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PURPOSE: An increasing number of patients with Duchenne muscular dystrophy (DMD) now have access to improved standard of care and disease modifying treatments, which improve the clinical course of DMD and extend life expectancy beyond 30 years of age. A key issue for adolescent DMD patients is the transition from paediatric- to adult-oriented healthcare. Adolescents and adults with DMD have unique but highly complex healthcare needs associated with long-term steroid use, orthopaedic, respiratory, cardiac, psychological, and gastrointestinal problems meaning that a comprehensive transition process is required. A sub-optimal transition into adult care can have disruptive and deleterious consequences for a patient's long-term care. This paper details the results of a consensus amongst clinicians on transitioning adolescent DMD patients from paediatric to adult neurologists that can act as a guide to best practice to ensure patients have continuous comprehensive care at every stage of their journey. METHODS: The consensus was derived using the Delphi methodology. Fifty-three statements were developed by a Steering Group (the authors of this paper) covering seven topics: Define the goals of transition, Preparing the patient, carers/parents and the adult centre, The transition process at the paediatric centre, The multidisciplinary transition summary - Principles, The multidisciplinary transition summary - Content, First visit in the adult centre, Evaluation of transition. The statements were shared with paediatric and adult neurologists across Central Eastern Europe (CEE) as a survey requesting their level of agreement with each statement. RESULTS: Data from 60 responders (54 full responses and six partial responses) were included in the data set analysis. A consensus was agreed across 100% of the statements. CONCLUSIONS: It is hoped that the findings of this survey which sets out agreed best practice statements, and the transfer template documents developed, will be widely used and so facilitate an effective transition from paediatric to adult care for adolescents with DMD.
Subject(s)
Delphi Technique , Muscular Dystrophy, Duchenne , Humans , Muscular Dystrophy, Duchenne/therapy , Adolescent , Israel , Neurologists , Greece , Adult , Transition to Adult Care , Consensus , Male , Child , Female , EuropeABSTRACT
Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.
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BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
Subject(s)
Anticonvulsants , Mitochondrial Diseases , Seizures , Humans , Mitochondrial Diseases/complications , Mitochondrial Diseases/therapy , Seizures/therapy , Seizures/drug therapy , Anticonvulsants/therapeutic use , Consensus , Epilepsy/therapy , Epilepsy/drug therapy , Delphi TechniqueABSTRACT
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.
Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , Humans , Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , DNA Copy Number Variations , Genes, Regulator , Risk FactorsABSTRACT
BACKGROUND: Schizophrenia (SCZ) is a severe neuropsychiatric disorder of complex, poorly understood etiology, associated with both genetic and environmental factors. De novo mutations (DNMs) represent a new source of genetic variation in SCZ, however, in most cases their biological significance remains unclear. We sought to investigate molecular disease pathways connected to DNMs in SCZ by combining human induced pluripotent stem cell (hiPSC) based disease modeling and CRISPR-based genome editing. METHODS: We selected a SCZ case-parent trio with the case individual carrying a potentially disease causing 1495C > T nonsense DNM in the zinc finger MYND domain-containing protein 11 (ZMYND11), a gene implicated in biological processes relevant for SCZ. In the patient-derived hiPSC line the mutation was corrected using CRISPR, while monoallelic or biallelic frameshift mutations were introduced into a control hiPSC line. Isogenic cell lines were differentiated into hippocampal neuronal progenitor cells (NPCs) and functionally active dentate gyrus granule cells (DGGCs). Immunofluorescence microscopy and RNA sequencing were used to test for morphological and transcriptomic differences at NPC and DGCC stages. Functionality of neurons was investigated using calcium-imaging and multi-electrode array measurements. RESULTS: Morphology in the mutant hippocampal NPCs and neurons was preserved, however, we detected significant transcriptomic and functional alterations. RNA sequencing showed massive upregulation of neuronal differentiation genes, and downregulation of cell adhesion genes. Decreased reactivity to glutamate was demonstrated by calcium-imaging. CONCLUSIONS: Our findings lend support to the involvement of glutamatergic dysregulation in the pathogenesis of SCZ. This approach represents a powerful model system for precision psychiatry and pharmacological research.
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BACKGROUND: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. AIM: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). METHODS: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. RESULTS: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. CONCLUSIONS: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.
Subject(s)
Delivery of Health Care , Nervous System Diseases , Adult , Adolescent , Humans , Child , Surveys and Questionnaires , Europe , Nervous System Diseases/diagnosis , Nervous System Diseases/therapy , Rare Diseases/diagnosis , Rare Diseases/therapyABSTRACT
BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease, characterised by motor disturbances and non-motor (i.e., psychiatric) symptoms. Motor symptoms are the hallmark features of HD and take many forms. Their emergence is related to alterations in striatal dopaminergic neurotransmission: dopamine levels increase in the early stages of the disease, while more advanced stages are characterised by reduced dopamine levels. Such a biphasic change potentially explains the alterations in motor symptoms: increased dopamine-production induces hyperkinetic movements early in the disease course, while depleted dopamine storage leads to hypokinetic symptoms in the advanced phase. Dopamine D2-D3 partial agonists could be a promising treatment option in HD, as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course. Therefore, the present study aimed at exploring the effects of cariprazine, a dopamine D2-D3 partial agonist with high affinity to D3 receptors, on motor symptoms associated with HD. METHODS: This was a single-centre, retrospective study where sixteen patients received off-label cariprazine treatment for 12 weeks (1.5-3 mg/day). Motor symptoms were evaluated using the Motor Assessment of the Unified Huntington's Disease Rating Scale. Least Square (LS) Mean Changes from Baseline (BL) to Week 8 and Week 12 in the Total Motor Score (TMS) were analysed using the Mixed Model for Repeated Measures method. In addition, improvement from BL to Week 8 and 12 was calculated for all motor items. RESULTS: Data of 16 patients were collected, but data of only 15 patients were analysed as one patient dropped out due to non-compliance. Significant changes were observed from BL to Week 8 (LS Mean Change: -9.4, p < 0.0001) and to Week 12 (LS Mean Change: -12.8, p < 0.0001) in the TMS. The improvement was captured in the majority of motor functions, excluding bradykinesia and gait. Mild akathisia was the most commonly reported side-effect, affecting 3 patients. CONCLUSION: This is the first study investigating the effectiveness of a D2-D3 partial agonist, cariprazine, in the treatment of HD. The findings of this study revealed that cariprazine was effective in the treatment of a wide range of motor symptoms associated with HD.
