Neonatal screening for spinal muscular atrophy: A pilot study in Brazil

Abstract

Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In Brazil, the National Neonatal Screening Program tests for six diseases, with a new law issued in 2021 stating that it should incorporate more diseases, including SMA. In the present study, dried blood spot (DBS) samples collected by the Reference Services of Neonatal Screening of RS and SP, to perform the conventional test were also screened for SMA, using real-time PCR, with SALSA MC002 technique. A total of 40,000 samples were analyzed, enabling the identification of four positive cases of SMA, that were confirmed by MLPA. Considering our sampling, Brazil seems to have an incidence comparable to the described in other regions. This work demonstrated that the use of the MC002 technique in samples routinely collected for the conventional NBS program is suitable to screen for SMA in our conditions and can be included in the expansion of the neonatal screening programs.

Systematic Review of Newborn Screening Programmes for Spinal Muscular Atrophy

“…The review identified 37 cohort studies of newborn screening for SMA [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. No RCTs of newborn screening were identified.…”

“…Cohort studies relating to newborn screening programmes for SMA were identified from the following 17 countries ( Table 1 ): the UK [ 9 ], Belgium [ 10 , 11 , 12 ], Germany [ 13 , 14 , 15 , 16 , 17 , 18 ], Italy [ 19 , 20 ], Latvia [ 21 ], Portugal [ 22 ], Poland [ 23 ], Ukraine [ 24 ], Norway [ 25 ], Australia [ 26 , 27 , 28 , 29 ], the USA, Canada [ 30 , 31 , 32 ], Brazil [ 45 ], Japan [ 46 , 47 , 48 , 49 , 50 ], Taiwan [ 51 , 52 ], China [ 53 , 54 , 55 ] and Russia [ 56 , 57 ]. The USA screening programmes were reported for several US states: California [ 33 ], Georgia [ 34 ], Kentucky [ 35 ], Massachusetts [ 36 , 37 ], New York [ 38 , 39 , 40 ], North Carolina [ 41 ], Wisconsin [ 42 ], Utah [ 43 ] and Ohio [ 44 ].…”

“…This confirmatory testing, rather than the various tiers of screening on the initial DBS, was considered the reference standard within this review when determining test accuracy. Methods of confirmatory testing included the following (some studies used more than one method): MLPA ( n = 17) [ 10 , 13 , 20 , 21 , 23 , 26 , 29 , 32 , 41 , 45 , 46 , 47 , 49 , 52 , 53 , 56 , 57 ], PCR ( n = 5) [ 21 , 33 , 44 , 46 , 57 ], ddPCR ( n = 3) [ 25 , 41 , 49 ], sequencing ( n = 3) [ 25 , 55 , 56 ], restriction fragment length polymorphism PCR (RFLP-PCR, n = 1) [ 19 ], analysis of splicing variants ( n = 1) [ 19 ], or the method was not reported ( n = 15). The three studies which used cohorts of anonymised DBS samples [ 44 , 54 , 55 ] could not conduct confirmatory testing on a new blood sample and relied instead on the second-tier testing of screen-positive cases using the original DBS samples.…”

“…This was most commonly conducted on a new blood sample in the specialist centre, but it was also conducted on the DBSs in some studies ( Table 1 ). Again, a variety of methods were reported for this, including the following (some studies used more than one method): MLPA ( n = 11) [ 10 , 13 , 21 , 30 , 32 , 45 , 46 , 47 , 52 , 53 , 56 ], ddPCR ( n = 7) [ 25 , 26 , 33 , 38 , 42 , 49 , 52 ], qPCR ( n = 4) [ 19 , 26 , 33 , 38 ], sequencing ( n = 3) [ 10 , 25 , 36 ], or the method was not reported ( n = 18).…”

“…Due to the low prevalence, a small number of false-positives could substantially reduce the positive predictive value. Where this could be calculated, it was 100% in 15 studies [ 10 , 13 , 18 , 19 , 21 , 30 , 33 , 38 , 40 , 42 , 44 , 46 , 53 , 56 , 57 ], and in the remainder, it was 4% [ 55 ], 17% [ 49 ], 38% [ 34 ], 50% [ 41 ], 69% [ 35 ], 80% [ 45 ], 83% [ 32 ], 90% [ 36 ], 92% [ 17 ], 93% [ 43 ] and 95% [ 26 ]. A lower positive predictive value means that a study had more false-positives.…”