Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1

Abstract

Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans.

Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy

“…In particular, some cases of CHN present with defects in respiration, swallowing and early death (17). Respiratory failure may be caused by central or peripheral mechanisms, such as impaired respiratory drive (18), or peripheral dysfunction or degeneration of NMJs (19). Recently, it was reported that Tr J heterozygote mice, similar to other animal models of CMT1, show axonal degeneration and denervated NMJs (20, 21).…”

Distal Spinal Muscular Atrophy: An Overlooked Etiology of Weaning Failure in Children with Respiratory Insufficiency

“…Future studies are needed to define novel treatment strategies. [20][21][22] In conclusion, spinal muscular atrophy with respiratory distress type 1 is an unusual type of SMA with respiratory failure and an ominous prognosis. It is of the utmost importance for pediatric intensivists to keep this life-threatening diagnosis in mind in infants dying with undetermined respiratory illness, weaning failure, or sudden death.…”

Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2

“…In addition, he had a second homozygous variant c.861C>G, which has been reported with an allele frequency of 0.0033 in the South Asian population in the ExAC database. Since SMARD1 is recognized as an extremely rare disorder [16], the relatively high allele frequency of the c.861C>G variant indicates it is a non-pathogenic rare genetic variant. In any case, the c.861C>G is not expected to have an impact on IGHMBP2 in Patient 1, because the c.2T>C variant likely abolishes protein production.…”

“…Typically SMARD1 patients die within the first year of life due to respiratory failure [4,10,11]. However, the disease severity in SMARD1 may be variable, and juvenile onset of respiratory distress [12][13][14][15] with survival up to 20 years has been reported [14,16]. At the mild end of the IGHMBP2 mutation disease spectrum, patients present with CMT2S, a sensorimotor axonal polyneuropathy, usually with less pronounced neurophysiological changes compared to SMARD1, relatively spared respiratory function, and longer survival [1,15,17].…”