Publications by authors named "Thomas Klopstock"

228 Publications

Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers.

Int J Mol Sci 2021 Oct 14;22(20). Epub 2021 Oct 14.

Department of Proteomics a Signal Transduction, Max Planck Institute of Biochemistry, 82352 Martinsried, Germany.

Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.
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http://dx.doi.org/10.3390/ijms222011080DOI Listing
October 2021

Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study.

J Neuroophthalmol 2021 Sep;41(3):309-315

Departments of Ophthalmology (VB, NJN), Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia; Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit (PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit (PY-W-M), Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital (PY-W-M, SE), London, United Kingdom; UCL Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom; IRCCS Istituto delle Scienze Neurologiche di Bologna (VC, CLM), Programma di Neurogenetica, Bologna, Italy; Unit of Neurology (VC, CLM), Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; Departments of Neurology and Ophthalmology (MLM, RCS), Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Neuro Ophthalmology and Emergencies (CV-C), Rothschild Foundation Hospital, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts (CV-C, RH, J-AS), Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France; Department of Neurology (TK), Friedrich-Baur-Institute, University Hospital, LMU Munich, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (TK), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy) (TK), Munich, Germany; Doheny Eye Institute/UCLA School of Medicine (AAS, RK), Los Angeles, California; Department of Ophthalmology (CP), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany; Department of Ophthalmology (RK), University of Ottawa Eye, Ottawa ON, Canada; GenSight Biologics (LB, MT), Paris, France; Sorbonne Université (J-AS), INSERM, CNRS, Institut de la Vision, Paris, France; Fondation Ophtalmologique A. de Rothschild (J-AS), Paris, France; and Department of Ophthalmology (J-AS), the University of Pittsburgh School of Medicine, Pittsburgh.

Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials.

Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25).

Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline.

Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.
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http://dx.doi.org/10.1097/WNO.0000000000001367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366761PMC
September 2021

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy-Response to Dr. Finsterer's Letter.

J Neuroophthalmol 2021 Aug 6. Epub 2021 Aug 6.

Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany Department of Ophthalmology, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany Department of Ophthalmology, University Hospital and University of Zurich, Zurich, Switzerland Emory University School of Medicine, Atlanta, Georgia School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom Department of Ophthalmology, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

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http://dx.doi.org/10.1097/WNO.0000000000001318DOI Listing
August 2021

Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.

J Neuroophthalmol 2021 Sep;41(3):298-308

Departments of Neurology and Ophthalmology (MLM, RCS, AAD), Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania; Departments of Ophthalmology (NJN, VB), Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia; Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit (PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit (PY-W-M), Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital (PY-W-M), London, United Kingdom; UCL Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom; IRCCS Istituto Delle Scienze Neurologiche di Bologna (VC, MC), UOC Clinica Neurologica, Bologna, Italy; Unit of Neurology (VC), Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; Institute of Health Research and Policy (MSB), University of Illinois, Chicago, Chicago, Illinois; Statistics Consultant (GS), GenSight Biologics, CaliforniaDepartment of Neuro Ophthalmology and Emergencies (CV-C, RH), Rothschild Foundation Hospital, Paris, France; Centre Hospitalier National D'Ophtalmologie des Quinze Vingts (CV-C, RH), Paris, France; Department of Neurology (TK), Friedrich-Baur-Institute, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (TK), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy) (TK), Munich, Germany; Doheny Eye Center UCLA (AAS, RK), Department of Ophthalmology David Geffen School of Medicine at UCLA, Doheny Eye Institute, Los Angeles, CaliforniaDepartment of Ophthalmology (SP), University Hospital, LMU Munich, Munich, Germany; Department of Ophthalmology (RK), University of Ottawa Eye Institute, Ottawa Canada; GenSight Biologics (LB, MT), Paris, France; Medical Consultant (BK), GenSight Biologics; Sorbonne Université (JAS), INSERM, CNRS, Institut de La Vision, 75012 Paris, France; Fondation Ophtalmologique A. de Rothschild (JAS), 25-29 Rue Manin, Paris; Department of Ophthalmology (JAS), the University of Pittsburgh School of Medicine, PittsburghCHNO des Quinze-Vingts (JAS), Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France.

