Katharina Vill

Intrathecal (IT) delivery of gene therapy is an emerging strategy for spinal muscular atrophy (SMA), aiming to enhance central nervous system targeting while potentially reducing systemic exposure. The new administration route of onasemnogene abeparvovec is associated with a distinct safety profile, including dorsal root ganglia toxicity, and requires structured monitoring beyond existing intravenous guidelines, including planning for long-term multidisciplinary follow-up in pediatric and adult care as well as structured transition protocols. We expanded the existing intravenous monitoring guideline by incorporating surveillance for potential dorsal root ganglia-related adverse effects. The protocol integrates clinical, laboratory, electrophysiological, imaging, and long-term follow-up recommendations. The protocol defines pre-treatment assessment, peri-procedural management, and longitudinal follow-up in both pediatric and adult care settings, with emphasis on proactive evaluation of dorsal root ganglia function and structured transition of adolescents treated before adulthood to specialized multidisciplinary adult neurology services. A structured, multimodal monitoring approach—including dorsal root ganglia surveillance, multidisciplinary long-term follow-up, and coordinated transition from pediatric to adult care—is essential for the safe implementation of IT onasemnogene abeparvovec in SMA.

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder that results from a deficiency of the arylsulfatase A (ARSA) enzyme and leads to progressive neurodegeneration and demyelination. Due to its narrow pre-symptomatic window of opportunity for disease-modifying therapies, the implementation of newborn screening (NBS) for MLD seems crucial and the incorporation of MLD screening into existing NBS programs is required. In many NBS programs, DNA-based assays have already been established, for instance to screen for severe combined immunodeficiency, sickle cell disease, or spinal muscular atrophy. Utilizing these DNA eluates, we established high-multiplex mutation testing (HMMT), a novel DNA-based method, as a genetic first-tier to screen for MLD. By multiplex allele-specific amplification, the assay detects thirteen frequent ARSA variants within the European population identifying newborns with MLD with a modelled, gnomAD-based sensitivity of approximately 92%. Anonymized DNA eluates from 3,078 newborns were tested retrospectively. Variants were identified in nine samples (0.3%) confirmed by an allele-specific differentiation assay and next-generation sequencing. HMMT proved capable to identify frequent ARSA variants as a genetic first-tier test, while panel composition and achievable sensitivity remain to be tested and optimised in a real-world cohort. When biochemical testing cannot be implemented as first tier screening, our approach might be useful to set up as simple screening algorithm for MLD.

Objective: PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by generalized joint laxity, severe congenital hypotonia, progressive kyphoscoliosis, hyperextensible and easily bruised skin, ocular abnormalities, and significant vascular complications. Methods: We report on nine patients from seven families, eight of them carrying the common homozygous duplication of exons 10-16 in PLOD1 . Longitudinal clinical assessments included muscle ultrasound (n=6) and vascular ultrasound (n=4). Genetic diagnostics varied, with most patients ultimately undergoing trio exome or genome sequencing. Urine pyridinoline analysis was performed in seven of nine patients. A literature review and age-stratified recalculation of vascular incidence, including our cohort, were conducted. Results: Diagnosis was challenging in five families, as the exon 10–16 duplication often escaped detection due to its high allele frequency. Seven patients were initially diagnosed with congenital myopathy. Muscle ultrasound revealed abnormalities in five of six sonographically examined cases. Severe vascular events included neonatal intracranial hemorrhage, fatal aortic aneurysm rupture at the age of 13 years, multiple aneurysms/dissections (ages 14–19 years), and mesenteric dissection at the age of 10 years. Four younger patients (aged 3–9 years have had no vascular complications to date. Urine pyridinoline analysis was abnormal in all tested cases. Discussion: PLOD1 -related kEDS often presents with a phenotype of congenital myopathy, complicating genetic diagnosis and potentially leading to underdiagnosis - especially in cases where the common PLOD1 duplication may be missed by strict frequency filters in exome or genome sequencing data. Literature and our data indicate a vascular event incidence from childhood age of ∼25%.

