RESUMEN
Spinal muscular atrophies are rare genetic disorders most often caused by homozygous deletion mutations in SMN1 that lead to progressive neurodegeneration of anterior horn cells. Ventral spinal root atrophy is a consistent pathological finding in post-mortem examinations of patients who suffered from various subtypes of spinal muscular atrophy; however, corresponding radiographic findings have not been previously reported. We present a patient with hypotonia and weakness who was found to have ventral spinal root atrophy in the lumbosacral region on MRI and was subsequently diagnosed with spinal muscular atrophy. More systematic analyses of imaging studies in spinal muscular atrophy will help determine whether such findings have the potential to serve as reliable diagnostic markers for clinical evaluations or as outcome measure for clinical trials.
Asunto(s)
Región Lumbosacra/patología , Atrofias Musculares Espinales de la Infancia/patología , Raíces Nerviosas Espinales/patología , Columna Vertebral/patología , Atrofia , Humanos , Lactante , Región Lumbosacra/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/patología , Atrofias Musculares Espinales de la Infancia/diagnóstico , Atrofias Musculares Espinales de la Infancia/diagnóstico por imagen , Raíces Nerviosas Espinales/diagnóstico por imagen , Columna Vertebral/diagnóstico por imagen , Proteína 1 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in SMN1 that stops production of SMN (survival of motor neuron) protein. Insufficient levels of SMN results in the loss of motor neurons, which causes muscle weakness, respiratory distress, and paralysis. A nearly identical gene (SMN2) contains a C-to-T transition which excludes exon 7 from 90% of the mature mRNA transcripts, leading to unstable proteins which are targeted for degradation. Although SMN2 cannot fully compensate for a loss of SMN1 due to only 10% functional mRNA produced, the discovery of the intronic splicing silencer (ISS-N1) opened a doorway for therapy. By blocking its function with antisense oligonucleotides manipulated for high specificity and efficiency, exon 7 can be included to produce full-length mRNA, which then compensates for the loss of SMN1. Nusinersen (Spinraza), the first FDA-approved antisense oligonucleotide drug targeting SMA, was designed based on this concept and clinical studies have demonstrated a dramatic improvement in patients. Novel chemistries including phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNAs), as well as peptide conjugates such as Pip that facilitate accurate targeting to the central nervous system, are explored to increase the efficiency of exon 7 inclusion in the appropriate tissues to ameliorate the SMA phenotype. Due to the rapid advancement of treatments for SMA following the discovery of ISS-N1, the future of SMA treatment is highly promising.
Asunto(s)
Exones , Atrofia Muscular Espinal/genética , Empalme del ARN , Animales , Modelos Animales de Enfermedad , Desarrollo de Medicamentos , Terapia Genética/métodos , Humanos , Intrones , Ratones , Atrofia Muscular Espinal/terapia , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Elementos Silenciadores TranscripcionalesRESUMEN
Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Unlike other autosomal recessive diseases, the SMN gene has a unique structure (an inverted duplication) that presents potential therapeutic targets. Although there is currently no effective treatment of SMA, the field of translational research in this disorder is active and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with SMA also offer hope for improved life expectancy and quality of life.