Newborn Screening for SMA - Results after Two Years of a German Pilot Project

Abstract

Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since early diagnosis and treatment are essential to prevent major disability, newborn screening (NBS) has come into focus.

Methods: The pilot project in two federal states of Germany started in January 2018 and is still ongoing. Genetic screening via PCR of the SMN1 gene from dried blood spots was implemented in the routine NBS structure.  Follow-up included neuropediatric and neurophysiological examinations, CHOP INTEND and HINE-2.

Findings: Among 297,163 screened children, 43 cases of SMA were identified resulting in an íncidence of 1:6910. Two SMN2 copies were identified in 39.5%, 3 SMN2 copies in 21% and 4 SMN2 copies in 39.5% of patients.  In 21 patients with ≤3 SMN2 copies, treatment with Nusinersen was started within 14-39 days after birth. To date, all presymptomatically treated patients have remained asymptomatic. 41% of patients with 2 SMN2 copies had already had early, mostly subtle signs of disease such as ulnar CMAP <1 mV or hypotonia of the legs in the first month of life. These patients gained motor function and reached motor milestones, however with a certain delay. None developed respiratory symptoms. Two untreated patients with 2 SMN2 copies died. Three untreated patients with 3 SMN2 copies, one of whom was initially diagnosed with 4 SMN2 copies by a different method, developed proximal weakness at ages 8-11 months. Two siblings of babies with 4 SMN2 copies were identified with a missed diagnosis of SMA type 3.

Interpretation: Identification of newborns with infantile SMA improves neurodevelopmental outcomes enormously.  It should be introduced in all countries where therapy is available. Detection of SMA via NBS did not increase the expected incidence rate in Germany. Early treatment of patients with 4 SMN2 copies should be considered.

Funding: The Cystinosis Foundation funded the pilot project between January 2018 and May 2019.

Declaration of Interests: Astrid Blaschek, Bernhard Olgemöller, Erik Harms, Katja Eggermann and Uta Nennstiel have nothing to declare. Siegfried Burggraf, Wulf Röschinger, Jürgen Durner, Ludwig Czibere and Marc Becker are employed by / the owner of a commercial entity (Laboratory Becker and colleagues MVZ GbR, Führichstraße 70, 81871 München, Germany) Dieter Gläser is employed by / the owner of a commercial entity (Genetikum ®, Wegenerstr. 15, 89231 Neu-Ulm, Germany) Katharina Vill received travel and speaker honoraria from Biogen. Oliver Schwartz is serving on a scientific advisory board for Avexis and received travel and speaker honoraria from Biogen. Heike Kölbel is serving on a scientific advisory board for Avexis and received travel and speaker honoraria from Biogen and Sanofi-Aventis. Ulrika Schara is serving on a scientific advisory board or data safety monitoring board for Biogen, Avexis and Novartis Brunhilde Wirth is serving on a scientific advisory board or data safety monitoring board for SMA Europe and received travel and speaker honoraria from Biogen Wolfgang Müller-Felber is serving on a scientific advisory board for Biogen, Avexis, PTC, Sanofi-Aventis, Roche and Cytokinetics and received travel and speaker honoraria from Biogen, Avexis, PTC and SanofiAventis.

Ethics Approval Statement: The study was approved by the local ethics committee of the participating universities (project no. 18-269).