BACKGROUND:Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia. METHODS:In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing. FINDINGS:Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred. INTERPRETATION:Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects. FUNDING:IntraBio.

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.

Abstract Background Classic lissencephaly is a malformation of cortical development that includes agyria and pachygyria. The major clinical symptoms are developmental impairment, muscular hypotonia, and drug-resistant epilepsy. The severity of the clinical phenotype depends on the associated gene and mutation. This study aimed to systematically investigate the genotype-specific course of the disease including neurodevelopmental outcome, medical complications, use of non-pharmacological supportive therapies, and its impact on the quality of life of the affected families. Methods 47 patients with genetically and radiologically confirmed lissencephaly were included with mutation in LIS1/PAFAH1B1 (n = 38), DCX (n = 5 males), DYNC1H1 (n = 2), TUBA1A (n = 1) and TUBG1 (n = 1) genes. Standardized questionnaires were completed by families and treating pediatricians. Quality of life was assessed with the PedsQL™ Family Impact Module. Results Prenatal abnormalities, most commonly microcephaly, were observed in 14/37 (38%) of LIS1/PAFAH1B1 patients and 2/5 (40%) of DCX patients. Early symptoms included microcephaly, developmental delay, muscular hypotonia, and epileptic seizures. The median age at suspected diagnosis was 5 months for LIS1/PAFAH1B1 patients and 9 months for DCX patients. Compared to LIS1/PAFAH1B1, DCX-related lissencephaly patients showed significantly better neurodevelopmental outcome in reaching more advanced milestones such as walking unassisted (z=-2.23, p = 0.026) and speaking sentences (z=-2.53, p = 0.011). Frequent medical complications included recurrent respiratory infections (14/38 (37%) of LIS1/PAFAH1B1 patients; 1/4 (25%) of DCX patients) and dysphagia/ vomiting (23/37 (62%); 2/4 (50%)), which may require tube feeding (15/38 (40%); 1/5 (20%)). A median of eight different supportive therapies was used per patient (range 1–17), with physiotherapy and respiratory therapy considered the most effective. The scores obtained for health-related quality of life (HRQL) were low (parental HRQL mean 61.23; SD 16.79). Conclusions Our study confirms the severely impaired developmental potential and frequent neurological and medical complications in lissencephaly patients from an early age. The psychomotor prognosis in LIS1/PAFAH1B1-related lissencephaly is significantly worse compared to DCX-related lissencephaly. Supportive therapies are used intensively and are considered to be very effective. The disease puts a high burden on caregivers and the entire family. This emphasizes the need for appropriate epilepsy treatment, personalized care for patients and professional support for their families.

Background and objectivesThe severity of the phenotype of spinal muscular atrophy (SMA) is highly variable, yet little is known about the phenotypic variation among siblings. We systematically investigated the phenotypic variability of therapy-naïve 5q-SMA siblings leveraging a large multicentre cohort from the SMArtCARE registry.ResultsClinical information was available from 132 siblings of 65 families. There were 24 (18.2%) type 1, 38 (28.7%) type 2, 54 (40.9%) type 3 patients, and 16 (12.1%) presymptomatic individuals. In 17 families (32.1%), there was discordance in the type of SMA among symptomatic siblings. We found no influence of gender on discordance in SMA type among siblings (p = 0.528). The median age at disease onset within all sibships varied by 6 months (interquartile range (IQR) = 1-30). There was no correlation in age of onset among siblings (r = 0.405; p = 0.052). Among siblings who lost ambulation, the median interval between the start of wheelchair use was 12 months, but the maximal interval was 18 years. In one pair of siblings, one sibling lost the ability to walk at the age of 13, whereas the other sibling was still ambulatory at the age of 54. In 6 sibling pairs (9.5%), only one of both siblings had a history of scoliosis surgery. Analysing SMN2 copy numbers, in one sibling pair (1.8%) 1 SMN2 gene copy was detected, while 10 (17.5%) had 2 copies, 23 (40.4%) had 3 copies, and 17 (29.8%) had 4 copies. Concordance in SMN2 copy numbers across siblings was observed in 90% of families. With increasing SMN2 copy number, the median differences in age of onset among siblings increased without reaching statistical significance.ConclusionThis study reports considerable phenotypic variability in therapy-naïve SMA sibships that cannot solely be explained by differences in SMN2 copy numbers.

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.

