Publications by authors named "Hanns Lochmuller"

403 Publications

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Eur J Paediatr Neurol 2021 Feb 16;31:54-60. Epub 2021 Feb 16.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.005DOI Listing
February 2021

Costs of Illness of Spinal Muscular Atrophy: A Systematic Review.

Appl Health Econ Health Policy 2021 Feb 12. Epub 2021 Feb 12.

Department of Women's and Children's Health, Karolinska Institutet, Karolinska Vägen 37A, 171 76, Stockholm, Sweden.

Objectives: The objective of our study was to conduct a systematic literature review of estimates of costs of illness of spinal muscular atrophy (SMA).

Methods: We searched MEDLINE (through PubMed), CINAHL, Embase, Web of Science, National Health Service Economic Evaluation Database, and the National Health Service Health Technology Assessment Database for studies published from inception up until 31 August, 2020, reporting direct medical, direct non-medical, and/or indirect costs of any phenotype of SMA. Two reviewers independently screened records for eligibility, extracted the data, and assessed studies for risk of bias using the Newcastle-Ottawa Scale. Costs were adjusted and converted to 2018 US dollars.

Results: The search identified 14 studies from eight countries (Australia, France, Germany, Italy, Spain, Sweden, the UK, and the USA). The mean per-patient annual direct medical cost of illness was estimated at between $3320 (SMA type III, Italy) and $324,410 (SMA type I, USA), mean per-patient annual direct non-medical cost between $25,880 (SMA types I-III, Spain) and $136,800 (SMA type I, Sweden), and mean per-patient annual indirect cost between $9440 (SMA type I, Germany) and $74,910 (SMA type II, Australia). Most studies exhibited a risk of bias.

Conclusions: The current body of evidence of costs of illness of SMA is relatively scarce and characterized by considerable variability across geographical settings and disease phenotypes. Our review provides data pertaining to the economic impact of SMA, which is of particular relevance in light of emerging treatments and ongoing research in this field, and underscores the substantial unmet medical need in this patient population.
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http://dx.doi.org/10.1007/s40258-020-00624-2DOI Listing
February 2021

Results from a 3-year Non-interventional, Observational Disease Monitoring Program in Adults with GNE Myopathy.

J Neuromuscul Dis 2021 Jan 10. Epub 2021 Jan 10.

University of California Irvine, Orange, CA, USA.

Background: GNE myopathy is a rare, autosomal recessive, muscle disease caused by mutations in GNE and is characterized by rimmed vacuoles on muscle biopsy and progressive distal to proximal muscle weakness.

Objective: Investigate the clinical presentation and progression of GNE myopathy.

Methods: The GNE Myopathy Disease Monitoring Program was an international, prospective, observational study in subjects with GNE myopathy. Muscle strength was assessed with hand-held dynamometry (HHD), with upper extremity (UE) and lower extremity (LE) composite scores reflecting upper and lower extremity muscle groups, respectively. The GNE myopathy-Functional Activity Scale (GNEM-FAS) was used to further assess impairment in mobility, upper extremity function, and self-care.

Results: Eighty-seven of 101 enrolled subjects completed the trial until study closer by the sponsor; 60 completed 36 months. Mean (SD) HHD UE composite score decreased from 34.3 kg (32.0) at baseline to 29.4 kg (32.6) kg at month 36 (LS mean change [95%CI]: -3.8 kg [-5.9, -1.7]; P = 0.0005). Mean (SD) HHD LE composite score decreased from 32.0 kg (34.1) at baseline to 25.5 kg (31.2) at month 36 (LS mean change [95%CI]: -4.9 [-7.7, -2.2]; P = 0.0005). GNEM-FAS scores were more severe at baseline in subjects who walked <  200 meters versus≥200 meters in 6 minutes; in both groups, GNEM-FAS total, mobility, UE, and self-care scores decreased from baseline through month 36.

