X-linked infantile spinal muscular atrophy (XLSMA) – UBA1 gene
X-linked infant spinal muscular atrophy (XLSMA) is a condition characterized by severe progressive muscle weakness and areflexia. Signs and symptoms related to this process generally include arthrogryposis (limitation of joint movement), respiratory problems due to muscle weakness in the chest, micrognathia (small jaw), scoliosis or kyphosis (deviations of the spine) and cryptorchidism (incomplete descent of one or both testicles). In severe cases, affected newborns are born with fractured bones. In addition, children with XLSMA generally do not survive after early childhood, due to respiratory failure. However, some cases survive until adolescence.
Mutations in the UBA1 or UBE1 gene, (ubiquitin-like modifier-activating enzyme 1), located in the short arm of the X chromosome (Xp11.3), participate in the development of XLSMA. This gene is responsible for encoding ubiquitin for the activation of the enzyme E1. This enzyme is involved in a protein degradation process. The ubiquitin E1 enzyme activation center is part of the ubiquitin-proteosome system, which is responsible for degrading unnecessary proteins. Therefore, the ubiquitin-proteosome system acts as a cell quality control system.
At least 4 mutations of the UBA1 gene have been identified in individuals affected by XLSMA. In each of these mutations a nucleotide change occurs in exon 15 of the UBA1 gene. Two of the mutations (1617G> T and 1639A> G) are believed to result in an enzyme with impaired function. A third mutation (1731C> T) causes a decrease in the activity of the UBA1 gene, which decreases the amount of encoded enzyme. A functional enzyme deficiency can disrupt the protein degradation process. An accumulation of proteins in cells can cause the cell to die. The motor neurons that control muscle movement are very sensitive to protein accumulation damage.
X-linked infantile spinal muscular atrophy is inherited with an X-linked recessive pattern. The gene associated with this condition is found on the X chromosome, one of the two sex chromosomes. In men (who have only one X chromosome), an altered copy of the gene in each cell is sufficient to express this process. In women (who have two X chromosomes), a mutation would have to occur in both copies of the gene for the disease to express itself. Because women are unlikely to have two altered copies of this gene, men are affected by X-linked recessive processes much more frequently than women. A characteristic of the X-linked inheritance is that parents cannot transmit X-linked traits to their children.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with X-linked infantile spinal muscular atrophy (XLSMA), by means of the complete PCR amplification of the exons of the UBA1 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).