Background and Objective: GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric (greater than or equal to 6 years) and adult patients with GM2 gangliosidosis. Methods: We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients greater than or equal to 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9Hole Peg Test) during each study periods. Secondary outcomes included cerebellar rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments. Results: 30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (TaySachs or Sandhoff's disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: This study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide. Classification of Evidence: This study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis. Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

To the Editor Autosomal recessive primary microcephaly (MCPH) is characterized by congenital microcephaly (>2–3 standard deviations [SD] below the mean for age and gender) and intellectual disability without additional syndromic features (Alcantara & O'Driscoll, 2014). Up to now, 18 genes have been linked to MCPH, all of them involved in the neurogenesis of radial glia cells as the primary progenitor cells of the developing cerebral cortex (Jayaraman, Bae, & Walsh, 2018). Most of these genes encode centrosomal proteins involved in centriole biogenesis (WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, SASS6) (Jayaraman et al., 2018). Others are involved in DNA replication and repair, kinetochore function, transmembrane or intracellular transport, autophagy, or cell polarity (Jayaraman et al., 2018). Barkovic et al. provide a comprehensive review on malformations of cortical development (MCD), a large heterogenous group of defects in cerebral cortex formation, resulting from dysfunctional neurogenesis, neuronal migration, and postmigrational development (Barkovich, Guerrini, Kuzniecky, Jackson, & Dobyns, 2012). MCPH was classified as group IA, representing a reduced size of the cerebral cortex due to reduced proliferation, generally without gross morphological abnormalities (Barkovich et al., 2012). Nonetheless, cases with structural changes have been reported, for example, cortical malformations and subcortical heterotopia in WDR62 patients and periventricular heterotopia in MCPH1 (Nicholas et al., 2010; Trimborn et al., 2004; Yu et al., 2010). Several MCD are predominantly characterized by clusters of neurons unable to migrate to their proper position in the cortex, referred to as heterotopic gray matter brain malformation (HET) (Oegema, Barkovich, Mancini, Guerrini, & Dobyns, 2019). Periventricular nodular heterotopia (PNH) is the most common subtype, formed by nodules in the wall of the lateral ventricles (Oegema et al., 2019). Recently, a new classification for the less common subcortical heterotopias (SUBH) was introduced (Oegema et al., 2019). SUBH are considered a different disease entity, defined as heterotopic gray matter located in the white matter between the lateral ventricles and the cortex (Oegema et al., 2019). Mutations in the Centrosomal Protein 135 gene (CEP135) are a very rare cause of primary microcephaly (MCPH8, OMIM 614673), since only three families have been reported without brain-MRI, and detailed information on brain morphology have been lacking. Here, we report a patient presenting with epilepsy as new feature in CEP135 related disease and provide the first brain-MRI images identifying subcortical heterotopia as underlying cerebral malformation. The female patient is the only child of healthy unrelated German parents. Microcephaly had already been diagnosed prenatally. The girl was born spontaneously at term without complications after an otherwise uneventful pregnancy. Head circumference at birth was 31 cm (1.5 cm T; p.Lys1071*) in CEP135 (NM_025009.4). The mutation was confirmed by Sanger Sequencing, and both parents are heterozygous carriers. The variant has not been reported in any database and was classified as pathogenic (PVS1, PM2, PM3) according to the ACMG classification (Richards et al., 2015). In addition, two heterozygous variants in the FAT4 gene (NM_024582.4), known to cause autosomal-recessive syndromic periventricular nodular heterotopia were apparent (Alders et al., 2014). But as both variants in FAT4 were inherited form the healthy mother and the reported FAT4-phenotypes including the pattern of brain malformation and pathognomonic facial features did not match our patient, they were not considered disease causing. A missense variant c.12778G>A (p.Asp4260Asn) was detected in HUWE1 (NM_031407.6), variants in HUWE1 are known to cause dominant X-linked intellectual disability of the Turner Type (OMIM: 309590). For HUWE1 patients multiple brain-MRI reports are available, none of them depicting cortical brain malformations, and in animal models, no structural nervous system anomalies were reported (Moortgat et al., 2018; Vandewalle et al., 2013). Thus, we considered this variant to be a less probable cause of the subcortical nodular heterotopia compared to the CEP135 variant. Nonetheless, it may act as a disease modifier for the intellectual disability depending on