Publications by authors named "Bjarne Udd"

191 Publications

Panorama of the distal myopathies.

Acta Myol 2020 Dec 1;39(4):245-265. Epub 2020 Dec 1.

Folkhälsan Research Center, Helsinki, Finland.

Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the distribution of muscle weakness (upper versus lower limbs) and the histological findings (ranging from nonspecific myopathic changes to myofibrillar disarrays and rimmed vacuoles) are extremely variable. However, despite being characterized by a wide clinical and genetic heterogeneity, the distal myopathies are a category of muscular dystrophies: genetic diseases with progressive loss of muscle fibers. Myopathic congenital arthrogryposis is also a form of distal myopathy usually caused by focal amyoplasia. Massive parallel sequencing has further expanded the long list of genes associated with a distal myopathy, and contributed identifying as distal myopathy-causative rare variants in genes more often related with other skeletal or cardiac muscle diseases. Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Pathogenic changes in four genes (ADSSL, ANO5, DYSF, GNE) cause an autosomal recessive form; and disease-causing variants in five genes (DES, MYH7, NEB, RYR1 and TTN) result either in a dominant or in a recessive distal myopathy. Finally, a digenic mechanism, underlying a Welander-like form of distal myopathy, has been recently elucidated. Rare pathogenic mutations in SQSTM1, previously identified with a bone disease (Paget disease), unexpectedly cause a distal myopathy when combined with a common polymorphism in TIA1. The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.36185/2532-1900-028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783427PMC
December 2020

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

Brain 2020 09;143(9):2696-2708

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

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

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

Genotype-phenotype correlations in recessive titinopathies.

Genet Med 2020 Dec 11;22(12):2029-2040. Epub 2020 Aug 11.

Folkhälsan Research Center, Helsinki, Finland.

Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort.

Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).

Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364).

Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0914-2DOI Listing
December 2020

The constantly evolving spectrum of phenotypes in titinopathies - will it ever stop?

Authors:
Bjarne Udd

Curr Opin Neurol 2020 10;33(5):604-610

Tampere Neuromuscular Center, Tampere University Hospital, Tampere.

Purpose Of Review: The last few years have confirmed previous assumptions of an enormous impact of the titin gene (TTN) on the occurrence of muscle disease, cardiomyopathy, or both together. The reason for this rather late understanding of its importance is because of the huge size which prevented sequencing of the whole gene by the previous Sanger technique in the individual cases. An update of the advances in diagnosing titinopathies is the main focus of this review.

Recent Findings: High throughput methods are now widely available for TTN sequencing and a corresponding explosion of different types of identified titinopathies is observed and published in the literature, although final confirmation is lacking in many cases with recessive missense variants.

Summary: The implications of these findings for clinical practice are easy to understand: patients with previously undiagnosed muscle disease can now have a correct diagnosis and subsequently receive a likely prognosis, can have accurate genetic counseling for the whole family and early treatment for predictable complications from the heart and respiratory muscles. In addition not to forget, they can avoid wrong diagnoses leading to wrong treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WCO.0000000000000850DOI Listing
October 2020

Identification and Characterization of Splicing Defects by Single-Molecule Real-Time Sequencing Technology (PacBio).

J Neuromuscul Dis 2020 ;7(4):477-481

Folkhälsan Research Center, Helsinki, Finland.

Although DNA-sequencing is the most effective procedure to achieve a molecular diagnosis in genetic diseases, complementary RNA analyses are often required.Reverse-Transcription polymerase chain reaction (RT-PCR) is still a valuable option when the clinical phenotype and/or available DNA-test results address the diagnosis toward a gene of interest or when the splicing effect of a single variant needs to be assessed.We use Single-Molecule Real-Time sequencing to detect and characterize splicing defects and single nucleotide variants in well-known disease genes (DMD, NF1, TTN). After proper optimization, the procedure could be used in the diagnostic setting, simplifying the workflow of cDNA analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-200523DOI Listing
January 2020

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

J Neuromuscul Dis 2020 ;7(3):203-216

Folkhälsan Research Center, Helsinki, Finland.

Human genes have a variable length. Those having a coding sequence of extraordinary length and a high number of exons were almost impossible to sequence using the traditional Sanger-based gene-by-gene approach. High-throughput sequencing has partly overcome the size-related technical issues, enabling a straightforward, rapid and relatively inexpensive analysis of large genes.Several large genes (e.g. TTN, NEB, RYR1, DMD) are recognized as disease-causing in patients with skeletal muscle diseases. However, because of their sheer size, the clinical interpretation of variants in these genes is probably the most challenging aspect of the high-throughput genetic investigation in the field of skeletal muscle diseases.The main aim of this review is to discuss the technical and interpretative issues related to the diagnostic investigation of large genes and to reflect upon the current state of the art and the future advancements in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-190459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369045PMC
January 2020

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results.

