(Abstracted from JAMA Pediatr 2024;178(6):540–547 Spinal muscular atrophy (SMA) is a genetic disorder characterized by progressive muscle weakness and atrophy, with the most severe cases leading to ventilator dependency or death within 2 years. Three new therapies have significantly improved outcomes, especially with early treatment.

ImportanceThere is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking.ObjectiveTo compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset.Design, Setting, and ParticipantsThis nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months.ExposurePatients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system.Main OutcomesThe primary end point was the achievement of motor milestones.ResultsA total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%).Conclusions and RelevanceThis nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group.Trial RegistrationGerman Clinical Trials Register: DRKS00012699

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2 , and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0–4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype–phenotype correlations that may help to improve the diagnostic approach and patient management.

BACKGROUND AND OBJECTIVES:Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months.METHODS:SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function.RESULTS:Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients.CONCLUSION:Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.

An overarching goal of genetics research in dystonia is the definition of converging molecular pathways, allowing grouping of patients according to disease biology rather than phenomenology.1 This may improve the development of stratification schemes and contribute to the transition from empiric selection of treatments to etiology-directed therapeutics. One downstream mechanistic effect shared by different mutant dystonia-associated gene products includes the perturbation of translational control.1 For example, abnormalities in eIF2α-signaling, induced by mutations in EIF2AK2 or PRKRA, are considered to result in aberrant protein synthesis via translation-initiation impairments.2 Most recently, Sleiman and colleagues have introduced a new player in translational defect-mediated dystonia, SHQ13; the gene encodes a component of the H/ACA–ribonucleoprotein complex, responsible for the modification of various RNA species, including those that regulate protein synthesis in the ribosome.4 Although two SHQ1-mutated families with dystonia have been described,3 the gene–phenotype relationship has not yet been firmly established.5 We have prioritized compound heterozygous SHQ1 variants, c.523G>T (p.Asp175Tyr) and c.828_831del (p.Asp277Serfs*27), in whole-exome sequencing data of a female study proband with infantile-onset dystonia (Table 1); these variants remained of uncertain significance during initial analysis (August 2021).6 Eventually, bioinformatics pipeline-based (re-) assessment of latest literature/ClinVar data revealed that our candidate SHQ1 variants were identical to mutations observed in one of the families reported by Sleiman and colleagues.3 These published carriers of c.523G>T/c.828_831del developed dystonia before the age 6 months, with diurnal fluctuations and partial response to levodopa.3 Similarly, our proband manifested dystonia in her first months of life, and the disorder was levodopa responsive. Her motor milestones were delayed. Over time, movement abnormalities evolved into a more complex pattern, and she experienced a generalized tonic–clonic seizure at age 14 years. On recent examination, she displayed a mixed hyperkinetic disorder characterized by dystonia, myoclonus, and chorea affecting the limbs, trunk, and facial region (Video S1). There was worsening of hyperkinesia in the evening, cognitive impairment, and truncal hypotonia, leading to an initially suspected diagnosis of ADCY5-related dyskinesia.1 All routine diagnostic studies were unrevealing except for an isolated moderate decrease in HVA levels in cerebrospinal fluid. SHQ1 variants RefSeq transcript: NM_018130.3 HVA: 277 nmol/L (normal: 300–1000 nmol/L) 5-HIAA: 239 nmol/l (normal: 200–600 nmol/l) HVA: 0.32 nmol/L (normal: 0.49–0.66 nmol/L) 5-HIAA: 0.26 nmol/L (normal: 0.19–0.30 nmol/L) HVA: 174 nmol/L (normal: 233–928 nmol/L) 5-HIAA: 105 nmol/L (normal: 74–345 nmol/L) HVA: 194 nmol/L (normal: 294–1115 nmol/L) 5-HIAA: 172 nmol/L (normal: 129–520 nmol/L) Recurrence of c.523G>T/c.828_831del in two separate dystonia-affected families provides strong evidence for pathogenicity of these variants. Moreover, c.828_831del has been detected in combination with another SHQ1 mutation in a third family3 (Table 1). Observing the same set of compound-heterozygous alleles in two nonrelated pedigrees is