SEQC Spanish Society of Laboratory Medicine

Spinal muscular atrophy (SMA) is a rare and progressive genetic neuromuscular disease characterized by irreversible degeneration of motor neurons, which causes symmetric proximal weakness and progressive muscular atrophy of muscle groups, affecting motor functions and, in the most serious forms, breathing and swallowing.

The approximate prevalence is 1 in 10,000 live newborns. In Spain, it is estimated that there are 1,500 families that have or have had patients affected by this disease, which is classified into four groups (I-IV) based on severity, age of onset of symptoms, and clinical evolution. Types I and II are the most serious phenotypes, and at the same time, the most frequent. Type I presents before 6 months of life with hypotonia, flaccidity, symmetrical muscle weakness and absence or decrease of deep tendon reflexes, causing death or the need for permanent assisted ventilation in the first two years of life in more than 90% of cases if no treatment is received.

In recent years, the development of new molecular-based therapies has opened possibilities for the treatment of some genetic diseases, including SMA. The effectiveness of these SMA-modifying therapies is significantly higher when treatment is started in the presymptomatic phase, as recent clinical trials have shown. The time from birth to the onset of symptoms is a window of opportunity to detect the disease early and prevent damage to motor neurons. This is why the detection of this disease is being incorporated into neonatal screening programs.

For this reason, on April 8 the Spanish Society of Laboratory Medicine, with the sponsorship of Novartis, analysed the 'Advances in neonatal screening: a new horizon for those born with spinal muscular atrophy', within the framework of its virtual training project SEQC^ML ACADEMY, launched recently.

Neonatal screening is of vital importance, since early intervention can stop the progression of the disease in children born with spinal muscular atrophy and save lives, according to the moderators of the course, Doctors Raquel Yahyaoui, of the Metabolopathies Laboratory of the Regional University Hospital (HRU) of Malaga, and Hugo Rocha, of the Neonatal Screening, Metabolism, and Genetics Unit of the Department of Human Genetics of the National Institute of Health- Doctor Ricardo Jorge of Oporto, Portugal.

In the same vein, Dr. Rocío Calvo Medina, neuropaediatrician and researcher in Rare Diseases for 12 years at HRU Málaga and participating speaker in the seminar, stressed that if for almost all diseases early diagnosis is important for avoiding unnecessary tests and saving time and suffering for families, in SMA it is even more so, since the available treatments can completely modify the progression of the disease. This can allow for preservation and even improvement of the motor situation of these children.

As this expert explained, in the studies that have been carried out with these treatments, it has been seen that the early initiation of disease-modifying therapy after diagnosis is correlated with a much more favourable motor and vital prognosis. For this reason, paediatricians, neurologists, and other specialists are currently being activated and trained to quickly identify potential symptoms of concern, and neonatal screening studies are being launched to be able to diagnose patients before the development of symptoms.

Professionals who have lived through the stage prior to the development of these therapies, she assured, know what it is like to see the disease progress without hope. The effectiveness of the treatments is evident in symptomatic patients, in whom hope, quality and vital functionality improve. But in presymptomatic patients, the results are spectacular, preserving a motor function close to normal in the studies carried out, and a future life expectancy that we could not imagine a few years ago.

These therapies pave the way for future treatment possibilities in many genetically based diseases. In all of them, early diagnosis will allow more efficient results, so developing presymptomatic diagnosis techniques should be an objective within the approach to the global care of all these pathologies. Multidisciplinary collaboration at all levels of care (diagnosis, treatment, social integration, and support for families) is essential for all these patients, highlighted Dr. Calvo.

Heterogeneous implementation of screening

The experiences in the implementation of neonatal screening for spinal muscular atrophy are varied, according to the session moderators. In 2018, for example, it was recommended in the US and is currently being carried out in 34 American states, which represents a coverage of 69% of newborns. In Europe, the process of introducing this screening is a little slower and more heterogeneous, they noted. The first European pilot study was carried out in southern Belgium between 2018 and 2020 and obtained good results, so in 2021 screening has been officially incorporated in this region. Some countries such as Germany, the Netherlands, Poland, Slovenia, Norway, and Serbia have already approved its implementation, and there are active pilot studies in regions of Italy and Russia.

Recently, a committee of experts that includes Dr Raquel Yahyaoui, a SEQC^ML member, published a white paper to promote neonatal screening for SMA in Europe. This initiative, promoted by the European Alliance for Newborn Screening in Spinal Muscular Atrophy (an organization that includes patient associations, scientific societies and institutions, academic networks, and pharmaceutical and health technology companies), aims to ensure that neonatal screening for SMA is established throughout Europe by 2025.

Although as of yet the Spanish Ministry of Health, Consumption and Social Welfare has not evaluated the inclusion of SMA in neonatal screening programs at the national level, Drs Yahyaoui and Rocha believe that the development of methodologies that allow for simultaneous screening for SMA and for severe combined immunodeficiency (SCID) will accelerate its evaluation in Spain, since favourable reports have already been published for SCID that support the clinical effectiveness and cost effectiveness of neonatal screening.

The start of pilot studies of neonatal screening for SMA in Andalusia and the Valencian Community is planned for 2021, and in the coming years it is very possible that other Autonomous Communities in Spain will join this effort. These experts stressed that their hope is that the results obtained from these pilot studies will help to promote its implementation in Spain.

Advances in neonatal screening

Currently, neonatal screening consists of the detection, using molecular biology techniques, of a very prevalent mutation that causes the disease in approximately 95% of cases (of the homozygous deletion of exon 7 of the SMN1 gene). This genetic analysis could be performed on the same dried capillary blood specimen on paper that is currently collected in neonatal screening programs.

In the last decade, various methods have been developed to perform neonatal screening for SMA, such as that based on LAMP (loop-mediated isothermal amplification) technology or real-time PCR, the latter being the most commonly used method. These techniques are very reliable as they have a high sensitivity and specificity (95/100%) and can be automated to adapt them to the work needs of neonatal screening laboratories. In addition, some of these methods have the advantage of allowing simultaneous determination of severe combined immunodeficiency (SCID) screening, concluded Drs Yahyaoui and Rocha.