Background: Systematic protocols for long-term surveillance of children with spinal muscular atrophy treated with onasemnogene abeparvovec are lacking. Together with best practice recommendations for safety monitoring and management, such recommendations should increase patient safety and confidence levels of healthcare providers. Objective: Based on systematic literature review and evidence grading from part 1, this initiative aims to develop a structured treatment plan applicable across all treatment centers in Germany, Austria and Switzerland. Additionally, it seeks to establish consensus recommendations for the clinical management of safety alerts. Methods: Part 2 describes the methodology used to formulate Delphi consensus statements, the development of a structured treatment plan for OA treatment, and the anonymous consensus voting process with standardized follow-up in case of disagreement. Results: A total of 12 consensus statements were developed, addressing diagnostic work-up, safety evaluation, and best practice management of common adverse drug reactions associated with OA gene therapy. All statements achieved >95% consensus in the anonymous Delphi voting. Additionally, two consensus recommendations for handling of positive newborn screening result achieved consensus of 97% and 87%, respectively. A structured treatment plan for gene therapy was consented with 100% agreement, as were standardized recommendations for laboratory testing and a consensus-based algorithm for management of liver transaminase elevations. Conclusions: Delphi-based expert recommendations, developed in co-creation with patient representatives, provide a framework to minimize complications associated with gene therapy and establish the basis for standardized post-marketing data collections. The methodology used in this Delphi-consensus-group can serve as a blueprint for future gene therapy approvals.

Objective: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and usually manifests in the first two decades of life. However, prospective data on the natural course during childhood remain scarce. Methods: This two-year, prospective, observational cohort study was conducted at two German pediatric neuromuscular centers. Annual standardized clinical assessments were performed. Sixty-eight pediatric patients with CMT (age range: 4–18 years; 35 females) were included. The primary outcome was the CMTPedS score, assessed at baseline and after a mean interval of 2.03 ± 0.23 years. Changes in the 11 individual CMTPedS subitems were also analyzed. Results: The mean baseline CMTPedS score for the total cohort (n=68) was 20.5 ± 8.8. Stratified by genotype, mean scores were: CMT1A (n=31), 16.5 ± 7.6; CMT1B (n=6), 21.5 ± 9.4; CMT2A (n=4), 35.8 ± 10.0; CMT4C (n=4), 27.0 ± 3.7; CMTX (n=4), 24.3 ± 10.1); others (n=13), 24.6 ± 7.7; genetically unsolved (n=6), 19.8 ± 8.6. Over a two-year observation period, the mean change in CMTPedS was 0.0 ± 2.7, indicating overall no significant progression. Conclusion: In this well-characterized cohort, overall disease course was non-progressive over two years—most notably in CMT1A, the most prevalent subtype. CMT2A and CMT1B showed numerically greater changes, yet none reached statistical significance. These results emphasize the slow-progressive nature of pediatric CMT and highlight the limitations of using short-term clinical progression as an outcome measure in therapeutic trials.

