Abstract
Pediatric neuromuscular disorders arise from a wide range of etiologies, among which genetic mutations play a major role. These mutations may alter protein function by causing gain of function, loss of function, complete absence of protein expression, or protein misfolding, thereby leading to clinical manifestations and progressive motor deterioration. At present, the management of most inherited neuromuscular disorders is primarily supportive, focusing on early diagnosis, multidisciplinary neurological care, and management of systemic comorbidities to maximize motor function, minimize complications, and prolong survival. With increasing understanding of the functional consequences of genetic alterations and the relationship between genotype and phenotype, targeted therapies have been developed and are increasingly being investigated and implemented to provide optimal interventions and improve survival. Gene-based therapies can generally be categorized into three major strategies: (1) gene augmentation (enhancing gene expression), (2) gene suppression (reducing gene expression), and (3) gene editing. In addition to gene replacement therapies for disorders caused by gene deletions, the CRISPR/Cas9 genome-editing system has emerged as one of the most promising approaches under active investigation. Currently available genetic therapies are designed to treat affected individuals only and are not heritable by subsequent generations. Globally, targeted therapies have become available for several pediatric neuromuscular disorders. Spinal muscular atrophy (SMA) is treated through strategies aimed at increasing SMN2 expression or replacing the SMN1 gene. The U.S. Food and Drug Administration (FDA) has approved nusinersen (2017), onasemnogene abeparvovec (Zolgensma®, 2019), and risdiplam (2020) for the treatment of SMA. Duchenne muscular dystrophy (DMD) has also been treated using exon-skipping antisense oligonucleotides, including eteplirsen (exon 51), golodirsen (exon 53), and viltolarsen (exon 53). Other neuromuscular disorders, including hereditary motor and sensory neuropathies, congenital myasthenic syndromes, and other forms of muscular dystrophy, are also being investigated through targeted therapeutic approaches, with encouraging results demonstrating the potential to improve motor function. In Vietnam, access to targeted therapies for pediatric neuromuscular disorders remains limited because of several barriers, particularly the limited availability of medications, high treatment costs, and restricted access to international clinical trials. Nevertheless, a number of children with spinal muscular atrophy and Duchenne muscular dystrophy have received targeted therapies through international clinical trials or humanitarian drug access programs at Children's Hospital 2, the Neurology Center of the Vietnam National Children's Hospital, and several other medical institutions. In summary, targeted treatment for inherited pediatric neuromuscular disorders remains a major clinical challenge. Nevertheless, therapeutic strategies directed at correcting or modifying the underlying genetic defects have already transformed the management of several disorders and ushered in a new era of precision medicine for pediatric neuromuscular diseases.
