Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Cell Mol Life Sci. 2020 Sep;77(17):3351-3367. doi: 10.1007/s00018-020-03492-0. Epub 2020 Mar 2.


Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.

Keywords: Distal hereditary motor neuropathy type 6; Gene therapy; IGHMBP2; Motor neuron disease; Oligonucleotides; SMARD1.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell- and Tissue-Based Therapy
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Genetic Therapy
  • Humans
  • Muscular Atrophy, Spinal / complications
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / pathology*
  • Muscular Atrophy, Spinal / therapy
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / transplantation
  • Respiratory Distress Syndrome, Newborn / complications
  • Respiratory Distress Syndrome, Newborn / genetics
  • Respiratory Distress Syndrome, Newborn / pathology*
  • Respiratory Distress Syndrome, Newborn / therapy
  • Ribosomes / chemistry
  • Ribosomes / metabolism
  • Survival of Motor Neuron 1 Protein / genetics
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • IGHMBP2 protein, human
  • SMN1 protein, human
  • Survival of Motor Neuron 1 Protein
  • Transcription Factors

Supplementary concepts

  • Spinal muscular atrophy with respiratory distress 1