Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening

Abstract

The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs.Conclusions: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. What is Known:• The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease.• The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period. What is New:• Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients.• Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

“…To date, together with our six newly described patients, a total of 44 patients carrying c.859G>C have been reported worldwide, including a patient recently detected by newborn screening [ 21 , 22 , 23 , 25 , 31 , 32 , 33 , 34 ]. In general population databases, the c.859G>C variant is reported at a frequency of approximately 0.3% with 132 homozygotes detected [ 26 ].…”

Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis

“…Six patients (all men, 40%, figure 2B) were symptomatic or showed signs suggestive of disease onset at the first visit; the clinical details of these patients have already been reported 12. The median age at the diagnosis of SMA was 6 days of life (range: 5–9, excluding the child with late diagnosis); the turnaround time of the confirmatory test was 1–3 working days; the family was provided with an official report at a median age of 11 days (range: 7–21 days, figure 1).…”

“…Patients with two SMN2 or three copies were treated immediately; patients with SMN2 of > 4 were included in a strict clinical follow-up to detect the first signs of the disease (figure 1). 12 According to Italian law, the costs of allowed DMTs are covered by a dedicated national fund for innovative drugs for 3 years following the registration; subsequently, the costs are covered by the regional governments following hospital prescription.…”

Recommendations for Interpreting and Reporting Silent Carrier and Disease-Modifying Variants in SMA Testing Workflows

“…Others have suggested that disease modifier variant testing is also important to further refine the likely prognosis for SMA patients identified through NBS with two or three copies of SMN2 [ 17 ]. As NBS programs and our understanding of the intersection of screening and treatment continue to expand, it is likely that NBS testing will move toward providing as much genetic information as possible to maximize treatment benefits in newborns with SMA [ 41 ]. As the complexity of NBS is increasing, genetic programs in newborns should come along with adequate pre-test genetic counseling to provide more precise information to the families.…”