Regardless of the approach, the presented studies demonstrated better efficacy in SMA children pre-symptomatic or with the shortest disease duration [
72]. This is a consequence of the rapid denervation process occurring in the first six months of life and the aim of pre-symptomatic treatment is the precocious rescue of motoneurons. However, we recently demonstrated that the mean age at diagnosis is 4.70 months (SD ± 2.82) in SMA type I, 15.6 months (SD ± 5.88) in SMA type II, and 4.34 years (SD ± 4.01) in SMA type III [
73]. Therefore, these findings support the need of NBS to achieve a better efficacy of the available therapeutic options. NBS is nowadays performed in Italy, Taiwan, some States in US, Belgium and Germany as pilot studies [
74,
75,
76,
77,
78]. The decision of how to handle newborns who test positive in the screening is crucial. An algorithm, based upon
SMN2 copy number, has been proposed by the SMA NBS Multidisciplinary working group, sponsored by CureSMA. The experts reached a consensus to start immediately treatment in infants with one, two and three
SMN2 copies, regardless of the presence of symptoms and to strictly follow patients with four copies till symptoms’ onset and then start treatment. However, it is still under debate how to handle families and infants with four or more copies and expected to have mild and late-onset disease [
79,
80,
81]. Moreover, this aspect is further complicated by the fact that the correlation between
SMN2 copies and phenotype can be influenced by genetic modifiers, as demonstrated in siblings with the same SMA genotype [
82]. A qualified genetic counselling and psychological support are mandatory to help parents to face the stressful situation to receive a severe diagnosis in an apparently healthy baby and to take relevant treatment decisions.
The variability in treatment response among patients could be better understood with the availability of reliable biomarkers. This knowledge would help to identify prognostic factors, to avoid long-term exposure to expensive drugs with still unknown long-term drug-related adverse events. A variety of biomarkers is currently under investigation including epigenetic, genetic, proteomic, electrophysiological and imaging tools [
83]. Neurofilaments (NFs) muscle-specific miRNAs (myomiRs) and CSF proteomic profile, although biomarkers are not yet validated, have recently drawn attention as promising tools in SMA. NFs are markers of axonal degeneration. In infants with SMA type I the level of CSF NFs was significantly higher than in controls, with a response to nusinersen treatment that correlated with clinical improvement [
84]. Similar results were confirmed in plasma in the ENDEAR study in symptomatic SMA type I patients [
85]. In older patients with less severe forms of SMA, the role of NFs has not yet been confirmed probably as consequence of a slower disease progression [
86,
87].
SMN protein regulates RNA metabolism and biogenesis of microRNA (miRNA), which are gene expression modulators, and their dysregulation is implicated in a variety of neuromuscular diseases. Recently, a reduced expression level of circulating myomiRs miR-133a, -133b, miR-206 and −1 has been demonstrated in SMA type II and III patients under nusinersen treatment. Moreover, miR-133a decrement could be a predictor of motor function response to therapy [
88]. A recent study evaluated, by mass spectrometry, non-targeted CSF proteomic profiles in SMA type II and III patients. The analysis highlighted two groups with differences in age and expression of proteins related to neurodegeneration and neuroregeneration. Moreover, intraindividual CSF differences were present between non-responders and responders to nusinersen treatment, with a correlation with motor functional improvement in the latter group [
89].Considering the high costs of the approved new treatments and the limited data on long-term efficacy and safety, the scientific community feels the burning need to systematically collect “real-world data” to provide evidence for clinical decision-making and reimbursement. Only one study reported the results of a number needed to treat (NNT) analysis comparing the efficacy of nusinersen and onasemnogene abeparvovec on several outcomes using data from AVXS-101-CL-101 and ENDEAR studies in symptomatic SMA type I infants. Authors demonstrated an efficacy advantage of onasemnogene abeparvosec in terms of motor milestones achieved, motor function (CHOP-INTEND score) improvement and independence from permanent assisted ventilation. Moreover, the probability of preventing death was 20% higher in the onasemnogene abeparvosec treated group [
90]. However, the main drawback of this study is the use of an unanchored indirect analysis of NNT between two studies. Head-to-head clinical trials should be performed to estimate comparative efficacy of the available approaches, avoiding possible biases such as differences in study design and patient characteristics. Moreover, a recent study highlights wide variations in cost and benefit estimates of nusinersen and indicates that onasemnogene abeparvosec is unlikely to represent “value for money” according to current standards of reimbursement for the UK NHS [
91]. On the contrary, a US study demonstrated an incremental cost-effectiveness ratio (ICER), expressed as cost/quality-adjusted life year (
$/QALY), of
$46,947 for chronic treatment with nusinersen and of
$31,379 base case at a price of
$5M for onasemnogene abeparvosec, indicating that the latter was cost-effective with prices of ≤
$5M [
92]. Several international disease-specific registries have now been established (e.g., the International SMA Consortium Spinal Muscular Atrophy Patient Registry (iSMAC), the TREAT-NMD registry and the SMArtCARE project), collecting “real-world data” on treated and untreated SMA patients with standardized outcome measures, including patient-oriented tools on a longitudinal setting [
93,
94,
95,
96,
97,
98].
All studies so far have been conducted in patients followed in tertiary referral centers with the recommended standards of care and this likely contributed to the positive results of the trials. Nowadays, families have different therapeutic options, but it has to be highlighted by clinicians that the efficacy of these new compounds is significantly related to the adherence to a careful multidisciplinary management of care. Moreover, increment in muscle strength, acquisition of new milestones and increased survival are bringing attention to emerging phenotypes [
15]. Treated SMA type I patients can be able to sit also unsupported and; therefore, with the effect of gravity, they exhibit a higher rate of scoliosis with often severe kyphoscoliosis in the first years of life. A careful X-ray and clinical monitoring, the use of braces and eventually the surgical option with “growing rods” are crucial. Moreover, the increase in muscle strength promotes the worsening of contractures, therefore intensive stretching and the use of standing frame or knee-ankle-foot-orthoses when possible have to be envisaged. The reported cognitive involvement might be more frequent in longer-surviving SMA type I patients and this aspect has to be elucidated in long term follow-up [
99].