Objective: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss.

Methods: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion).

Results: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively).

Conclusion: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.
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http://dx.doi.org/10.1097/WNO.0000000000001316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366757PMC
September 2021

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias.

Front Neurol 2021 25;12:677551. Epub 2021 Jun 25.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the , a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.
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http://dx.doi.org/10.3389/fneur.2021.677551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267795PMC
June 2021

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers' Lives.

Brain Sci 2021 Jun 4;11(6). Epub 2021 Jun 4.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs ( = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r = -0.555, < 0.001, 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], < 0.001) and was interrelated with the CGs' depression (r = 0.627, < 0.001, 234), anxiety (r = 0.550, < 0.001, 234), and poorer physical condition (r = -0.362, < 0.001, 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r = -0.280, < 0.001, 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
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http://dx.doi.org/10.3390/brainsci11060748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228206PMC
June 2021

Mitochondrial Disorders.

Dtsch Arztebl Int 2021 Oct 1(Forthcoming). Epub 2021 Oct 1.

Background: Mitochondrial disorders are among the most common heritable diseases, with an overall lifetime risk of approximately one in 1500. Nonetheless, their diagnosis is often missed because of their extreme phenotypic and genotypic heterogeneity.

Methods: This review is based on publications retrieved by a selective literature search on the clinical features, genetics, pathogenesis, diagnosis, and treatment of mitochondrial diseases.

Results: Pathogenic defects of energy metabolism have been described to date in over 400 genes. Only a small number of these genes lie in the mitochondrial DNA; the corresponding diseases are either maternally inherited or of sporadic distribution. The remaining diseaseassociated genes are coded in nuclear DNA and cause diseases that are inherited according to Mendelian rules, mostly autosomal recessive. The most severely involved organs are generally those with the highest energy requirements, including the brain, the sensory epithelia, and the extraocular, cardiac, and skeletal musculature. Typical manifestations include epileptic seizures, stroke-like episodes, hearing loss, retinopathy, external ophthalmoparesis, exercise intolerance, and diabetes mellitus. More than two manifestations of these types should arouse suspicion of a disease of energy metabolism. The severity of mitochondrial disorders ranges from very severe disease, already evident in childhood, to relatively mild disease arising in late adulthood. The diagnosis is usually confirmed with molecular-genetic methods. Symptomatic treatment can improve patients' quality of life. The only disease-modifying treatment that has been approved to date is idebenone for the treatment of Leber hereditary optic neuropathy. Intravitreal gene therapy has also been developed for the treatment of this disease; its approval by the European Medicines Agency is pending.

Conclusion: Patients with mitochondrial diseases have highly varied manifestations and can thus present to physicians in practically any branch of medicine. A correct diagnosis is the prerequisite for genetic counseling and for the initiation of personalized treatment.
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http://dx.doi.org/10.3238/arztebl.m2021.0251DOI Listing
October 2021

Mitochondrial disease in adults: recent advances and future promise.

Lancet Neurol 2021 07;20(7):573-584

Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Electronic address:

Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
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http://dx.doi.org/10.1016/S1474-4422(21)00098-3DOI Listing
July 2021

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A Mutation: Systematic Review and Indirect Comparison.

Front Neurol 2021 24;12:662838. Epub 2021 May 24.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2- vs. 11 pooled NH studies used as an external control. The LHON subjects carried the m.11778G>A mutation and were aged ≥15 years at onset of vision loss. A total of 76 subjects received a single intravitreal rAAV2/2- injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2- treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-. The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes ( < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes ( < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, < 0.0001). The m.11778G>A LHON patients treated with rAAV2/2- exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. NCT02652767, NCT02652780, NCT03406104, and NCT03295071.
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http://dx.doi.org/10.3389/fneur.2021.662838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181419PMC
May 2021

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse.

