Newborn screening for spinal muscular atrophy_Advance assessment of extension of screening to the general population in France

Newborn screening (NBS) is a public health intervention designed to detect certain rare but serious diseases at birth. The objective is to implement appropriate measures before the onset of symptoms in order to prevent or limit the negative consequences of these diseases on the health of children. In France, this screening is carried out as part of a national programme. 

The Haute Autorité de santé (French National Authority for Health, HAS) undertook to assess the relevance of including spinal muscular atrophy in the national NBS programme. 

Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease characterised by progressive muscle weakness. The most severe form can result in the infant’s death before the age of 2 years. Between 2017 and 2021, several gene therapies emerged aimed at limiting or even preventing the development of the disease. Since these treatments need to be administered to infants in the presymptomatic phase to be effective, newborn screening for SMA would make it possible to identify the infants concerned before the onset and irreversible development of symptoms. 

 HAS recommendations 

• Considering the following factors in favour of introducing newborn screening, in particular: the demonstrated seriousness of SMA, especially type I, which is the severest form, the availability of a recognised newborn screening test (qPCR), the vital importance of obtaining timely information enabling rapid treatment before the development of irreversible symptoms, the existence of therapies modifying the natural history of the disease, the individual benefit of early diagnosis, 
• Also taking into consideration the fact that SMA is a rare disease for which it would be very difficult to demonstrate a positive impact of screening on even a very large sample and that only a comprehensive roll-out across the whole country would enable such a demonstration: 
  • the HAS recommends the extending newborn screening for SMA to the general population, using the qPCR technique; 
  • the HAS recommends that for cases of SMA with four or more copies of the SMN2 gene, information and psychological support should be provided to parents and medical monitoring of the infant should be implemented, with a view to rapid management in the event of onset of the first symptoms; 
  • the HAS considers that the introduction of this screening implies that all the steps leading to the initiation of treatment should aim to achieve this no later than one month after birth. To this end, it is essential to adhere strictly to the timeframes for each step in the entire sequence, from screening through to the initiation of treatment; 
  • it will be necessary to ensure that this national programme is harmonised and facilitated across the country, to avoid any regional inequalities. 
    
    

 Implementation methods 

The HAS recommends that: 

• screening for SMA should be introduced, ideally at the same time as screening for SCID, since the same screening technique is used for these two diseases; 
• the addition of SMA to the NBS programme should be performed on the same blood spot card as the other diseases currently screened for and that the card remains available within the regional newborn screening centre to carried out new required tests without delay, if necessary; 
• the blood spot card should be revised to indicate parental consent to genetic screening tests; 
• all the spaces for depositing samples on the blood spot card should be filled to enable screening for all the diseases included in the programme. 
• The organisation will have to be adapted to ensure that all the timeframes are strictly adhered to, in particular those for initiating treatment, an essential condition for the success of screening. 
  
  
  

Timeframes for delivering screening results and the diagnosis 

The HAS recommends that: 

•  maternity units transmit blood spot cards to regional newborn screening centres (CRDN) daily; 
• the screening time enables the diagnosis to be made as soon as possible and no later than 20 days after birth, so that treatment can be initiated as early as possible and no later than 30 days after birth. Although the time taken to initiate treatment takes into account the time required for delivery of the diagnosis, assimilation of information and organisation, it should not exceed the end of the first month after birth, to ensure optimum treatment of the newborn concerned. 
  
  

More specifically, the committee on newborn screening of the FILNEMUS network targets the following timeframes in its NBS screening and management protocol for SMA: 

• target timeframe for notifying parents of the positive result: D7; 
• timeframe for arranging a meeting with the parents: 24 to 48 hours; 
• timeframe for multidisciplinary meeting meeting: within 72 hours following the second consultation; 
• treatment initiation: between D15 and D20. 

Screening algorithm 

The HAS recommends that a validated screening algorithm should be used, in line with the neuromuscular diseases network - FILNEMUS. 

 Infant care protocols 

The HAS recommends that standard care protocols should be defined for infants with SMA, specifying the steps and the need for combined treatment and/or non-medicinal management, if applicable. 

 Training and information 

The HAS recommends that: 

•  extension of NBS to SMA should be accompanied by training of all healthcare professionals involved in NBS. This training should cover both the technical aspects and relational aspects, in particular delivering the information to families; 
• delivery of a positive screening result and the diagnosis should be carried out by an experienced physician, with good knowledge of SMA and its management; 
• families should be offered psychological support by a professional with good knowledge of SMA, from the time of delivery of the diagnosis, including for the parents of infants with four or more copies of the SMN2 gene; 
• that the first information on NBS should be given to parents during pregnancy, at third-trimester antenatal consultations; 
• that information materials should be developed that are adapted to the different publics (in particular, easy read sheets), including parents and future parents, the healthcare professionals involved in NBS and the management of screened patients, families and the general public. 
  
  

Technical means and resources 

• The HAS recommends that sufficient human, material and financial resources be made available for the implementation of this screening, and for follow-up, data feedback and assessment (milestones and final assessment). 
  
  
  

Follow-up and assessment 

• The HAS highlights the importance of the indicators reported in annex I of the order of 28 February 2018, compliance with which will make it possible to evaluate the time taken to obtain the sample, the time taken to transport it, its quality, the time taken to perform the laboratory screening tests, the time taken to deliver the results, the results of NBS, the prevalence of the new diseases screened for recommended here, the performance of the test (false positives, PPV, false negatives), etc. 

 The HAS recommends: 

• checking that introduction of the new genetic screening test does not adversely affect the biochemical screening already in place for other diseases (increase in parent refusals or additional logistical difficulties); 
• proactive monitoring of the parameters for performing this screening and the ensuing management in order to rapidly rectify the various circuits if deviations from the timeframes are observed; 
• that the national SMA France registry, already in place, be linked to the NBS programme in order to improve the completeness and relevance of the recorded criteria. Linking of the registry to the French national health data system (SNDS) should be envisaged in order to collect more data on management of the disease and the associated costs; 
• that all symptomatic SMA patients, corresponding to potential false negatives not detected by NBS due to a point mutation in a gene (approximately 5% of cases), be included in the national registry; 
• that clinical follow-up studies be conducted to assess the long-term efficacy and safety of innovative treatments, depending on the number of SMN2 copies; 
• that medical monitoring of patients with four or more copies of the SMN2 gene be defined and be the subject of a protocol enabling practices to be standardised on a national level (types of test, frequency, etc.) in order to guarantee rapid management in the event of onset of the first clinical signs; 
• that the possibility of treating SMA cases with four or more copies of the SMN2 gene be reassessed in the light of future clinical data relative to the possibility of treating them from birth. 
• This public health guideline is aimed at public policymakers.