An atypical phenotype of a patient with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD 1).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive disease characterized by infancy-onset diaphragmatic palsy and symmetrical distal muscular weakness. SMARD1 is caused by loss-of-function mutations in IGHMBP2 gene. In this article, we report a male SMARD1 patient with two compound heterozygous mutations (NM_002180.2: c.688C > G; p.(Gln230Glu)) and (NM_002180.2: c.1737C > A; p.(Phe579Leu)), one of which (c.688C > G; ClinVar accession: SUB3344743: SCV000612189) is novel. He suffered from diaphragmatic palsy and distal muscular weakness from 6 months of age. His lower limbs were at first in hypertonia, and then gradually progressed into hypotonia. More interestingly, bronchoscopy has shown the diffuse tracheobronchomalacia, which had been reported only once in a SMARD1 patient who also had the same mutation (c.1737C > A) as our patient. We constructed the model of IGHMBP2 and mapped both mutations in the structure to analyze the structural impact of both mutations (c.688C > G and c.1737C > A) on the IGHMBP2 protein, which showed that mutation c.688C > G reduces greatly the stability of domain 1A of IGHMBP2, while the structural impact of c.1737C > A is not extensive.