Conclusions: These findings demonstrate progressive decline in muscle strength in GNE myopathy and provide insight into the appropriate tools to detect clinically meaningful changes in future GNE myopathy interventional trials.
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http://dx.doi.org/10.3233/JND-200565DOI Listing
January 2021

Autosomal recessive variants in alter the γ-tubulin ring complex leading to neurodevelopmental disease.

iScience 2021 Jan 30;24(1):101948. Epub 2020 Dec 30.

John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.
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http://dx.doi.org/10.1016/j.isci.2020.101948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797523PMC
January 2021

Molecular pathophysiology of human MICU1 deficiency.

Neuropathol Appl Neurobiol 2021 Jan 11. Epub 2021 Jan 11.

Department of Neuropediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Aims: MICU1 encodes the gatekeeper of the mitochondrial Ca uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology.

Methods: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans.

Results: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca transport and proteomic studies on lymphoblastoid cells revealed that the [Ca ] threshold and the cooperative activation of mitochondrial Ca uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms.

Conclusions: Our findings (i) link dysregulation of mitochondrial Ca uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.
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http://dx.doi.org/10.1111/nan.12694DOI Listing
January 2021

Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome.

Front Mol Neurosci 2020 17;13:594220. Epub 2020 Dec 17.

Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.

Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The gene is one of over 30 genes known to harbor mutations causative for CMS. In this study, we aimed to determine if a compound (NT1654), developed to stimulate the acetylcholine receptor (AChR) clustering pathway, would benefit a mouse model of CMS caused by a loss-of-function mutation in ( mouse). mice received an injection of either NT1654 or vehicle compound daily, with wild-type litter mates used for comparison. Animals were weighed daily and underwent grip strength assessments. After 30 days of treatment animals were sacrificed, and muscles collected. Investigations into NMJ and muscle morphology were performed on collected tissue. While minimal improvements in NMJ ultrastructure were observed with electron microscopy, gross NMJ structure analysis using fluorescent labelling and confocal microscopy revealed extensive postsynaptic improvements in mice with NT1654 administration, with variables frequently returning to wild type levels. An improvement in muscle weight and myofiber characteristics helped increase forelimb grip strength and body weight. We conclude that NT1654 restores NMJ postsynaptic structure and improves muscle strength through normalization of muscle fiber composition and the prevention of atrophy. We hypothesize this occurs through the AChR clustering pathway in mice. Future studies should investigate if this may represent a viable treatment option for patients with CMS, especially those with mutations in proteins of the AChR clustering pathway.
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http://dx.doi.org/10.3389/fnmol.2020.594220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773664PMC
December 2020

Long Term Follow-Up on Pediatric Cases With Congenital Myasthenic Syndromes-A Retrospective Single Centre Cohort Study.

Front Hum Neurosci 2020 7;14:560860. Epub 2020 Dec 7.

Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany.

: Congenital myasthenic syndromes (CMS) refer to a heterogenic group of neuromuscular transmission disorders. CMS-subtypes are diverse regarding exercise intolerance and muscular weakness, varying from mild symptoms to life-limiting forms with neonatal onset. Long-term follow-up studies on disease progression and treatment-response in pediatric patients are rare. : We analyzed retrospective clinical and medication data in a cohort of 32 CMS-patients including the application of a standardized, not yet validated test (CMS-ST) to examine muscular strength and endurance in 21 patients at the last follow-up. Findings obtained in our cohort were compared with long-term follow-up studies of (adult) CMS-cohorts from the literature by considering the underlying molecular mechanisms. Outcomes of CMS-ST were compared to results of normal clinical assessment. : Thirty-two pediatric patients with defects in eight different CMS-genes were followed by a median time of 12.8 years. Fifty-nine percentage of patients manifested with first symptoms as neonates, 35% as infants. While 53% of patients presented a reduced walking distance, 34% were wheelchair-bound. Even under adequate therapy with pyridostigmine (PS) and 3,4-diaminopyridine, -mutations led to the progression of muscular weakness partly in combination with persistent respiratory and bulbar symptoms. , and patients with neonatal manifestation, early respiratory problems, and bulbar symptoms showed a good and maintained treatment response. and patients required higher PS dosages, whereas patients needed a lower mean dosage at the last follow-up. The benefits of short-term medication and long-term progression of symptoms were highly dependent on the specific genetic defect. CMS-ST was carried out in 17/21 patients, determined affected muscle groups including bulbar and ocular symptoms, some of which were not reported by the patients. : Our findings and comparison with the literature- suggest a better treatment-response and less severe progression of symptoms present in patients suffering from mutations in CMS-genes directly associated with receptor deficiency, while patients with defects leading to synaptopathy and presynaptic defects tend to have worse outcomes. Assessment of affected muscular groups and clinical symptoms by CMS-ST may be a useful tool for optimal therapeutic management of the patients, especially for future clinical studies.
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http://dx.doi.org/10.3389/fnhum.2020.560860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750519PMC
December 2020

Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa.

J Inherit Metab Dis 2020 Dec 15. Epub 2020 Dec 15.

Institut für Medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Several inborn errors of metabolism show cutis laxa as a highly recognizable feature. One group of these metabolic cutis laxa conditions is autosomal recessive cutis laxa type 2 caused by defects in v-ATPase components or the mitochondrial proline cycle. Besides cutis laxa, muscular hypotonia and cardiac abnormalities are hallmarks of autosomal recessive cutis laxa type 2D (ARCL2D) due to pathogenic variants in ATP6V1A encoding subunit A of the v-ATPase. Here, we report on three affected individuals from two families with ARCL2D in whom we performed whole exome and Sanger sequencing. We performed functional studies in fibroblasts from one individual, summarized all known probands' clinical, molecular, and biochemical features and compared them, also to other metabolic forms of cutis laxa. We identified novel missense and the first nonsense variant strongly affecting ATP6V1A expression. All six ARCL2D affected individuals show equally severe cutis laxa and dysmorphism at birth. While for one no information was available, two died in infancy and three are now adolescents with mild or absent intellectual disability. Muscular weakness, ptosis, contractures, and elevated muscle enzymes indicated a persistent myopathy. In cellular studies, a fragmented Golgi compartment, a delayed Brefeldin A-induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in ATP6V1A as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of ATP6V1A related phenotypes even within the same family.
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http://dx.doi.org/10.1002/jimd.12341DOI Listing
December 2020

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

EMBO J 2020 Dec 31;39(23):e105364. Epub 2020 Oct 31.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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http://dx.doi.org/10.15252/embj.2020105364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705457PMC
December 2020

A Phase 2 Study of AMO-02 (Tideglusib) in Congenital and Childhood-Onset Myotonic Dystrophy Type 1 (DM1).

Pediatr Neurol 2020 11 5;112:84-93. Epub 2020 Aug 5.

Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy.

Methods: Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained.

Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments.

Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.08.001DOI Listing
November 2020

A guide to writing systematic reviews of rare disease treatments to generate FAIR-compliant datasets: building a Treatabolome.

Orphanet J Rare Dis 2020 08 12;15(1):206. Epub 2020 Aug 12.

Sorbonne Universite - Inserm UMRS 974, Center of Research in Myology, Institut de Myologie, G.H. Pitié-Salpêtrière Paris, 47, boulevard de l'Hopital, F-75 651, Paris Cedex 13, France.

Background: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families.

Aims: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD.

Results: Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence.

Conclusions: This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data.
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http://dx.doi.org/10.1186/s13023-020-01493-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424983PMC
August 2020

Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.

Brain 2020 08;143(8):2406-2420

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.
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http://dx.doi.org/10.1093/brain/awaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447519PMC
August 2020

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Am J Med Genet A 2020 10 10;182(10):2272-2283. Epub 2020 Aug 10.

Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.
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http://dx.doi.org/10.1002/ajmg.a.61765DOI Listing
October 2020

Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy.

Front Genet 2020 3;11:605. Epub 2020 Jul 3.

Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment.

Methods And Findings: We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in the gene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts ( = 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results.