Mamm Genome 2021 10 27;32(5):332-349. Epub 2021 May 27.

Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.

Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.
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http://dx.doi.org/10.1007/s00335-021-09875-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458197PMC
October 2021

Rational Design of Novel Therapies for Pantothenate Kinase-Associated Neurodegeneration.

Mov Disord 2021 09 18;36(9):2005-2016. Epub 2021 May 18.

Departments of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses.

Objectives: A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms.

Methods: Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated.

Conclusions: Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28642DOI Listing
September 2021

Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.

Front Neurol 2021 15;12:629414. Epub 2021 Apr 15.

Department of Neurology With Friedrich Baur Institute, University Hospital of Ludwig-Maximilians-Universität München, Munich, Germany.

Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4'-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4'-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.
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http://dx.doi.org/10.3389/fneur.2021.629414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082061PMC
April 2021

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Brain Sci 2021 Mar 14;11(3). Epub 2021 Mar 14.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, < 0.001). "Limb-onset" ALS (ALS) was associated with a better QoL than "bulbar-onset" ALS (ALS) (mean ALSAQ-5 total score 55.46 versus 60.99, = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, = 0.001), being tracheostomized (β = -14.80, = 0.004) and using non-invasive ventilation (β = -5.71, = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, = 0.007), and increasing age (β = 0.18, = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
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http://dx.doi.org/10.3390/brainsci11030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998410PMC
March 2021

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study.

Lancet Neurol 2021 05 23;20(5):362-372. Epub 2021 Mar 23.

Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich and RWTH Aachen University, Aachen, Germany.

Background: The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia.

Methods: EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509.

Findings: Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included.

Interpretation: Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia.

Funding: European Commission, Voyager Therapeutics, and EuroAtaxia.
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http://dx.doi.org/10.1016/S1474-4422(21)00027-2DOI Listing
May 2021

Smoking and alcohol, health-related quality of life and psychiatric comorbidities in Leber's Hereditary Optic Neuropathy mutation carriers: a prospective cohort study.

Orphanet J Rare Dis 2021 03 11;16(1):127. Epub 2021 Mar 11.

Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians University München, Ziemssenstr. 1a, 80336, Munich, Germany.

Background: Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial disorder, characterized by acute or subacute bilateral vision loss, frequently leading to significant chronic disability, mainly in young people. The causal LHON mutations of the mitochondrial DNA have incomplete penetrance, with the highest risk of disease manifestation for male mutation carriers in the second and third decades of life. Here we evaluated smoking, alcohol drinking habits, health-related quality of life (QOL) and psychiatric comorbidities in a cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral centre.

Methods: Cross-sectional analysis of the ongoing Munich LHON prospective cohort study. Participants included all LHON patients and asymptomatic LHON mutation carriers older than 16 years at baseline, who were recruited between February 2014 and June 2015 and consented to participate. General, neurological and ophthalmological investigations were performed, including validated questionnaires on smoking, alcohol drinking habits, depressive symptoms and health-related QOL.

Results: Seventy-one participants were included, 34 LHON patients (82% male) and 37 asymptomatic mutation carriers (19% male). Median age at baseline was 36 years (range 18-75 years). For LHON patients, median age at visual loss onset was 27 years (9 to 72 years). Smoking is more frequent in LHON patients than asymptomatic LHON mutation carriers, and significantly more frequent in both groups than in the general population. Sixty percent of LHON patients, who smoked at disease onset, stopped or significantly reduced smoking after visual loss onset, yet 40% of LHON patients continued to smoke at study baseline. Excessive alcohol consumption is more frequent in male LHON patients than in LHON asymptomatic and more frequent than in the male general population. Further, female asymptomatic LHON mutation carriers are at risk for depression and worse mental QOL scores.