Int J Mol Sci 2020 Feb 19;21(4). Epub 2020 Feb 19.

Folkhälsan Research Center, Helsinki, Finland and Medicum, University of Helsinki, FI-00290 Helsinki, Finland.

Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21041409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073051PMC
February 2020

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies.

J Neuromuscul Dis 2020 ;7(2):153-166

Folkhälsan Research Center, Helsinki, Finland.

Background: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.

Objective: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants.

Methods: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort.

Results: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified.

Conclusions: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-190423DOI Listing
November 2020

Mutations in the J domain of DNAJB6 cause dominant distal myopathy.

Neuromuscul Disord 2020 01 19;30(1):38-46. Epub 2019 Nov 19.

Neuromuscular Research Center, Tampere University Hospital and Tampere University, P.O. box 100, FIN-33014 Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland and University of Helsinki, Medicum, Helsinki, Finland.

Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.11.005DOI Listing
January 2020

Improving Copy Number Variant Detection from Sequencing Data with a Combination of Programs and a Predictive Model.

J Mol Diagn 2020 01 13;22(1):40-49. Epub 2019 Nov 13.

Folkhälsan Research Center, Helsinki, Finland.

Bioinformatics tools for analyzing copy number variants (CNVs) from massively parallel sequencing (MPS) data are less well developed compared with other variant types. We present an efficient bioinformatics pipeline for CNV detection from gene panel MPS data in neuromuscular disorders. CNVs were generated in silico into samples sequenced with a previously published MPS gene panel. The in silico CNVs from these samples were analyzed with four programs having complementary CNV detection ranges: CoNIFER, XHMM, ExomeDepth, and CODEX. A logistic regression model was trained with the obtained set of in silico CNV detections to predict true-positive CNV detections among all CNV detections from samples. This model was validated using 66 control samples with a verified true-positive (n = 58) or false-positive (n = 8) CNV detection. Applying all four programs together provided more sensitive detection results with in silico CNVs than other program combinations or any program alone. Furthermore, a model with CNV detection-specific scores from all four programs as variables performed overall best in the validation. No single program could detect all CNV sizes and types equally or with enough accuracy. Therefore, a combination of carefully selected programs should be used to maximize detection accuracy. In addition, the detected CNVs should be reviewed with a statistical model to streamline and standardize the filtering of the detections for annotation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2019.08.009DOI Listing
January 2020

MYO-MRI diagnostic protocols in genetic myopathies.

Neuromuscul Disord 2019 11 16;29(11):827-841. Epub 2019 Sep 16.

Robert-Yves Carlier, Service de Radiologie et Imagerie Médicale Hôpital Raymond Poincaré, Hôpitaux de Paris (AP-HP), Garches, France; Centre de référence des maladies neuro-musculaires Paris-Nord-ESt, Filenemus, France. Electronic address:

Whole-body magnetic resonance imaging has emerged as a useful imaging tool in diagnosing and characterizing the progression of myopathies and muscular dystrophies. Whole-body MRI indications and diagnostic efficacy are becoming better defined with the increasing number of cases, publications and discussions within multidisciplinary working groups. Advanced Whole-body MRI protocols are rapid, lower cost, and well-tolerated by patients. Accurate interpretation of muscle Whole-body MRI requires a detailed knowledge of muscle anatomy and differential pattern of involvement in muscle diseases. With the surge in recently identified novel genetic myopathies, Whole-body MRI will become increasingly useful for phenotypic validation of genetic variants of unknown significance. In addition, Whole-body MRI will be progressively used as a biomarker for disease progression and quantify response to therapy with the emergence of novel disease modifying treatments. This review outlines Whole-body MRI indications and updates refined protocols and provides a comprehensive overview of the diagnostic utility and suggested methodology of Whole-body MRI for pediatric and adult patients with muscle diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.08.011DOI Listing
November 2019

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

Hum Mutat 2020 02 3;41(2):403-411. Epub 2019 Dec 3.

Kids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306402PMC
February 2020

Consensus-based care recommendations for adults with myotonic dystrophy type 2.

