Case reportInfantile-onset spinal muscular atrophy with respiratory distress-1 diagnosed in a 20-year-old man
Introduction
Spinal muscular atrophy with respiratory distress (SMARD1; MIM#604320) is a rare infantile neuromuscular disorder that presents with diaphragmatic paralysis and a length-dependent polyneuropathy [1], [2]. Also known as autosomal-recessive distal spinal muscular atrophy 1 or distal hereditary motor neuronopathy type 6, this disorder is caused by mutations in the IGHMBP2 gene, which resides on chromosome 11q13.3 and encodes the immunoglobulin μ-binding protein 2 [3]. A member of the DEXDc DEAD-like superfamily of DNA/RNA helicases, IGHMBP2 is thought to function in transcriptional activation and/or associates with pre-messenger RNA (mRNA) splicing complexes [4].
Initially described as an unusual variant of spinal muscular atrophy (SMA; MIM#600354), SMARD1 has now been recognized to have its own unique phenotype. Features include decreased fetal movements, oligohydramnios, low birth weight, distal muscular atrophy, foot/finger deformities, and diaphragmatic dysfunction resulting in the need for ventilation prior to 13 months of age [2], [5]. The numerous individuals reported with SMARD1 [2], [3], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14] presented in a fairly homogenous fashion. A similar phenotype is found in the neuromuscular degeneration (nmd) mouse, a spontaneously-generated model with mutations in Ighmbp2. These mice present with a motor neuron disease that is fatal by 3–4 months of age [15]. Interestingly, neuron-specific rescue of Ighmbp2 expression revealed that nmd mice also exhibit a skeletal myopathy and dilated cardiomyopathy [4], [9], [16]. The cardiomyopathy has not been seen in humans to date. Most reported SMARD1 patients have been under the age of 10 and so the disease course and prognosis for adolescence and young adulthood have not been documented. We present a recently diagnosed 20 year-old male with infantile-onset SMARD1 requiring ventilation since 4 months of age.
Section snippets
Case report
A 20 year-old male of non-consanguineous parentage presented to the NIH Undiagnosed Diseases Program with a history of infantile-onset distal weakness, right hemi-diaphragmatic paralysis, and ventilator dependence. In childhood, he developed a length-dependent progressive sensory-motor neuropathy associated with loss of sensation, muscular denervation and atrophy. He has remained ventilator dependent since age 4 months and had no functional motor control except for facial expression, shoulder
Discussion
SMARD1 is an autosomal-recessive neuromuscular disorder due to mutations in IGHMBP2. This protein is thought to be involved in transcriptional activation and pre-mRNA processing [9], [15]. In most cases, alteration of IGHMBP2 function results in infantile-onset of distal weakness and respiratory failure requiring ventilatory support, although some cases of juvenile-onset SMARD1 have been reported [10]. To date, most cases of infantile-onset SMARD1 have resulted in lethality in the first decade
Acknowledgements
The staff of the Undiagnosed Diseases Program were all instrumental in this work and we thank them for their help and efforts. Additional thanks to Barrington Burnet for critical review of the manuscript. We would like to acknowledge the hard work and generosity of the patient, his family, and his caregivers. TMP, DA, GG, CJT, CT, and WAG were supported by the NIH Undiagnosed Diseases Program, National Institutes of Health.
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