Conclusions: Given the high prevalence of smoking and excessive drinking in LHON mutation carriers, implementing effective measures to reduce these risk factors may have a significant impact in reducing LHON disease conversion risk. The underrecognized prevalence of mental health issues in this population of LHON mutation carriers highlights the need for awareness and more timely diagnosis, which may lead to improved outcomes.
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http://dx.doi.org/10.1186/s13023-021-01724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953635PMC
March 2021

Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON)-An International Network on Care and Research for Patients With Neurodegeneration With Brain Iron Accumulation (NBIA).

Front Neurol 2021 22;12:642228. Epub 2021 Feb 22.

Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany.

In order to improve clinical care, coordinate research activities and raise awareness for the ultra-orphan Neurodegeneration with Brain Iron Accumulation (NBIA) disorders, a group of NBIA clinicians and researchers, industry partners and patient advocacies from six European countries, Canada and the US joined forces in 2010 to set-up the collaborative initiative TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration). As a research project, TIRCON received funding in the 7th Framework Programme (FP7) of the European Union (EU) from 2011 to 2015. After successful and timely completion of the initial FP7 project, funding and donations from industry and patient organizations have sustained the further development of TIRCON's dedicated clinical research infrastructure and its governance architecture, as well as the ongoing efforts undertaken in the NBIA community to establish a network of care. From the beginning, the University Hospital of the Ludwig-Maximilians-University in Munich, Germany has been coordinating the TIRCON initiative. It consists of 8 work packages, of which the first double-blind, placebo-controlled, randomized, multi-site clinical trial in NBIA (deferiprone in PKAN, completed) and a global patient registry and biobank, currently comprising baseline and follow-up data of > 400 NBIA patients have gained particular importance. Here we describe TIRCON's history with all the challenges and achievements in diagnosing and treating NBIA. Today, TIRCON lays the ground for future clinical care and research. In these times, it may also serve as a good example of well-directed governmental funding and fruitful international scientific collaboration.
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http://dx.doi.org/10.3389/fneur.2021.642228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937633PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy.

Orphanet J Rare Dis 2021 02 4;16(1):64. Epub 2021 Feb 4.

Interdisciplinary Pediatric Center for Children With Developmental Disabilities and Severe Chronic Disorders, University Medical Center Göttingen, Göttingen, Germany.

Background: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I-XIV.

Results: We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control.

Conclusions: Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients.
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http://dx.doi.org/10.1186/s13023-021-01690-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860214PMC
February 2021

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

J Clin Invest 2021 03;131(6)

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.
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http://dx.doi.org/10.1172/JCI138267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954600PMC
March 2021

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

Ophthalmology 2021 05 12;128(5):649-660. Epub 2021 Jan 12.

Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; Fondation Ophtalmologique A. de Rothschild, Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; CHNO des Quinze-Vingts, Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC, Paris, France.

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).

Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.

Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.

Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 10 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.

Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.

Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.

Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
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http://dx.doi.org/10.1016/j.ophtha.2020.12.012DOI Listing
May 2021

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

Sci Transl Med 2020 12;12(573)

Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, FOReSIGHT, INSERM-DGOS CIC 1423, 75012 Paris, France.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2- in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A () mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2- (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2--treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met ( = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.
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http://dx.doi.org/10.1126/scitranslmed.aaz7423DOI Listing
December 2020

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

Mov Disord 2021 06 16;36(6):1342-1352. Epub 2020 Nov 16.

Research and Development, Retrophin, Inc., San Diego, California, USA.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments.

Objectives: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression.

Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL.

Results: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups.

Conclusions: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246547PMC
June 2021

Biotinidase deficiency: A treatable cause of hereditary spastic paraparesis.

Neurol Genet 2020 Dec 13;6(6):e525. Epub 2020 Oct 13.