Neurol Clin Pract 2019 Aug;9(4):343-353

Ludwig-Maximilians- Universität (BS); Friedrich-Baur-Institut (FM), Munich, Germany; Institut de Myologie (GB), Paris, France; U.O. Neurologia (BF), IRCCS Policlinico San Donato, Milan, Italy; Vall d'Hebron University Hospital (JG), Barcelona, Spain; University of Rochester (CH, JH, RM, CT), Rochester, NY; University Hospital of Bonn (CK), Germany; Medical University of Warsaw (AK-P), Poland; University of Texas (RK) MD Anderson cancer center; Medical University of Warsaw (AL), Poland; Department of Biomedical Sciences for health (GM), University of Milan, Italy; Tampere University (BU), Finland; Myotonic Dystrophy Foundation (PF), San Francisco.

Purpose Of Review: Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients.

Summary: The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745739PMC
August 2019

Valosin-containing protein-related myopathy and Meige syndrome: Just a coincidence or not?

Muscle Nerve 2019 12 23;60(6):E43-E45. Epub 2019 Oct 23.

First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Greece.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26704DOI Listing
December 2019

New family with 8-associated autosomal dominant rimmed vacuolar myopathy.

Neurol Genet 2019 Aug 10;5(4):e349. Epub 2019 Jul 10.

Division of Genetics and Genomic Medicine (S.A.-T., L.W., H.Y.), Department of Pediatrics, University of California, Irvine; Opti West (S.A.-T.), West Anaheim Medical Center, Anaheim; Ambry Genetics (S.T.), Mission Viejo, CA; Miller School of Medicine (M.S.), University of Miami, FL; Folkhälsan Institute of Genetics and the Department of Medical Genetics (A.V., B.U.), Medicum, University of Helsinki; Neuromuscular Research Center (A.V., B.U.), Tampere University and University Hospital, Neurology, Finland; Neuromuscular Program (T.M.), Department of Neurology, University of California-Irvine, Orange; and Neurology Department (B.U.), Vasa Central Hospital, Finland.

Objective: We clinically and molecularly characterize a new family with autosomal dominant rimmed vacuolar myopathy (RVM) caused by mutations in the gene.

Methods: We performed whole-exome and whole-genome sequencing in the family. Western blot and immunocytochemistry were used to analyze 3 patient fibroblasts, and findings were compared with their age- and sex-matched controls.

Results: Affected patients have distal and proximal myopathy, with muscle biopsy showing rimmed vacuoles, muscle fiber atrophy, and endomysial fibrosis typical of RVM. Muscle MRI showed severe relatively symmetric multifocal fatty degenerative changes of the lower extremities. We identified a duplication of C at position 515 of the gene (c.515dupC) by whole-genome sequencing, which caused a frameshift with a predicted alternate stop codon p.P173SFS*43 in all affected individuals, resulting in an elongated protein product. Western blot and immunocytochemistry studies revealed reduced expression of heat shock protein beta 8 in patient fibroblasts compared with control fibroblasts, in addition to disrupted autophagy pathology.

Conclusions: We report a novel family with autosomal dominant RVM caused by the c.515dupC mutation of the gene, causing a translational frameshift that results in an elongated protein. Understanding the mechanism for the RVM pathology caused by mutated chaperone will permit novel targeted strategies to alter the natural history progression. As next-generation sequencing becomes more available, additional myopathic families will be identified with mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659134PMC
August 2019

Clinical spectrum and gene mutations in a Chinese cohort with anoctaminopathy.

Neuromuscul Disord 2019 08 12;29(8):628-633. Epub 2019 Jun 12.

Department of Neurology, Huashan Hospital Fudan University, Shanghai 200040, China. Electronic address:

Recessive mutations in anoctamin-5 (ANO5) are causative for limb-girdle muscular dystrophy (LGMD) 2 L and non-dysferlin Miyoshi-like distal myopathy (MMD3). ANO5 mutations are highly prevalent in European countries; however it is not common in patients of Asian origin, and there is no data regarding the Chinese population. We retrospectively reviewed the clinical manifestations and gene mutations of Chinese patients with anoctaminopathy. A total of five ANO5 mutations including four novel mutations and one reported mutation were found in four patients from three families. No hotspot mutation was found. Three patients presented with presymptomatic hyperCKemia and one patient had limb muscle weakness. Muscle imaging of lower limbs showed preferential adductor magnus and medial gastrocnemius involvement. No hotspot mutation has been identified in Chinese patients to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.06.005DOI Listing
August 2019

HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes.

J Neurol 2019 Oct 2;266(10):2524-2534. Epub 2019 Jul 2.

Neuropathology and Neuromuscular Diseases Laboratory, Buenos Aires, Argentina.

