We use cookies to offer you the best experience on our site. You can find out more about the cookies we use or disable them in the Cookie settings
Rare diseases
Spinal Muscular Atrophy in Newborns
History
The management of anterior spinal muscular atrophy (SMA) in newborns has evolved significantly over the last few years. Different trials to increase the production of deficient SMN protein in SMA have consistently shown efficacy inversely proportional to disease duration.
Therefore, implementation of a spinal muscular atrophy screening program in newborns has quickly become medical-economic evidence in many countries.
Spinal Muscular Atrophy Prevalence by Geographic Region
Overall, the prevalence of spinal muscular atrophy is estimated at 1 in 12,000 individuals. However, it appears higher in Caucasian populations (1/8,000), whereas Hispanic and African populations seem less affected (1/19,000).
Clinic
Spinal muscular atrophy is a rare neuromuscular disease characterized by progressive muscle weakness caused by premature loss of anterior motor neurons of the spinal cord and brainstem nuclei.
The disease is associated, in almost 95% of cases, with a homozygous deletion of exon 7 of the SMN1 gene, a gene located on chromosome 5 (5q12.2-q13.3). This deletion hinders SMN protein synthesis, which is essential for survival of motor neurons. Approximately 5% of patients with SMA carry a heterozygous deletion of exon 7 from SMN1 combined with a point mutation in the second allele (i.e., Composite heterozygous).
The clinical severity of SMA is closely linked to the presence of a second gene, SMN2. This pseudogene, having more than 99% homology with the SMN1 gene, only produces approximately 10% functional SMN protein. The phenotype of SMA patients is thus found to be less severe and more slowly evolving as the number of copies of the SMN2 gene is high (Table 1).
Table 1. SMA Subtype Spinal Muscular Atrophy Classification
| Type | Number of SMN2 copies expected* | Age at onset of first clinical signs | Life expectancy | Motor phenotype |
|---|---|---|---|---|
| SMA 0 | 1 | Prenatal | < 6 months |
Severe neonatal hypotonia, early respiratory distress |
|
SMA I Werdnig-Hoffmann disease |
2-3 |
< 6 months |
Typically < 2 years |
Sitting position not acquired, variable ingestion difficulty, requiring respiratory support |
| SMA II | 3 | 6-18 months |
70% are alive at 25 years |
Maintains independent sitting position, no gait acquisition |
|
SMA III Kugelberg-Welander disease |
3-4 | >18 months | Normal |
Independent walking then progressive motor loss |
| SMA IV | >4 | Adult | Normal | Normal |
| * Discrepancies between expected SMN2 copy number and patient phenotype may be multiple: cryptic mutation, partial deletion or hypermethylation of SMN2 gene, modifying or epigenetic effect of other unidentified genes at this time. Thus, rare SMA patients with 4, or even 5 SMN2 copies have a type I phenotype, and conversely, patients with 2 SMN2 copies may manifest the first symptoms very late. | ||||
Screening for Spinal Muscular Atrophy in Newborns
A PCR-quantitative method (qPCR) dedicated to identifying homozygous exon 7 deletions of SMN1 gene.
Composite heterozygous individuals (i.e., carrying SMN1 exon 7 deletion on one allele and point mutation on second allele) are not screened by this screening test. The method is also not intended to identify heterozygous SMN1 exon 7 deletion subjects.
Treatment for Types of Spinal Muscular Atrophy
The management of type I spinal muscular atrophy was mostly in the palliative care field.
Recently, however, two clinical trials have demonstrated that a new injectable intrathecal therapy, Nusinersen®, allows patients with SMA type I and type II to significantly prolong their survival for SMA type I and acquire new motor functions for SMA type I and II. The results of these trials were confirmed in older patients, but with less efficacy. Nusinersen is an antisense oligonucleotide that interferes with SMN2 gene splicing. This action restores, from the SMN2 gene, a synthesis of the complete SMN protein. The results of the different therapeutic trials led to the Food and Drug Administration (FDA) and European Medicine Agency (EMA) to rapidly approve the marketing of this new treatment.
At the same time, a gene therapy trial implementing an Adenovirus-Associated-Virus delivering a functional SMN1 copy (i.e., AVXS-101) has also demonstrated remarkable efficacy in patients with SMA type I. This treatment option is now approved by the FDA.
Finally, the efficacy of a splicing modifier (risdiplam) is also assessed across various therapeutic trials in SMA type I and SMA type II. Other approaches to increase muscle mass (antimyostatin) or activate muscle contraction (troponin activator) are also in clinical development.
Heredity
Spinal muscular atrophy is inherited in an autosomal recessive pattern.