Conclusion: We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.
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http://dx.doi.org/10.3389/fgene.2020.00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350910PMC
July 2020

A novel, pathogenic dinucleotide deletion in the mitochondrial MT-TY gene causing myasthenia-like features.

Neuromuscul Disord 2020 08 24;30(8):661-668. Epub 2020 Jun 24.

Wellcome Centre for Mitochondrial Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

Mitochondrial DNA (mtDNA)-related diseases often pose a diagnostic challenge and require rigorous clinical and laboratory investigation. Pathogenic variants in the mitochondrial tRNA gene MT-TY, which encodes the tRNA, are a rare cause of mitochondrial disease. Here we describe a novel m.5860delTA anticodon variant in the MT-TY gene in a patient who initially presented with features akin to a childhood onset myasthenic syndrome. Using histochemical, immunohistochemical and protein studies we demonstrate that this mutation leads to severe biochemical defects of mitochondrial translation, which is reflected in the early onset and progressive phenotype. This case highlights the clinical overlap between mtDNA-related diseases and other neuromuscular disorders, and demonstrates the potential pitfalls in analysis of next generation sequencing results, given whole exome sequencing of a blood DNA sample failed to make a genetics diagnosis. Muscle biopsy remains an important requirement in the diagnosis of mitochondrial disease and in establishing the pathogenicity of novel mtDNA variants.
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http://dx.doi.org/10.1016/j.nmd.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477489PMC
August 2020

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion.

J Neurol 2020 Dec 12;267(12):3643-3649. Epub 2020 Jul 12.

Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.

Background: Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing.

Methods: Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother.

Results: Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1.

Conclusions: The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.
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http://dx.doi.org/10.1007/s00415-020-10059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674332PMC
December 2020

Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity.

J Mol Diagn 2020 09 30;22(9):1205-1215. Epub 2020 Jun 30.

Centro Nacional de Análisis Genómico (CNAG)-Centro de Regulación Genómica (CRG), Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:

Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)-Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477492PMC
September 2020

Change over time in ability to perform activities of daily living in myotonic dystrophy type 1.

J Neurol 2020 Nov 15;267(11):3235-3242. Epub 2020 Jun 15.

Department of Neuropediatrics and Muscle Disorders, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objective: The objective of this longitudinal, observational study was to investigate change over time in ability to perform activities of daily living in myotonic dystrophy type 1 (DM1).

Methods: Adults with genetically confirmed DM1 were recruited as part of the PhenoDM1 study in the UK. Data on activities of daily living were recorded through the DM1-Activ at baseline and a follow-up visit after 12 (± 3) months. A subset of patients had advanced genetic testing to determine the size of the progenitor allele.

Results: Our sample comprised 150 patients with DM1 (mean age: 45 years; 52% female). Mean follow-up was 383 days. Mean DM1-Activ total score at baseline was 71.24 (95% confidence interval 67.77-74.71) and at the follow-up visit 69.04 (65.54-72.54). Approximately 43% of patients had a lower score at the follow-up visit (indicating a decreased ability to perform activities of daily living), 24% a higher score (indicating an increased ability), and 33% the same score at baseline and follow-up. The mean annual change in the DM1-Activ total score, estimated at - 2.06 (- 3.54 to - 0.59), was significantly related to patients' baseline score, but not sex, disease duration, timed test results, or cytosine-thymine-guanine repeat length.

Conclusions: Change over time in ability to perform activities of daily living as recorded through the DM1-Activ varies substantially between patients with DM1. Our data contribute to the understanding of the natural evolution of the disease, and should be helpful to inform the design of future trials based on the DM1-Activ.
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http://dx.doi.org/10.1007/s00415-020-09970-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578145PMC
November 2020

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

Can J Neurol Sci 2020 11 4;47(6):810-815. Epub 2020 Jun 4.

Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.

Background: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.

Methods: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.

Results: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.

Conclusion: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
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http://dx.doi.org/10.1017/cjn.2020.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656664PMC
November 2020

Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development.

Lancet Neurol 2020 06 26;19(6):522-532. Epub 2020 May 26.

Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Medicine, Ottawa Research Institute, Ottawa, ON, Canada; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. Electronic address:

Advances in DNA sequencing technologies have resulted in a near doubling, in under 10 years, of the number of causal genes identified for inherited neuromuscular disorders. However, around half of patients, whether children or adults, do not receive a molecular diagnosis after initial diagnostic workup. Massively parallel technologies targeting RNA, proteins, and metabolites are being increasingly used to diagnose these unsolved cases. The use of these technologies to delineate pathways, biomarkers, and therapeutic targets has led to new approaches entering the drug development pipeline. However, these technologies might give rise to misleading conclusions if used in isolation, and traditional techniques including comprehensive neurological evaluation, histopathology, and biochemistry continue to have a crucial role in diagnostics. For optimal diagnosis, prognosis, and precision medicine, no single ruling technology exists. Instead, an interdisciplinary approach combining novel and traditional neurological techniques with computer-aided analysis and international data sharing is needed to advance the diagnosis and treatment of neuromuscular disorders.
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http://dx.doi.org/10.1016/S1474-4422(20)30028-4DOI Listing
June 2020

Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

J Neuromuscul Dis 2020 ;7(3):301-308

Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.

Background: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease.

Objective: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype.

Methods: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families.

Results: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15).

Conclusions: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.
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http://dx.doi.org/10.3233/JND-200510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458500PMC
January 2020

Blood-derived biomarkers correlate with clinical progression in Duchenne muscular dystrophy.

J Neuromuscul Dis 2020 ;7(3):231-246

Department of Protein Science, School of Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Stockholm, Sweden.

Background: Duchenne Muscular Dystrophy is a severe, incurable disorder caused by mutations in the dystrophin gene. The disease is characterized by decreased muscle function, impaired muscle regeneration and increased inflammation. In a clinical context, muscle deterioration, is evaluated using physical tests and analysis of muscle biopsies, which fail to accurately monitor the disease progression.

Objectives: This study aims to confirm and asses the value of blood protein biomarkers as disease progression markers using one of the largest longitudinal collection of samples.

Methods: A total of 560 samples, both serum and plasma, collected at three clinical sites are analyzed using a suspension bead array platform to assess 118 proteins targeted by 250 antibodies in microliter amount of samples.

Results: Nine proteins are confirmed as disease progression biomarkers in both plasma and serum. Abundance of these biomarkers decreases as the disease progresses but follows different trajectories. While carbonic anhydrase 3, microtubule associated protein 4 and collagen type I alpha 1 chain decline rather constantly over time, myosin light chain 3, electron transfer flavoprotein A, troponin T, malate dehydrogenase 2, lactate dehydrogenase B and nestin plateaus in early teens. Electron transfer flavoprotein A, correlates with the outcome of 6-minutes-walking-test whereas malate dehydrogenase 2 together with myosin light chain 3, carbonic anhydrase 3 and nestin correlate with respiratory capacity.

Conclusions: Nine biomarkers have been identified that correlate with disease milestones, functional tests and respiratory capacity. Together these biomarkers recapitulate different stages of the disorder that, if validated can improve disease progression monitoring.
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http://dx.doi.org/10.3233/JND-190454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369103PMC
January 2020

Economic Costs of Myasthenia Gravis: A Systematic Review.

Pharmacoeconomics 2020 07;38(7):715-728

Division of Neurology, Department of Medicine, The Ottawa Hospital, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.

Objectives: The objective of our study was to conduct a systematic literature review of economic costs (henceforth costs) associated with myasthenia gravis (MG).

Methods: We searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies reporting costs of MG published from inception up until March 18, 2020, without language restrictions. Two reviewers independently screened records for eligibility, extracted the data, and assessed included studies for risk of bias using the Newcastle-Ottawa Scale. Costs were inflated and converted to 2018 United States dollars ($).

