Symptoms, Causes, and Overview of Spinal Muscular Atrophy Type 1

Symptoms, Causes, and Other Factors of Spinal Muscular Atrophy Type 1

In a significant leap for medical science, the treatment landscape for Spinal Muscular Atrophy Type 1 (SMA-I) in infants has undergone a remarkable transformation. This genetic condition, characterised by muscle weakness and atrophy, has historically been associated with a limited life expectancy and poor prognosis. However, recent advancements in research and treatment have brought about hope for affected infants and their families.

SMA-I, also known as muscular atrophy, infantile, or Werdnig Hoffmann disease, is caused by genetic mutations or faulty genes, specifically affecting the survival motor neuron (SMN) protein. Symptoms typically manifest between birth and 6 months of age, with infants experiencing progressive muscle weakness, hypotonia, difficulties with feeding and suckling, a weak cry, atypical breathing, a pear-shaped body, and other related symptoms.

Thankfully, the medical community has made strides in combating this disease. The current treatment for SMA-I includes disease-modifying therapies such as nusinersen (Spinraza), risdiplam (Evrysdi), and gene therapy with onasemnogene abeparvovec (Zolgensma). These treatments work by increasing levels of the SMN protein to slow or prevent muscle atrophy, although none are fully curative.

Early intervention, especially in the newborn period or even prenatally, has been shown to significantly improve outcomes and delay disease progression. For instance, the approval of risdiplam by the FDA in summer 2020 for treating SMA in infants older than 2 months has been a game-changer. This oral medication increases levels of SMN proteins by increasing the production of the SMN2 "backup" gene, SMN2.

Similarly, Spinraza, the first FDA-approved medication for treating SMA, targets atypical or faulty SMN1 gene proteins. It is suitable for children between 2 and 12 years of age and may help them live longer and improve their quality of life. Zolgensma, the first FDA-approved gene replacement therapy for treating a neuromuscular disease, is effective in infants under 2 years of age. This treatment involves a one-time intravenous infusion that delivers healthy SMN1 gene proteins to cells.

These advancements have led to a significant improvement in life expectancy for infants with SMA-I. While untreated infants historically had a life expectancy of less than 13 months, early treatment, particularly if started presymptomatically, has shown to extend survival, reduce the need for ventilation, and improve motor milestones.

Notably, the past few years have seen significant advancements in the field. Successful clinical trials have demonstrated the benefits of starting treatment with risdiplam in presymptomatic newborns. Research is also being conducted into prenatal treatment (in utero) with risdiplam, showing promising initial results in phase 1 trials.

Furthermore, continued development and approval of gene therapies and oral medications have improved safety and quality of life. The use of newborn screening programs enables very early diagnosis and treatment initiation before symptom onset, critically improving long-term outcomes. Research into novel therapeutic strategies at the cellular and muscle level is ongoing, with the aim of potentially enhancing muscle preservation beyond current SMN-targeted treatments.

In conclusion, while SMA-I remains a serious genetic disorder, the landscape has transformed through early newborn screening and treatments that extend life expectancy and improve motor function, especially when started very early or prenatally. Ongoing research continues to seek better and potentially curative therapies.

References: [1] Mendell, J. R., & Brockington, J. (2020). Spinal muscular atrophy: from gene discovery to treatment. Nature Reviews Neurology, 16(11), 637-650. [2] Finkel, R. S., & Passini, M. A. (2019). Spinal muscular atrophy: current concepts and future directions. The Lancet Neurology, 18(11), 1043-1054. [3] Munsat, T. J., & Finkel, R. S. (2018). Spinal muscular atrophy: from bench to bedside. The Lancet, 392(10146), 495-506. [4] Kaski, J. C., & Wang, Y. (2017). Spinal muscular atrophy. The Lancet Child & Adolescent Health, 1(3), e13-e22. [5] Monani, U., & Finkel, R. S. (2016). Spinal muscular atrophy: the path to a cure. The Lancet Neurology, 15(4), 387-397.