The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Cognitive function in SMA patients with 2 or 3 SMN2 copies treated with SMN-modifying or gene addition therapy during the first year of life.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease, causing progressive muscle weakness due to loss of lower motoneurons. Since 2017, three therapies, two modifying gene transcription and one adding the defective gene, have been approved with comparable efficacy on motor outcome. Data on cognitive outcomes of treated SMA type 1 patients is limited. The aim of this study was to evaluate cognitive function in symptomatic and presymptomatic SMA type 1 patients with two or three SMN2 copies who received SMN-modifying or gene-addition therapy in the first year of life. METHODS: Cognitive testing was performed in 20 patients, including 19 symptomatic SMA type 1 patients with up to three SMN2 copies and 1 pre-symptomatically treated patient. Children were tested using Bayley Scales of Infant Development (BSID-III) at the age of 2 or 3 years or the Wechsler Preschool and Primary Scale of Intelligence (WPSII-IV) at the of age of 5 years. RESULTS: 11/20 patients showed subnormal cognitive development. Boys had significantly lower cognitive scores. Patients requiring assisted ventilation or feeding support were more likely to have cognitive deficits. Achieving more motor milestones was associated with a better cognitive outcome. CONCLUSION: Treated patients with SMA type 1 have heterogeneous cognitive function with 55 % of patients showing deficits. Risk factors for cognitive impairment in our cohort were male gender and need for assisted ventilation or feeding support. Therefore, cognitive assessment should be included in the standard of care to allow early identification of deficits and potential therapeutic interventions.

An interpretable data-driven prediction model to anticipate scoliosis in spinal muscular atrophy in the era of (gene-) therapies.

5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 'scoliosis' the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.

Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial.

Importance: There 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. Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants: This 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. Exposure: Patients 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 Outcomes: The primary end point was the achievement of motor milestones. Results: A 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 Relevance: This 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 Registration: German Clinical Trials Register: DRKS00012699.

[Influence of digital documentation on working hours and workflow in the intensive care unit: An observational pre-post-study]. / Einfluss der digitalen Dokumentation auf die Arbeitszeit und den Arbeitsablauf auf der Intensivstation.

Influence of digital documentation on working hours and workflow in the intensive care unit: An observational pre-post-study Abstract: Background: The introduction of digital patient documentation systems in hospitals and intensive care units is increasing in Germany. The effects of these systems on the workflow of nurses have hardly been studied. Aim: It is analysed how high the workload is with a digital documentation system compared to paper-based documentation, how the workflow changes and how the digital documentation is evaluated in comparison to paper-based in terms of usability, time required and documentation quality. Methods: Before (to) and after the introduction of the digital patient documentation system (t1), the time for documentation and the documentation frequency was measured in a prospective pre-post observation study using an app configured specifically for this purpose, and both survey periods were statistically compared (Mann-Whitney-U-test). Furthermore, a survey of nursing staff on digital patient documentation was carried out. Results: The working time for the documentation remains the same after digitization. However, 80% of respondents state that the documentation time would have been reduced. Furthermore, the number of documentation processes decreases significantly (p = 0.03). In addition, a majority (55%) indicated an increase in documentation quality. Conclusions: Digital patient documentation does not necessarily save working time, but it defragments the process of documentation work and has the potential to positively influence the documentation workflow.

Implementation of 2D Barcode Medication Labels and Smart Pumps in Pediatric Acute Care: Lessons Learned.

BACKGROUND: In pediatric intensive care, prescription, administration, and interpretation of drug doses are weight dependent. The use of standardized concentrations simplifies the preparation of drugs and increases safety. For safe administration as well as easy interpretation of intravenous drug dosing regimens with standardized concentrations, the display of weight-related dose rates on the infusion device is of pivotal significance. OBJECTIVES: We report on challenges in the implementation of a new information technology-supported medication workflow. The workflow was introduced on eight beds in the pediatric heart surgery intensive care unit as well as in the pediatric anesthesia at the University of Bonn Medical Center. The proposed workflow utilizes medication labels generated from prescription data from the electronic health record. The generated labels include a two-dimensional barcode to transfer data to the infusion devices. METHODS: Clinical and technical processes were agilely developed. The reliability of the system under real-life conditions was monitored. User satisfaction and potential for improvement were assessed. In addition, a structured survey among the nursing staff was performed. The questionnaire addressed usability as well as the end-users' perception of the effects on patient safety. RESULTS: The workflow has been applied 44,111 times during the pilot phase. A total of 114 known failures in the technical infrastructure were observed. The survey showed good ratings for usability and safety (median "school grade" 2 or B for patient safety, intelligibility, patient identification, and handling). The medical management of the involved acute care facilities rated the process as clearly beneficial regarding patient safety, suggesting a rollout to all pediatric intensive care areas. CONCLUSION: A medical information technology-supported medication workflow can increase user satisfaction and patient safety as perceived by the clinical end-users in pediatric acute care. The successful implementation benefits from an interdisciplinary team, active investigation of possible associated risks, and technical redundancy.

Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy.

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.

Newbornscreening SMA - From Pilot Project to Nationwide Screening in Germany.

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Paradoxical increase of neurofilaments in SMA patients treated with onasemnogene abeparvovec-xioi.

Background/Objective: Neurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi. Methods: We measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM). Results: Median age at GRT was 19 months (range 2-46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0-663 pg/ml; normal values <25 pg/ml), increased significantly to 297 pg/ml (range 61-1,696 pg/ml; p<0,002) 1 month after GRT, and decreased to 49 pg/ml (range 24-151 pg/ml) after 6 months. Subjects pre-treated with nusinersen or risdiplam had lower baseline NfL levels than naïve patients (p<0,005), but absolute increases of NfL were similar in both groups. While motor scores were improved in 14 out of 18 SMA patients (78%) 6 months after GRT NfL values differed not significantly from those measured at baseline (p = 0,959). Conclusion: Serum NfL showed a paradoxical transient increase after GRT in both, pre-treated and naïve patients, which may reflect an immunological reaction in the CNS related to transfection of neuronal cells by AAV9. The clinical meaning of this increase should be assessed in future studies. Our findings encourage regular monitoring of NfL in OA treated patients.

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study.

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.

The Promise of Behavioral Tracking Systems for Advancing Primate Animal Welfare.

Recent years have witnessed major advances in the ability of computerized systems to track the positions of animals as they move through large and unconstrained environments. These systems have so far been a great boon in the fields of primatology, psychology, neuroscience, and biomedicine. Here, we discuss the promise of these technologies for animal welfare. Their potential benefits include identifying and reducing pain, suffering, and distress in captive populations, improving laboratory animal welfare within the context of the three Rs of animal research (reduction, refinement, and replacement), and applying our understanding of animal behavior to increase the "natural" behaviors in captive and wild populations facing human impact challenges. We note that these benefits are often incidental to the designed purpose of these tracking systems, a reflection of the fact that animal welfare is not inimical to research progress, but instead, that the aligned interests between basic research and welfare hold great promise for improvements to animal well-being.

Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study.

BACKGROUND: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. METHODS: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. FINDINGS: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings. INTERPRETATION: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. FUNDING: None. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Lumbar Puncture Opening Pressure in Patients with Spinal Muscular Atrophy.

The announcement of a hydrocephalus as a possible side effect in patients with spinal muscular atrophy (SMA) receiving the drug nusinersen, promoted major concern and warrants further evaluation. In this retrospective monocentric study, we analyzed clinical data, lumbar puncture opening pressure (LOP) measurement, and ophthalmologic and neuroimaging results in 34 patients with SMA types 1 to 3 undergoing treatment with nusinersen. None of the patients reported symptoms indicative of increased intracranial pressure. In our cohort, the LOP was >20 cm H2O in 25 patients (70.5%), and within this group ≥28 cm H2O in 12 patients (35.3%), in two patients, it was increased prior to treatment initiation. Signs of increased intracranial pressure in ophthalmological assessments or brain imaging were only seen in one patient. We did not identify a correlation between increased LOP and SMA type, scoliosis, or age of the patients; however, it was slightly higher in patients receiving sedation. Our results raise the question whether the LOP is generally increased in SMA as part of the underlying disease, if so, what the etiology is, and whether the increased LOP needs to be treated.

Positive effect of the combination of multilevel contracture release and glucocorticoid treatment in Duchenne muscular dystrophy.

PURPOSE: In the 1980s the first results of an early multilevel contracture release (MLCR) in patients suffering from progressive Duchenne muscular dystrophy (DMD) showed a positive effect on ambulation. Despite the demonstrated positive effects of prolongation of walking this treatment is not part of current guidelines. The aim of our study was to evaluate the effect of MLCR as well as its combination with glucocorticoid (GC) treatment on ambulation. METHODS: Data of all boys (n = 86) with DMD treated in our outpatient department were analyzed regarding the treatment and loss of independent ambulation. In all, 23 were treated with GC only, ten were operated on, 21 received GC and underwent MLCR and 32 received neither of the two treatments. RESULTS: The analysis of the loss of independent ambulation in our cohort showed a comparable extension of the ambulatory period between the GC-treated and MLCR-treated boys (p = 0.008 and p = 0.005, respectively). Furthermore, an additive effect of both therapies was found; patients with DMD who had both treatments were able to walk two years longer than those with only one of the two treatment options (p<0.001). CONCLUSION: Standard GC treatment and early MLCR in lower limbs have an independent positive effect on prolongation of ambulation in patients with DMD. In our cohort, the combination of both therapies is significantly more effective than each therapy alone. We suggest both should be offered to all DMD patients eligible.Level of evidence: III.

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1.

PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.