Friedrich Baur Institute at the Department of Neurology (F.R., T.K.), University Hospital, LMU Munich; Institute of Human Genetics (K.M.R., T.M., M.W.), Klinikum rechts der Isar, Technical University of Munich; Department of Nephrology (K.M.R.), Klinikum rechts der Isar, Technical University of Munich; Department of Ophthalmology (L.F.K.), Ludwig-Maximilians-University, Munich; Department of Pediatrics (G.G.), Division for Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg; Institute of Human Genetics (T.M., M.W.), Helmholtz Zentrum München, Neuherberg; German Center for Neurodegenerative Diseases (DZNE) (T.K.), Munich; Munich Cluster of Systems Neurology (SyNergy) (T.K.), Munich; and Institute of Neurogenomics (M.W.), Helmholtz Zentrum München, Neuherberg, Germany.

Objective: To expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD).

Methods: We performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional rating scales. We performed ophthalmologic examinations and metabolic testing.

Results: A 41-year-old patient presented with slowly progressive lower limb spasticity combined with optic atrophy. He was clinically diagnosed with complex hereditary spastic paraparesis. The initial panel diagnostics did not reveal the disease-causing variant; therefore, ES was performed. ES revealed biallelic pathogenic variants in the gene leading to the genetic diagnosis of BD. BD is an autosomal recessive metabolic disorder causing a broad spectrum of neurologic symptoms, optic atrophy, and dermatologic abnormalities. When treatment is initiated in time, symptoms can be prevented or reversed by biotin supplementation. After diagnosis in our patient, biotin supplementation was started. One year after the onset of therapy, symptoms remained stable with slight improvement of sensory deficits.

Conclusions: These findings expand the genetic spectrum of the clinical diagnosis of complex hereditary spastic paraparesis by a treatable disease. Today, most children with BD should have been identified via newborn screening to start biotin supplementation before the onset of symptoms. However, adult patients and those born in countries without newborn screening programs for BD are at risk of being missed. Therapeutic success depends on early diagnosis and presymptomatic treatment.
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http://dx.doi.org/10.1212/NXG.0000000000000525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577526PMC
December 2020

Corrigendum to "Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases" [EBioMedicine 54 (2020) 102730].

EBioMedicine 2020 Nov 21;61:103072. Epub 2020 Oct 21.

Friedrich-Baur-Institute, Department of Neurology, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.103072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581886PMC
November 2020

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy.

J Neuroophthalmol 2020 12;40(4):558-565

Department of Neurology (CBC, OM, TK), Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (CBC, TK), Munich, Germany; Department of Ophthalmology (BL, CP, FL, GR), University Hospital of the Ludwig-Maximilians-University Munich, Germany; New York Eye and Ear Infirmary of Mount Sinai (RB), New York, New York; Ophthalmology Department (SM), Waikato Hospital, Hamilton, New Zealand; Scheie Eye Institute (MAT), University of Pennsylvania, Philadelphia, Pennsylvania; Institut Català de Retina (LC), Barcelona, Spain; Augenklinik (CF), Universitätsklinikum Giessen, Giessen, Germany; University Hospital Southampton (CAH), Southampton, United Kingdom; McGovern Medical School (JAL), UTHealth, Houston, Texas; Department of Ophthalmology (GLT, KL, SJL), University Hospital and University of Zurich, Zurich, Switzerland; Neuro-ophthalmology Associates (GA), Ankara, Turkey; Manchester Centre for Genomic Medicine (GCMB), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, United Kingdom; Division of Evolution and Genomic Sciences (GCMB), Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Ophthalmology Unit (CD), Hospital de Poniente, El Ejido, Almería, Spain; Save Sight Institute (CLF), University of Sydney, Sydney, Australia; Department of Pediatric Traumatology and Emergency Medicine (JJ), Wroclaw Medical University, Poland; Poland SPEKTRUM Ophthalmology Clinic (JJ), Wroclaw, Poland; University Hospital Ramon y Cajal (FJM-N), IRYCIS, Madrid, Spain; Emory University School of Medicine (NJN), Atlanta Georgia; Nuffield Dept Obstetrics and Gynaecology (JP), University of Oxford, The Women's Centre, Oxford, United Kingdom; Department of Ophthalmology (ES), East Kent Hospitals University Foundation Trust, United Kingdom; Neuro-Ophthalmology Division (PS), University of Colorado School of Medicine, Aurora, Colorado; Department of Neuroinflammation (ATT), Queen Square MS Centre, UCL Institute of Neurology, University College London, London, United Kingdom; Hospital Sant Joan de Déu Barcelona (MV), Barcelona, Spain; Eye Department (ALV), Greenlane Clinical Centre, Auckland, New Zealand; School of Optometry and Vision Sciences (MV), Cardiff University, Cardiff, United Kingdom; Department of Developmental Neurology (MZ), Poznan University of Medical Sciences, Poznan, Poland; Manchester Centre for Clinical Neuroscience (AZ), Salford Royal NHS Foundation Trust, Salford, United Kingdom; Neuro-ophthalmology Unit (MS, XL, GM) Santhera Pharmaceuticals, Pratteln, Switzerland; and Munich Cluster for Systems Neurology (SyNergy) (TK), Munich, Germany.