an uncommon finding and could be explained by the population frequency of the variants. Notably, both c.523G > T and c.828_831del are very rare but observed in an appreciable number of gnomAD controls (Table 1); c.523G>T is even found in 1 gnomAD individual in the homozygous state, indicating that it could represent a hypomorphic allele.3 We expect that SHQ1-associated dystonia is underdiagnosed and may have been ignored in some exome-sequenced cases analyzed using standard filter settings (often removing variants present in homozygous controls).7 Our report provides replication for the involvement of SHQ1 in autosomal recessive early-onset dystonia, which appears to be a more complex and progressive movement disorder. SHQ1 should be added to the compendium of dystonia-associated genes involved in translational control, expanding our understanding of common molecular themes in dystonia pathogenesis. We thank the patient and her family for their generous participation and permission to publish this case. We thank Philip Harrer, Institute of Neurogenomics (Helmholtz Zentrum München), for assistance with processing of video material. Open Access funding enabled and organized by Projekt DEAL. E.I.: acquisition of data, clinical examination, analysis and interpretation of data, and revision of manuscript for critical intellectual content. S.B.: study design and concept, acquisition of data, clinical examination, analysis and interpretation of data, and revision of manuscript for critical intellectual content. M.B.: acquisition of data, clinical examination, and revision of manuscript for critical intellectual content. B.P.: acquisition of data, clinical examination, and revision of manuscript for critical intellectual content. J.W.: study supervision and revision of manuscript for critical intellectual content. M.Z.: study design and concept, study supervision, analysis and interpretation of data, and wrote manuscript. Nothing to report. Full data set available from the corresponding author upon request. Video S1. Our patient with SHQ1 variants presented with a mixed hyperkinetic disorder comprising dystonic, choreatic, and myoclonic elements; note task-(gait)-specific dystonic mobile anterocollis (anterocapus). Rapid dystonic movements (right upper limb) and tics (mainly cervical) observed in the third segment of the video may be, in part, a consequence of levodopa chronic therapy. During infancy and early childhood, dystonia was the predominant movement disorder. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Background: Bathing epilepsy is a very rare form of reflex epilepsy. Seizures were usually of focal onset in rare cases even evolution to bilateral tonic–clonic seizures were observed. In literature we, differentiate between “hot water epilepsy (40–50°C),” bath epilepsy on diving into water of body temperature (36–38°C), and bath epilepsy triggered by lukewarm water (<36°C). Affected individuals may show genetic changes, in particular at the SYN1 gene, as well as interictal changes, in particular upon sleep EEG. Concerning our case, awake, as well as sleep EEG, and extensive genetic testing were nondescriptive. Avoiding known triggers usually controls seizures, but carbamazepine, valproate, and levetiracetam were also helpful. The prognosis regarding seizure free intervals is stated as good in the given literature. In the case of our patient, we were able to avoid further seizures by avoiding baths.

Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified. However, filtering for genes carrying two rare sequence variations detected 13 homozygous single nucleotide variants (SNV), all being located on chromosome 1. Further analysis strongly suggested that this finding might be best explained by uniparental disomy of chromosome 1. Because NTRK1 is also located on chromosome 1, we re‐evaluated WES data and detected a novel intronic sequence variation at position c.2188‐12 C>A, homozygously because of uniparental disomy. Subsequent analysis of NTRK1 transcripts in peripheral blood cells of the patient revealed an influence of the variant on mRNA splicing. The C>A transversion generated a novel splice‐site, which led to the incorporation of 10 intronic bases into the NTRK1 mRNA and consequently to a non‐functional gene product. © 2016 Wiley Periodicals, Inc.

We just found out that our honorary member Prof. Heinz F. R. Prechtl passed away in July 2014. We therefore express our deep gratitude and appreciation for his contribution to the field of pediatric neurology.

Nat. Genet. 47 803–808 (2015); published online 25 May 2015; corrected after print 8 July 2015 In the version of this article initially published, there was an error with the affiliations for author Roman Chrast. His correct affiliations are: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.