Results: The search identified 16 articles for data extraction and synthesis. Estimates of costs of MG were found for samples from eight countries spanning four continents (Europe, North America, South America, and Asia). Across studies, the mean per-patient annual direct medical cost of illness was estimated at between $760 and $28,780, and cost per hospitalization between $2550 and $164,730. The indirect cost of illness was estimated at $80 and $3550. Costs varied considerably by patient characteristics, and drivers of the direct medical cost of illness included intravenous immunoglobulin and plasma exchange, myasthenic crisis, mechanical ventilatory support, and hospitalizations.

Conclusions: We show that the current body of literature of costs of MG is sparse, limited to a few geographical settings and resource categories, mostly dated, and subject to non-trivial variability, both within and between countries. Our synthesis will help researchers and decision-makers identify gaps in the local health economic context of MG and inform future cost studies and economic evaluations in this patient population.
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http://dx.doi.org/10.1007/s40273-020-00912-8DOI Listing
July 2020

Severe congenital myasthenic syndrome associated with novel biallelic mutation of the CHRND gene.

Neuromuscul Disord 2020 04 24;30(4):336-339. Epub 2020 Feb 24.

Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada; Department of Medicine, Division of Neurology, The Ottawa Hospital, Ottawa, Canada.

Congenital myasthenic syndromes (CMS) are a group of inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular transmission. CMS is characterized by fatigable muscle weakness with onset at birth or in early childhood; rarely, symptoms may present later. The most frequently involved proteins are choline acetyltransferase, the endplate species of acetylcholinesterase and the acetylcholine receptor subunits. Defects in the cholinergic receptor nicotinic delta subunit (CHRND) are a rare cause for CMS but they should be considered in patients with a severe, early onset disease, with respiratory distress. We describe two sisters, clinically and genetically diagnosed with CMS, carrying two heteroallelic variants in the CHRND gene: c.730C>T; p.(Arg244Cys) and c.1304T>C; p.(Leu435Pro). The first variant has already been described yet no clinical relevance has been proved; the second one, is a novel variant documented here for the first time. These two cases expand the clinical spectrum of CMS linked to CHRND mutations.
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http://dx.doi.org/10.1016/j.nmd.2020.02.012DOI Listing
April 2020

Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9.

Ann Clin Transl Neurol 2020 05 28;7(5):757-766. Epub 2020 Apr 28.

John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Objective: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities.

Methods: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain.

Results: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129).

Interpretation: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.
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http://dx.doi.org/10.1002/acn3.51042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261761PMC
May 2020

Congenital myasthenic syndrome due to DOK7 mutation in a cohort of patients with 'unexplained' limb-girdle muscular weakness.

J Clin Neurosci 2020 May 29;75:195-198. Epub 2020 Mar 29.

Service of Neuromuscular Disorders, Division of Neurology, Department of Internal Medicine, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, Brazil. Electronic address:

Congenital myasthenic syndromes (CMS) associated with pathogenic variants in the DOK7 gene (DOK7-CMS) have phenotypic overlap with other neuromuscular disorders associated with limb-girdle muscular weakness (LGMW). Genetic analysis of the most common mutation (c.1124_1127dupTGCC) in DOK7 was performed in 34 patients with "unexplained" LGMW associated with non-specific changes in muscle biopsy. Of the 34 patients, one patient showed the DOK7 c.1124_1127dupTGCC variant in homozygousity. Our study estimates the minimum prevalence of undiagnosed DOK7-CMS to be 2.9% in southern Brazilian patients from our centre. Our data confirm that clinicians should look for DOK7-CMS patients when the clinical manifestation is an 'unexplained' LGMW, mainly if associated with non-specific changes in muscle biopsy.
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http://dx.doi.org/10.1016/j.jocn.2020.01.080DOI Listing
May 2020

An improved method for culturing myotubes on laminins for the robust clustering of postsynaptic machinery.

Sci Rep 2020 03 11;10(1):4524. Epub 2020 Mar 11.

Laboratory of Synaptogenesis, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.