Subject(s)
Antipsychotic Agents , Huntington Disease , Neurodegenerative Diseases , Humans , Huntington Disease/drug therapy , Dopamine , Antipsychotic Agents/therapeutic use , Retrospective StudiesABSTRACT
BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.
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Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first 'European Forum on Visceral Myopathy'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.
Subject(s)
Intestinal Pseudo-Obstruction , Malnutrition , Animals , Child , Humans , Quality of Life , Models, Animal , Mutation , Rare DiseasesABSTRACT
Gal et al address the issues raised by Gerber et al and reiterate that patients in their study showed decreased Misato homolog 1 (MSTO1) mRNA and protein levels, but also confirm finding of Gerber et al that the mutation is in MSTO2p pseudogene. Whether MSTO2p variant contributes to the observed decrease in MSTO1 levels in patients remains unclear.
Subject(s)
Cytoskeletal Proteins , Optic Atrophies, Hereditary , Humans , Cytoskeletal Proteins/genetics , Mutation , Cell Cycle Proteins/genetics , PedigreeABSTRACT
Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.
Subject(s)
Muscular Atrophy, Spinal , Muscular Diseases , Musculoskeletal Abnormalities , Humans , Muscle Hypotonia/diagnosis , Muscle Hypotonia/genetics , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Phenotype , Mutation , Nerve Tissue Proteins/genetics , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.
Subject(s)
Epilepsy , Postmenopause , Female , Humans , Animals , Rats , Case-Control Studies , Prospective Studies , Cross-Sectional Studies , Epilepsy/drug therapy , Seizures/drug therapy , Estrogens/pharmacology , Estrogens/therapeutic use , Gonadal Steroid Hormones/pharmacology , Gonadal Steroid Hormones/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Acid sphingomyelinase deficiency is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated SMPD1 variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine SMPD1 variants are present in this cohort, including 3 SMPD1 variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.
ABSTRACT
BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
Subject(s)
Mitochondrial Myopathies , Quality of Life , Humans , Female , Middle Aged , Male , Merozoite Surface Protein 1/therapeutic use , Mitochondrial Myopathies/drug therapy , Fatigue , Double-Blind Method , Treatment OutcomeABSTRACT
Fragmentation of health data and biomedical research data is a major obstacle for precision medicine based on data-driven decisions. The development of personalized medicine requires the efficient exploitation of health data resources that are extraordinary in size and complexity, but highly fragmented, as well as technologies that enable data sharing across institutions and even borders. Biobanks are both sample archives and data integration centers. The analysis of large biobank data warehouses in federated datasets promises to yield conclusions with higher statistical power. A prerequisite for data sharing is harmonization, i.e., the mapping of the unique clinical and molecular characteristics of samples into a unified data model and standard codes. These databases, which are aligned to a common schema, then make healthcare information available for privacy-preserving federated data sharing and learning. The re-evaluation of sensitive health data is inconceivable without the protection of privacy, the legal and conceptual framework for which is set out in the GDPR (General Data Protection Regulation) and the FAIR (findable, accessible, interoperable, reusable) principles. For biobanks in Europe, the BBMRI-ERIC (Biobanking and Biomolecular Research Infrastructure - European Research Infrastructure Consortium) research infrastructure develops common guidelines, which the Hungarian BBMRI Node joined in 2021. As the first step, a federation of biobanks can connect fragmented datasets, providing high-quality data sets motivated by multiple research goals. Extending the approach to real-word data could also allow for higher level evaluation of data generated in the real world of patient care, and thus take the evidence generated in clinical trials within a rigorous framework to a new level. In this publication, we present the potential of federated data sharing in the context of the Semmelweis University Biobanks joint project. Orv Hetil. 2023; 164(21): 811-819.
Subject(s)
Biomedical Research , Precision Medicine , Humans , Biological Specimen Banks , Europe , Information Dissemination , Databases, FactualABSTRACT
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense CCDC88C mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described CCDC88C mutations, we carried out in vitro functional tests. The CCDC88C alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the CCDC88C gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that CCDC88C mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.
Subject(s)
Spinocerebellar Ataxias , Spinocerebellar Degenerations , Humans , Female , HEK293 Cells , Hungary , Spinocerebellar Ataxias/genetics , Spinocerebellar Degenerations/genetics , Mutation , Ataxia , Microfilament Proteins/genetics , Intracellular Signaling Peptides and Proteins/geneticsABSTRACT
BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.
Subject(s)
Adrenoleukodystrophy , Adult , Male , Humans , Treatment Outcome , Adrenoleukodystrophy/drug therapy , France , Double-Blind Method , Disease ProgressionABSTRACT
BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform. CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.