Newborn screening for spinal muscular atrophy in Germany: clinical results after 2 years

Abstract

Background Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since motor neuron injury is usually not reversible, early diagnosis and treatment are essential to prevent major disability. Our objective was to assess the impact of genetic newborn screening for SMA on outcome. Methods We provided clinical data from 43 SMA patients, identified via polymerase chain reaction of the SMN1 gene from dried blood spots between January 2018 and January 2020 in Germany. Follow-up included neurophysiological examinations and standardized physiotherapeutic testing. Results Detection of SMA with newborn screening was consistent with known incidence in Germany. Birth prevalence was 1:6910; 39.5% had 2 SMN2 copies, 23% had 3 SMN2 copies, 32.5% had 4 copies, and 4.5% had 5 copies of the SMN2 gene. Treatment with SMA-specific medication could be started at the age of 14–39 days in 21 patients. Pre-symptomatically treated patients remained throughout asymptomatic within the observation period. 47% of patients with 2 SMN2 copies showed early, presumably intrauterine onset of disease. These patients reached motor milestones with delay; none of them developed respiratory symptoms. Untreated children with 2 SMN2 copies died. Untreated children with 3 SMN2 copies developed proximal weakness in their first year. In patients with ≥ 4 SMN2 copies, a follow-up strategy of “watchful waiting” was applied despite the fact that one of them was treated from the age of 6 months. Two infant siblings with 4 SMN2 copies were identified with a missed diagnosis of SMA type 3. Conclusion Identification of newborns with infantile SMA and prompt SMA-specific treatment substantially improves neurodevelopmental outcome, and we recommend implementation in the public newborn screening in countries where therapy is available. Electrophysiology is a relevant parameter to support the urgency of therapy. There has to be a short time interval between a positive screening result and referral to a therapy-ready specialized treatment center.

Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children

“…Earlier diagnosis and initiation of treatment could prevent motor neuron loss during this postnatal vulnerable period. Consistent with this notion, newborn screening (NBS) programs for SMA are explored and implemented in a growing number of countries 35,36 . Whether sNfL may serve as a biomarker of disease activity, able to confirm the urgency of therapy in presymptomatic children, needs to be further studied.…”

“…Consistent with this notion, newborn screening (NBS) programs for SMA are explored and implemented in a growing number of countries. 35,36 Whether sNfL may serve as a biomarker of disease activity, able to confirm the urgency of therapy in presymptomatic children, needs to be further studied. Recently, Otsuki et al established a promising semi-quantitative analysis, on the basis of which SMN protein changes in a peripheral blood nuclear cell population may be monitored using imaging flow cytometry.…”

“…Consistent with this notion, newborn screening (NBS) programs for SMA are explored and implemented in a growing number of countries. 35 , 36 Whether sNfL may serve as a biomarker of disease activity, able to confirm the urgency of therapy in presymptomatic children, needs to be further studied. Recently, Otsuki et al.…”

Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy

“…In the large study on SMA epidemiology, which was conducted in the USA on a multiethnic group of 68,478 people, SMA incidence was calculated to be 1:11,000 births and a carrier frequency 1 in 47–72 individuals ( 1 ). A recently published report from the German newborn screening pilot program indicated an SMA incidence of 1:7,000 (43/297,163) ( 2 ). In Israel, the carrier screening program started in 2013 revealed 5,741 cases in 309,352 individuals (carrier rate 1:54) ( 3 ).…”

Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1

“…Evidence of the crucial importance of neonatal screening in patients with SMA1 comes from a study conducted in 2021 in Germany by Katharina Vill et al [ 23 ]. This study analyzed the gene involved in the pathogenesis of SMA: in case of a test positivity, the families have been subsequently contacted for a diagnostic confirmation at the reference center.…”