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse.

Methods: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed.

Results: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor.

Conclusions: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.
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http://dx.doi.org/10.1097/WNO.0000000000001023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657145PMC
December 2020

The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria.

J Inherit Metab Dis 2021 03 21;44(2):426-437. Epub 2020 Sep 21.

Department of Biology, Concordia University, Montreal Quebec, Canada.

TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis-induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary to better counsel families regarding treatment options and nutrition management to mitigate the metabolic aspects of the disease. The few studies performed to address the pathway(s) in which TANGO2 functions have led to enigmatic results, with some suggesting defects in membrane traffic while others suggest unknown mitochondrial defects. Here, we have performed a robust membrane trafficking assay on fibroblasts derived from three different individuals harboring TANGO2 variants and show that there is a significant delay in the movement of cargo between the endoplasmic reticulum and the Golgi. Importantly, this delay was attributed to a defect in TANGO2 function. We further show that a portion of TANGO2 protein localizes to the mitochondria through a necessary but not sufficient stretch of amino acids at the amino terminus of the protein. Fibroblasts from affected individuals also displayed changes in mitochondrial morphology. We conclude that TANGO2 functions in both membrane trafficking and in some as yet undetermined role in mitochondria physiology. The phenotype of affected individuals can be partially explained by this dual involvement of the protein.
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http://dx.doi.org/10.1002/jimd.12312DOI Listing
March 2021

-associated neurodevelopmental disorder: Family with novel mutation expands the phenotypic spectrum.

Neurol Genet 2020 Oct 4;6(5):e500. Epub 2020 Aug 4.

Friedrich-Baur-Institute (C.M.N., C.B.C., T.K.), Department of Neurology, University Hospital, LMU Munich, Germany; Institute of Human Genetics (C.M.N.), University Medical Center Göttingen, Germany; Department of Pediatrics (H.S.), Medical Genetics, Dr. von Haunersches Kinderspital, University Hospital, LMU Munich, Germany; Department of Neuroradiology (K.S.), University Hospital, LMU Munich, Germany; Institute of Human Genetics (B.A., T.B.H.), Technical University Munich, Germany; Institute of Human Genetics (B.A., T.B.H.), Helmholtz Zentrum München, Neuherberg, Germany; German Center for Neurodegenerative Diseases (DZNE) (T.K.), Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy) (T.K.), Munich, Germany.

Objective: Clinical, neuroimaging, and genetic characterization of 3 patients with -associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits.

Methods: Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members.

Results: The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in , c.1672_1679del, and p.Gly558Pro*22, whereas both parents and healthy siblings are heterozygous for the mutation. No major brain malformations were evident in 3T brain MRI of the affected brothers.

Conclusion: This consanguineous family with a novel mutation expands the spectrum of -associated disorder to include developmental regression, oculomotor signs, and dystonia, previously not described in the published 9 cases of this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of -associated disorder.
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http://dx.doi.org/10.1212/NXG.0000000000000500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413627PMC
October 2020
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