Background: Risdiplam is approved for the treatment of 5q-SMA from birth for all types and stages. However, broader data for adults are scarce. We aimed to assess safety and efficacy of risdiplam in adults with SMA.Methods: This is an observational cohort study at 38 academic clinical sites in German-speaking countries. Patients with genetically confirmed 5q-SMA (age 16–69 years) were included and received risdiplam treatment for a minimum treatment time of 6 months to a follow-up of up to 30 months. Primary outcome was the change in the total Revised Upper Limb Module (RULM) score, assessed at baseline to months 4-6, 12-14 and 28-30, and based on pre–post comparisons. This study is registered with the German Clinical Trials Register (DRKS00012699).Findings: Risdiplam showed significant motor improvement across a wide phenotypic spectrum of adult SMA patients regardless of age, SMN2 copy number, and functional status. 74% of patients improved or stabilized at 30 months in RULM; patients do not only deteriorate less rapidly but continue to stabilize or even improve at later time points. Maximum RULM improvement was 1.37 points in SMA3 patients at month 12/14, while at all other timepoints, both in SMA1 and SMA2 patients, mean RULM improvement was below 1 and at all time points below the CMC of 2. We did not detect a correlation between RULM improvement and age, sex or body weight, nor significant changes in HFMSE and 6MWT. No new safety findings were detected.Interpretation: Our study provides real-world data from the multinational SMArtCARE registry on efficacy and safety of risdiplam in 194 adult ambulatory and non-ambulatory SMA patients over 4-30 months of treatment.Funding: Financial support for the SMArtCARE registry is provided by Biogen, Novartis and Roche. Declaration of Interest: BS, BK, CB, CS, CR, EH, GSa, GS, MS, OS and VP declare no conflicts of interest. AB received honoraria for advisory board attendance, speaker’s fees from Biogen, Novartis, Roche, Italpharmaco, SantheraMT received honoraria for advisory board attendance, speaker’s fees and research funding from Alexion, Amicus, AstraZeneca, Sanofi Genzyme, Takeda, outside of the present work. AE received speakers´ fees and honoraria for advisory board attendance from Novartis, Biogen, Roche AH received funding for Travel and/or Speaker Honoraria from Roche, Biogen, Novartis, PTC Therapeutics, Santhera, Biomarin, and Takeda. He received research support from Roche, Sanofi, Takeda, Biomarin. AR received speaker fees from Amylyx Pharmaceuticals, ROCHE, Argenx, UCB Pharma, Alexion Pharma, Zambon and ITF Pharma, travel support for congress from Zambon and Johnson&Johnson and served on advisory boards for Biogen and Argenx, outside of the submitted work. ASN reports Adborad Meetings with Roche, Biogen, Novartis and Santhera Pharmaceuticals. CN received honoraria for advisory board attendance, speaker’s fees and travel grants from Biogen USA, Biogen Switzerland, Roche, Sanofi Genezyme, Mitsubishi Tanabe, Alexion, Argenx, Amicus, Johnson & Johnson, Amgen, Jannsen DH received honoraria for advisory board attendance from Novartis. DZ received honoraria for advisory board attendance from Biogen and Amicus, for consultancy from Novartis, and travel support for conference attendance from Zambon, outside of the present work. FK received speaker honoraria from Roche, Amicus, Alexion, Sanofi; travel support for conference attendance from Roche, ITF Pharma and Amicus, and served on advisory boards for Amicus, Roche, and Abcuro. GMzH received compensation for serving on scientific advisory boards (JnJ, Immunovant), speaker honoraria (Amgen, Argenx) and scientific project funding (Biogen). GW has received honoraria for advisory board attendance, speaker’s fees from Roche, Novartis, Alnylam and AstraZeneca outside of the present work. HC received honoraria for advisory board attendance, speaker’s fees and research funding from Biogen, Novartis, and Roche. HK is serving on a scientific advisory board for Novartis and Scholar Rock and received travel expenses and speaker honoraria from Biogen, Pfizer, Roche, and Sanofi-Aventis. HLo received support for research projects and clinical trials from Amplo Biotechnology, AMO Pharma, argenx, Biogen, Desitin, Fulcrum Therapeutics, Harmony Biosciences, KYE Pharmaceuticals, Milo Biotechnology, Novartis, Pfizer, PTC Therapeutics, Hoffman-La Roche Limited, Sanofi-Genzyme, Santhera, Sarepta, Satellos, Spark Therapeutics and Ultragenyx. HL is the Editor-in-chief for the Journal of Neuromuscular Diseases (IOS Press). JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, IFT, Roche, PTC, Pfizer, Santhera and Sarepta Therapeutics. JKi received honoraria for advisory board attendance, speaker’s fees and research funding from Biogen, Novartis, ScholarRock and Roche. JK received support to attend scientific conferences or meetings from Roche KV received honoraria for lectures, travel expenses, and/or served as a consultant on advisory boards for Novartis, Roche, Biogen, Santhera, Sanofi, ITF, and Scholar Rock. MA received honoraria fro Roche for advisory board attendance. MB received compensation for advisory board attendance and speaker´s honoraria from Novartis, Biogen, Roche and ITF Pharma. MCW has served on advisory boards for Avexis, Biogen, Novartis, Pfizer, PharNext, PTC Therapeutics, Roche, Santhera, Sarepta, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Biogen, Novartis, PTC Therapeutics, Santhera, and worked as an ad-hoc consultant for Affinia, Audentes Therapeutics, Avexis, Biogen, BridgeBio, Edgewise, Fulcrum, Grünenthal, ML Bio, Novartis, Pfizer, PharNEXT, PTC Therapeutics, Roche. MD has received speaker fees, advisory board and consultant honoraria from Biogen, Hoffmann-La Roche, Sanofi and AstraZeneca, outside of the present work....

