Spinal muscular atrophy with respiratory distress type 1 (SMARD1) –  IGHMBP2 gene 

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as diaphragmatic spinal muscular atrophy, is a hereditary disease that usually manifests in childhood and produces muscle weakness and respiratory failure. The first manifestations of this disease are difficult and noisy breathing, weak crying, feeding problems and recurrent episodes of pneumonia. Usually, between 6 weeks and 6 months of age, affected infants show an inability to breathe due to diaphragm paralysis. Shortly after respiratory failure, affected people develop muscle weakness in the distal muscles, which extends to all muscles over a period of approximately 2 years. Some individuals may maintain a low level of muscle function, while others completely lose the ability to move. In addition, some affected children develop kyphoscoliosis (abnormal curvature of the spine). Generally, after the first year of life, individuals with SMARD1 may lose their deep tendon reflexes. Other features of this pathology may include a reduction in painful sensitivity, hyperhidrosis (excessive sweating), loss of bladder and bowel control, and arrhythmias.

This process is due to mutations in the IGHMBP2 gene (Immunoglobulin Mu DNA Binding Protein 2), located on the long arm of chromosome 11 (11q13.3). This gene encodes an enzyme called immunoglobulin µ-linked to protein 2 (IGHMBP2). This enzyme acts as a helicase and binds to particular regions of the DNA and temporarily unwinds the two spiral strands of these molecules. When a cell prepares to divide and form two cells, the chromosomes double so that each new cell gets a complete set (a pair) of chromosomes. The copying process involves unrolling the DNA so that it is accessible and can be copied. This mechanism is also involved in the production of RNA. In addition, it is considered that the IGHMBP2 protein may be involved in the production of proteins from RNA by translation too. The IGHMBP2 protein is produced in cells throughout the body.

More than 60 mutations in the IGHMBP2 gene have been identified that produce spinal muscular atrophy with type 1 respiratory distress (SMARD1). Most mutations change amino acids in the IGHMBP2 protein and disturb the functionality of this protein. Loss of helicase function prevents the copying of DNA and the production of RNA and other proteins. These problems mainly affect the alpha-motor neurons that control muscle movements. Although the exact mechanism is unknown, an alteration in the activity of the IGHMBP2 protein causes these neurons to become damaged and die over time, resulting in respiratory difficulties and progressive muscle weakness in children with SMARD1.

This disease is inherited with an autosomal recessive pattern, that is, both copies of the IGHMBP2 gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), by means of the complete PCR amplification of the exons of the IGHMBP2 gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).