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Genetics & Heredity
Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.
- spinal muscular atrophy
- classification
- SMN1
- SMN2
- antisense oligonucleotides
1. Detection of Pre-Symptomatic SMA
With the introduction of effective therapies with new drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) into the clinical setting, the timing and accuracy of SMA diagnosis have become much more important than ever before. If the treatment cannot be initiated at the proper time because of delayed diagnosis or misdiagnosis, the therapeutic efficacy may be markedly reduced.
Clinical trials of nusinersen and onasemnogene in pre-symptomatic patients showed that nearly all patients achieved good motor function. Patients enrolled in these clinical trials were those who, without treatment, would be expected to exhibit symptoms of SMA type I or II. If treated before symptoms develop, even infants predicted to have SMA type I (genetically diagnosed but asymptomatic) would be able to sit without support [137,144]. Additionally, if treated before symptoms develop, even infants predicted to have SMA type II (genetically diagnosed but asymptomatic) would be able to walk independently [137,145].
Following the success of clinical trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide [159]. As of 29 December 2020, neonatal screening programs for SMA were available in Taiwan, USA, Germany, Belgium, Australia, Italy, Russia, Canada, and Japan [160].
Establishing a neonatal screening system for SMA is essential to initiate treatment in the pre-symptomatic stage and to maximize the therapeutic efficacy.
It should be noted here that neonatal screening for SMA detects homozygous deletion of the SMN1 gene, not intragenic SMN1 mutations.
2. Prevention of Delayed Diagnosis of SMA
In the following discussion, we assume that the disease had already developed before the results of newborn screening were known and that pre-symptomatic treatment was impossible. Even in such cases, newborn screening would still be useful for patients with SMA.
It has long been noted that the diagnosis of SMA tends to be delayed [161]. Before SMA newborn screening started, the diagnosis of SMA type I was often delayed until the sixth month of life [161]. SMA types II and III were diagnosed at 20 and 50 months of age, respectively [161].
However, newborn screening would prevent such delays in diagnosis and allow patients to receive treatment as early as possible. Both pre-symptomatic and symptomatic SMA can now be detected by newborn screening and treated within 3 to 4 weeks after birth.
Kariyawasam et al. reported that patients who underwent SMA newborn screening achieved higher levels of motor function than those who did not undergo newborn screening [162]. They reported the outcomes of therapeutic treatment for symptomatic infants with SMA identified by newborn screening (most infants with symptomatic SMA carried two SMN2 copies). According to their report, newborn screening enabled infants with symptomatic SMA to access therapeutic treatment much earlier than before, resulting in incredibly good outcomes. Kariyawasam et al. demonstrated that with newborn screening followed by early treatment, even patients with SMN1 deletion who have two SMN2 copies could stand with/without assistance or walk with assistance.
In addition, SMA newborn screening is very useful for patients with SMA who have comorbidities. Differential diagnosis for hypotonia is difficult, particularly in the neonatal period. Development of respiratory or other problems in an infant with hypotonia can hamper the suspicion of SMA [163]. In such cases, SMA cannot be diagnosed without newborn screening, and its diagnosis will be delayed by several weeks or months because of the time needed for clinical referrals and investigations.
3. Treatment Algorithm for Patients Identified by Newborn Screening
In 2018, Glascock et al. published a report titled “Treatment Algorithm for Infants with SMA Detected by Newborn Screening” [164]. Newborn screening for SMA detects pre-symptomatic and symptomatic patients. Therefore, this treatment algorithm is not based on their symptoms but instead on their SMN2 copy number.
If patients carry only one SMN2 copy and show any symptoms (probable SMA type 0), initiation of treatment is left to the discretion of the physicians. If patients have two SMN2 copies (probable SMA type I), early initiation of treatment is required because symptoms of SMA type I are expected to develop without treatment. If three SMN2 copies are present (probable SMA type II or III), early initiation of treatment is required because symptoms of SMA type II or III are expected to develop without treatment.
If patients carry four or more copies (probable SMA type III or IV), early initiation of treatment may not be necessary, but the progress should be monitored carefully and treatment initiated later in life, when signs of SMA development are observed.
In 2020, however, the same group published a revised version of the above algorithm [165]. According to the revised version, even if the SMN2 copy number is four or more, the patient should be treated as soon as possible. With early treatment, the disease would be mostly eradicated in pre-symptomatic patients with four SMN2 copies. In addition, when the SMN2 copy number is four or more, the copy number is difficult to accurately measure (methodological problem in screening).
In an SMA newborn screening pilot project in Germany conducted by Müller-Felber et al., 278,970 infants were screened from January 2018 to November 2019, and 38 positive cases with a homozygous SMN1 deletion were detected. Of these cases, 40% had four or more SMN2 copies [166]. The incidence of homozygous SMN1 deletion was 1:7350. Of the 15 children with SMA who had 4 SMN2 copies, 1 child developed physical signs of SMA by the age of 8 months. Reanalysis of the SMN2 copy number using a different test method revealed three copies.
According to the follow-up to the above report [167], two families with newborns with four SMN2 copies reported during follow-up that the respective 5-year-old and 6-year-old brothers had unclear motor symptoms; both of them showed some walking disturbance at 3 years of age. In the two screened index patients, the start of treatment within the first year of life irrespective of the clinical status is under discussion with the parents. At present, immediate treatment might be recommended for patients with SMA detected during newborn screening, regardless of their SMN2 copy number.
4. Obstacles to Implementation of Newborn Screening for SMA
As mentioned above, effective therapies with new drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been introduced in the clinical setting. However, this is only practiced in a limited number of countries worldwide [160]. Despite the appearance of these new drugs, many countries have neither introduced new drugs, nor implemented newborn screening for SMA.
In many countries, the high cost of the new drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) hampers introduction of new treatments for SMA and/or implementation of newborn screening for SMA. People believe that newborn screening for SMA needs to be coupled with access to treatments with expensive drugs. To establish a national consensus on implementation of newborn screening for SMA, accurate and persuasive cost–benefit data of SMA newborn screening followed by treatment with new drugs should be collected in individual countries [160].
However, the high cost of drugs is not the only obstacle to the implementation of newborn screening for SMA. Low public awareness of SMA and stigmatization against SMA may also be major obstacles [168]. A recent study in Japan, where newborn screening for SMA is not yet widespread, found that many Japanese people have very limited knowledge of SMA and its new treatments [169]. The result suggested that raising public awareness of SMA should be the first step towards establishing a national consensus on implementing newborn screening for SMA in each country. In addition, along with raising public awareness of SMA, social issues regarding stigmatization or genetic discrimination against SMA patients or SMA-screen-positive infants and their families should be overcome in any country.
This entry is adapted from the peer-reviewed paper 10.3390/ijms241511939
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