Motor neurons form specialized synapses with skeletal muscle fibers, called neuromuscular junctions (NMJs). Cultured myotubes are used as a simplified in vitro system to study the postsynaptic specialization of muscles. The stimulation of myotubes with the glycoprotein agrin or laminin-111 induces the clustering of postsynaptic machinery that contains acetylcholine receptors (AChRs). When myotubes are grown on laminin-coated surfaces, AChR clusters undergo developmental remodeling to form topologically complex structures that resemble mature NMJs. Needing further exploration are the molecular processes that govern AChR cluster assembly and its developmental maturation. Here, we describe an improved protocol for culturing muscle cells to promote the formation of complex AChR clusters. We screened various laminin isoforms and showed that laminin-221 was the most potent for inducing AChR clusters, whereas laminin-121, laminin-211, and laminin-221 afforded the highest percentages of topologically complex assemblies. Human primary myotubes that were formed by myoblasts obtained from patient biopsies also assembled AChR clusters that underwent remodeling in vitro. Collectively, these results demonstrate an advancement of culturing myotubes that can facilitate high-throughput screening for potential therapeutic targets for neuromuscular disorders.
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http://dx.doi.org/10.1038/s41598-020-61347-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066178PMC
March 2020

Life expectancy at birth in Duchenne muscular dystrophy: a systematic review and meta-analysis.

Eur J Epidemiol 2020 Jul 27;35(7):643-653. Epub 2020 Feb 27.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

Several studies indicate that prognosis for survival in Duchenne muscular dystrophy (DMD) has improved in recent decades. However, published evidence is inconclusive and some estimates may be obsolete due to improvements in standards of care, in particular the routine use of mechanical ventilatory support in advanced stages of the disease. In this systematic review and meta-analysis (PROSPERO identifier: CRD42019121800), we searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies published from inception up until December 31, 2018, reporting results of life expectancy in DMD. We pooled median survival estimates from individual studies using the median of medians, and weighted median of medians, methods. Risk of bias was established with the Newcastle-Ottawa Scale. Results were stratified by ventilatory support and risk of bias. We identified 15 publications involving 2662 patients from 12 countries from all inhabited continents except Africa. Median life expectancy without ventilatory support ranged between 14.4 and 27.0 years (pooled median: 19.0 years, 95% CI 18.0-20.9; weighted pooled median: 19.4 years, 18.2-20.1). Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). Risk of bias had little impact on pooled results. In conclusion, median life expectancy at birth in DMD seems to have improved considerably during the last decades. With current standards of care, many patients with DMD can now expect to live into their fourth decade of life.
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http://dx.doi.org/10.1007/s10654-020-00613-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387367PMC
July 2020

-related autosomal recessive encephalopathy in 2 Turkish children.

Neurol Genet 2020 Feb 10;6(1):e392. Epub 2020 Jan 10.

Pediatric Neurology Clinic (A.Y.), Private Office, Diyarbakir, Turkey; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa, Canada; Division of Neurology (H.L.), Department of Medicine, The Ottawa Hospital, Canada; John Walton Muscular Dystrophy Research Centre (A.T.), Institute of Genetic Medicine, Newcastle University, UK; Dokuz Eylul University (S.H., E.S., E.Y., Y.O.), Izmir International Biomedicine and Genome Institute, Turkey; Faculty of Medicine (S.H., U.Y., A.I.P., P.E.), Department of Paediatric Neurology, Dokuz Eylul University, Izmir, Turkey; Faculty of Medicine (S.G.), Turgut Ozal Research Center, Department of Paediatric Neurology, Inonu University, Malatya, Turkey; CNAG-CRG (S.L., H.L., S.B.), Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain; Universitat Pompeu Fabra (S.L.), Barcelona, Spain; Koc University (A.Y.), School of Medicine, Medical Student, Istanbul, Turkey; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Izmir Biomedicine and Genome Center (Y.O.), Dokuz Eylul University Health Campus, Turkey; and Faculty of Medicine (Y.O.), Department of Medical Biology, Dokuz Eylul University, Izmir, Turkey.

Objective: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.

Methods: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.

Results: We have identified a homozygous missense mutation in (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.

Conclusions: has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that -related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.
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http://dx.doi.org/10.1212/NXG.0000000000000392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975172PMC
February 2020