Background: Since the approval of onasemnogen abeparvovec (OA) for gene addition therapy in children with spinal muscular atrophy (SMA), there has been a considerable increase of evidence regarding its effectiveness and safety. Consequently, the previous recommendations needed to be revised. Objective: The primary objective was to develop an evidence- and expert-based best practice protocol ensuring optimal patient safety and comprehensive support for affected families. The harmonization of treatment algorithms is expected to facilitate the collection of standardized real-world data, laying the foundation for future evidence-based adjustments. Methods: A modified, two-part Delphi process was selected as a standardized methodology. Experts specializing in SMA from all 31 neuromuscular treatment centers within Germany, Austria and Switzerland, and patient advocacy groups participated in an industry-independent Delphi panel. Existing evidence concerning effectiveness, safety, and guidelines of OA was analyzed in a systematic literature followed by development of consensus statements regarding its effectiveness. Results: Strong consensus was reached regarding the following statements on effectiveness: (1) OA gene addition therapy for SMA demonstrates a clear advantage compared to the natural progression of the disease. (2) Superiority of any of the three approved disease-modifying therapies has not been proven. (3) Earlier initiation of therapy with fewer symptoms and shorter disease duration leads to better outcomes. (4) There is no clinical evidence supporting the superiority of combining two treatments over monotherapy. Conclusions: The systematic literature analysis constitutes the basis for the subsequent part 2, which involves the generation of expert-based recommendations for the surveillance of SMA gene addition therapy.

An increasing number of adults with spinal muscular atrophy (SMA) wish to become parents. New disease-modifying therapies (DMT) have improved health outcomes and are expected to reduce disability in adults with SMA, but their current label prevents their use in pregnancy. While there is some information on pregnancy outcomes in the pre-DMT era, little has been published recently, and no ubiquitously accepted guidelines exist. Nonetheless, it is crucial to provide knowledgeable and open counselling, ideally in the context of treatments. Counseling for both adolescent and adult patients should include the subject of ‘reproductive choices’ when discussing the selection of DMTs for those considering parenthood. A multi-disciplinary team, including gynecologists and neurologists with expertise in neuromuscular disorders must closely monitor pregnant patients with SMA, preferably within disease registries, to detect potential complications early and ensure optimal treatment options are available. Real-world data in so far three patients with SMA showed a beneficial pregnancy outcome with nusinersen. It is anticipated that forthcoming real-world data will finally clarify the safety of administering Nusinersen during pregnancy, particularly in relation to child health and for preserving muscle function and preventing motor deterioration in the affected mother.

Epilepsy significantly impacts the health-related quality of life (HRQoL) of children and adolescents (CaA). This study aimed to assess HRQoL in pediatric epilepsy patients compared to their healthy peers, using both self- and proxy-reports, and to identify specific HRQoL domains affected by epilepsy.A single-center, cross-sectional study was conducted in Munich between October 2021 and June 2023. HRQoL was assessed in 139 patients aged 3 to 17 years with medically diagnosed epilepsy using age-adapted, validated KINDL© questionnaires, completed by the patients and one caregiver. The questionnaire comprised six subscales: “Physical Well-being,” “Emotional Well-being,” “Self-Esteem,” “Family,” “Friends,” and “Everyday Functioning.” Control values from healthy CaA aged 7 to 17 were drawn from the BELLA and KiGGS studies. Welch tests and Wilcoxon signed-rank tests were used for statistical comparisons.Compared to their healthy peers, CaA with epilepsy reported significantly lower HRQoL overall, particularly in the subscales “Physical Well-being,” “Emotional Well-being,” and “Friends.” No significant differences were observed in the “Family” subscale. Interestingly, self-reports revealed a trend toward higher “Self-Esteem” scores among CaA with epilepsy, though this did not reach statistical significance. No significant differences emerged between self- and proxy-reported total HRQoL scores.Epilepsy in CaA is associated with reduced HRQoL, especially in physical, emotional, and social domains. Stable family support can cushion some negative effects. In particular, the unexpectedly high results in the area of self-confidence should be the subject of future research.

This study explores the potential of ¹H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-naïve patients with SMA across five German centers were analyzed using ¹H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84–91%) and specificity (91–94%) in distinguishing treatment-naïve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that ¹H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.