neuromuscular disease.•Treatment with Onasemnogene abeparvovec requires a thorough risk-benefit analysis for each individual patient.•Gene therapy with Onasemnogene abeparvovec should only be used by qualified neuromuscular expert centres.•Systematic real-world data and additional clinical trials are needed to fill evidence gaps concerning safety and efficacy.
Objective
To evaluate plasma phosphorylated neurofilament heavy chain (pNF‐H) as a biomarker in spinal muscular atrophy (SMA).
Methods
Levels of pNF‐H were measured using the ProteinSimple® platform ...in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease.
Results
Median pNF‐H plasma level was 167.0 pg/mL (7.46–7,030; n = 34) in children without SMA (aged 7 weeks–18 years) and was higher in those aged < 1 versus 1–18 years (P = 0.0002). In ENDEAR participants with infantile‐onset SMA, median baseline pNF‐H level (15,400 pg/mL; 2390–50,100; n = 117) was ~10‐fold higher than that of age‐matched infants without SMA (P < 0.0001) and ~90‐fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF‐H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF‐H levels: nusinersen‐treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control–treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months.
Interpretation
Plasma pNF‐H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF‐H levels followed by relative stabilization. Together these data suggest plasma pNF‐H is a promising marker of disease activity/treatment response in infants with SMA.
Spinal muscular atrophy was the most common inherited cause of infant death until 2016, when three therapies became available: the antisense oligonucleotide nusinersen, gene replacement therapy with ...onasemnogene abeparvovec, and the small-molecule splicing modifier risdiplam. These drugs compensate for deficient survival motor neuron protein and have improved lifespan and quality of life in infants and children with spinal muscular atrophy. Given the lifelong implications of these innovative therapies, ways to detect and manage treatment-modified disease characteristics are needed. All three drugs are more effective when given before development of symptoms, or as early as possible in individuals who have already developed symptoms. Early subtle symptoms might be missed, and disease onset might occur in utero in severe spinal muscular atrophy subtypes; in some countries, newborn screening is allowing diagnosis soon after birth and early treatment. Adults with spinal muscular atrophy report stabilisation of disease and less fatigue with treatment. These subjective benefits need to be weighed against the high costs of the drugs to patients and health-care systems. Clinical consensus is required on therapeutic windows and on outcome measures and biomarkers that can be used to monitor drug benefit, toxicity, and treatment-modified disease characteristics.
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