the degree of X-chromosome inactivation. No further likely pathogenic variants in genes previously associated with MCPH or MCD were identified, nor were convincing novel candidate-genes found (see Supplementary Material). Still a modifying effect of the reported secondary variants on the phenotype together with other unknown genetic disease modifiers has to be considered. Because we have a whole-exome and not a whole genome sequencing, it is not possible to exclude the low probability of a digenic inheritance of deep intronic variants or structural variants in a second gene modifying the phenotype (Posey et al., 2017). Homozygous truncating mutations in CEP135 have first been identified in two Pakistani families with primary microcephaly, learning disability, speech impairment, and sloping forehead (Farooq et al., 2016; Hussain et al., 2012). In addition, a two-year-old boy was reported presenting with primordial dwarfism, spasticity, and developmental delay. His dysmorphic features included microcephaly, scoliosis, hypotelorism, sloping forehead, small face, and broad nose (Shaheen et al., 2019). All of these cases presented severe microcephaly with a head circumference of −10 to −13 standard deviation (SD). Our patient has milder primary microcephaly (−6.5 SD) and mild learning disabilities. Noteworthy in our case are the novel features: epilepsy and subcortical heterotopia group 1a associated with CEP135 mutations. CEP135 is involved in centrosomal microtubule assembly by serving as a linker protein directly connecting the central hub protein HsSAS-6 to the outer microtubule (Lin et al., 2013). It consists of an N-terminal microtubule interacting domain, a central CENPJ interacting domain, and a C-terminal HsSAS-6 interacting domain (Lin et al., 2013). Our stop mutation in CEP135 presumably results in a loss of the last sixth coiled-coil domains and is predicted to be deleterious as it covers part of the region responsible for interaction with HsSAS-6 (MCPH14, OMIM 616402). In addition, the transcript is predicted to undergo nonsense mediated decay (NMD) which would lead to a complete loss of function. The milder microcephaly and subcortical heterotopia could represent a hypomorphic allele manifestation in our case. The premature stop codon near the C-terminus of CEP135 might only lead to partial NMD with residual activity in contrast to the previously complete loss-of-function mutations causing a more severe microcephaly. Loss of CEP135 leads to disorganized interphase and multiple and fragmented centrosomes with disorganized microtubules (Hussain et al., 2012; Lin et al., 2013; Ohta et al., 2002). This disrupts cell division but also causes disordered neuronal cell polarity and basal body formation, which is essential for neuronal migration (Jana et al., 2018). CEP135 is not the very first MCPH gene being linked to neuronal migration defects. Interestingly, mutations of WDR62 (MCPH2, OMIM 604317) are reported in patients manifesting microcephaly and malformations of cerebral cortical architecture and subcortical heterotopia (Yu et al., 2010). Our patient presents microcephaly and solid nodular HET in the region of the peritrigonal optic pathway posterior to the deep gray nuclei (group 1a). The same pattern has been described by Oegema et al. in a patient with CENPJ mutations (MCPH6, OMIM 608393), which closely interacts with CEP135 in centrosome formation (Lin et al., 2013; Oegema et al., 2019; Tang, Fu, Wu, Hsu, & Tang, 2009). In addition, SUBH 1a was associated with TUBB (CDCBM6, OMIM 615771) coding for the microtubular subunit tubulin-beta, and KATNB1 (LIS6, OMIM 616212) which forms the microtubule-severing protein katanin together with KATNA1 and localizes to the centrosome (Breuss et al., 2012; Mishra-Gorur et al., 2014; Oegema et al., 2019). All these genes are involved in the asymmetrical division of neuronal progenitor cells and disruption leads to impaired neuronal proliferation and migration (Breuss et al., 2012; Insolera, Bazzi, Shao, Anderson, & Shi, 2014; Mishra-Gorur et al., 2014). Here, we report the first patient with a homozygous CEP135 nonsense mutation and subcortical heterotopia; thus CEP135 mutations shall be added to the genetic differential diagnosis of subcortical nodular heterotopia of the peritrigonal region (SUBH 1a). Furthermore, our findings emphasize the effect of CEP135 related centrosomal disruption on neuronal migration in human brain development. All authors declare that they have no conflict of interest. Daniel Bamborschke: Analysis and interpretation of data, drafting the manuscript. Hülya-Sevcan Daimagüler: Production and interpretation of data. Andreas Hahn: Clinical evaluation of the patient, reviewing the manuscript for intellectual content. Muhammad S. Hussain: Analysis and interpretation of data, reviewing the manuscript for intellectual content. Peter Nürnberg: Reviewing the manuscript for intellectual content. Sebahattin Cirak: Conception and design, analysis and interpretation of data, reviewing the manuscript for intellectual content. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1: Supporting information 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.