IMPORTANCIA DEL DIAGNÓSTICO MOLECULAR RÁPIDO PARA ENFERMEDADES GENÉTICAS CON TRATAMIENTO

Figure 1. Result of MLPA of the patient´s DNA with suspected AME type I. A homozygous deletion (exons 7 and 8) is observed of SMN1 gene (0 copies), as well as four copies for the SMN2 gene. Thus, the diagnostic suspicion is confirmed.

It is presented the diagnosis of Spinal Muscular Atrophy (AME in Spanish language) performed in the Molecular Genetics laboratory by means of an MLPA study (Multiplex Ligations Probe Amplification) by SALSA MLPA-P060-B2 (MRC-Holland®, Netherlands), furthermore SALSA MLPA-P021 is used to confirm the diagnosis(1). This method allows us to know the copy number of the survival genes of the motor neuron (SMN1 and SMN2) in a fast and reliable way (95% sensitivity and 100% specificity).

At present this diagnostic method is important due to the fact that there is a new treatment for SMA type I and II. The drug Spirinza®(2) consists of an antisense oligonucleotide that blocks the region of intron 7 of the SMN2 gene, this facilitates the activation of exon 7 of SMN2 in the mRNA of SMN2, generating a functional protein.

AME is a neuromuscular disease that is caused by the degeneration of alpha spinal cord motor neurons. It presents an autosomal recessive pattern of inheritance and it has been estimated that the annual incidence of 1/6.000 to 1/10.000 births and a carrier frequency of 1/40 – 1/60 individuals(3). SMN protein is encoded by two genes located on chromosome 5q13.2 (SMN1 and SMN2) and involves in the normal movement of muscles and control of limbs, abdomen, head and neck. The SMN1 gene produces a stable SMN protein, whereas the SMN2 gene differs from SMN1 at nucleotide c.840 C>T, this fact generates a new splicing site, and therefore a small proportion of unstable SMN protein that does not contain the exon 7 is created(4)(5). 95-99% of AME patients lack both copies of the SMN1 gene due to a deletion in homozygosis or a gene conversion of SMN1 in SMN2.

According to a Consensus of Standards document published in “Journal of Child Neurology”(6), AME is classified by the time the symptoms, the muscle activity achieved, and the survival gained by the patient into 4 subtypes: AME-I (age of onset: 0-6months, never sit independently), AME-II, AME-III and AME-IV.

We present the case of a female (4 months old) who presented hypotonia, developmental delay, normal metabolic screening and electromyography with a result compatible with SMA. The pediatrician requested the genetic diagnosis to confirm the disease and start the intrathecal treatment.

The study of AME type I through MLPA proved a quick and reliable way of confirming the diagnosis, specific treatment and identification of carriers.