Autosomal dominant limb girdle muscular dystrophy D3 HNRNPDL-related is a rare dominant myopathy caused by mutations in HNRNPDL. Only three unrelated families have been described worldwide, a Brazilian and a Chinese carrying the mutation c.1132G>A p.(Asp378Asn), and one Uruguayan with the mutation c.1132G>C p. (Asp378His), both mutations occurring in the same codon. The present study enlarges the clinical, morphological and muscle MRI spectrum of AD-HNRNPDL-related myopathies demonstrating the significant particularities of the disease. We describe two new unrelated Argentinean families, carrying the previously reported c.1132G>C p.(Asp378His) HNRNPDL mutation. There was a wide phenotypic spectrum including oligo-symptomatic cases, pure limb girdle muscle involvement or distal lower limb muscle weakness. Scapular winging was the most common finding, observed in all patients. Muscle MRIs of the thigh, at different stages of the disease, showed particular involvement of adductor magnus and vastus besides a constant preservation of the rectus femoris and the adductor longus muscles, defining a novel MRI pattern. Muscle biopsy findings were characterized by the presence of numerous rimmed vacuoles, cytoplasmic bodies, and abundant autophagic material at the histochemistry and ultrastructural levels. HNRNPDL-related LGMD D3 results in a wide range of clinical phenotypes from the classic proximal form of LGMD to a more distal phenotype. Thigh MRI suggests a specific pattern. Codon 378 of HNRNPDL gene can be considered a mutation hotspot for HNRNPDL-related myopathy. Pathologically, the disease can be classified among the autophagic rimmed vacuolar myopathies as with the other multisystem proteinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-019-09437-3DOI Listing
October 2019

Novel mutation in causes congenital limb-girdle myopathy with slow progression.

Neurol Genet 2019 Jun 2;5(3):e337. Epub 2019 May 2.

Folkhälsan Institute of Genetics and Department of Medical Genetics (A.V.), Medicum, University of Helsinki; Neuromuscular Research Center (J.P.), Tampere University and University Hospital of Tampere, Finland; Neuromuscular Unit (O.D.), Division of Neurology, Department of Clinical and Experimental Medicine, Linköping University, Sweden; Neuromuscular Research Center (S. Penttilä), Tampere University and University Hospital of Tampere, Finland; Department of Neurology (D.L.), Department of Neurology (S. Pittman), Department of Neurology (C.W.), Washington University School of Medicine, Saint Louis, MO; Folkhälsan Institute of Genetics and Department of Medical Genetics (B.U.), Medicum, University of Helsinki; Neuromuscular Research Center (B.U.), Tampere University and University Hospital of Tampere; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.

Objective: We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.

Methods: Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and constructs were used to study the effect of the mutations in transfected cells.

Results: We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 () gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells.

Conclusions: We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515942PMC
June 2019

Involuntary movements, vocalizations and cognitive decline.

Parkinsonism Relat Disord 2019 May 29. Epub 2019 May 29.

Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2019.05.029DOI Listing
May 2019

1st ENMC European meeting: The EURO-NMD pathology working group Recommended Standards for Muscle Pathology Amsterdam, The Netherlands, 7 December 2018.

Neuromuscul Disord 2019 06 15;29(6):483-485. Epub 2019 Mar 15.

Institut de Myologie, CHU Pitié-Salpêtrière, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.03.002DOI Listing
June 2019

Oligogenic basis of sporadic ALS: The example of p.Ala90Val mutation.

Neurol Genet 2019 Jun 23;5(3):e335. Epub 2019 Apr 23.

Department of Clinical Genetics (L.K.), Helsinki University Hospital; Department of Medical Genetics (L.K.), University of Helsinki, Helsinki, Finland; Molecular Neurology (K.K., M.V., P.J.T.), Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland; Department of Medical Genetics (S.M.), University of Helsinki, Helsinki, Finland and Turku; University Hospital (S.M.), Laboratory Division, Genetics and Saske, Department of Medical Genetics, Turku, Finland; Department of Neurology (H.L.), Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland; Neuromuscular Research Center (M.J., B.U.), Tampere University Hospital and University of Tampere, Tampere, Finland; Division of Clinical Neurosciences (M.J.), Turku University Hospital and University of Turku, Turku, Finland; Folkhälsan Research Center (B.U.), Biomedicum, University of Helsinki, Helsinki, Finland; Institute of Biomedicine (P.P., J.S.), University of Turku; Turku University Hospital (P.P., J.S.), Laboratory Division, Genetics and Saske, Department of Medical Genetics, Turku, Finland; Department of Pathology (A.P.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Laboratory of Neurogenetics (B.J.T.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Merck & Co. (D.J.S.), Inc., West Point, PA; Department of Clinical Genetics (M.P.), Helsinki University Hospital; Department of Medical Genetics (M.P.), University of Helsinki, Helsinki, Finland; Department of Neurology (P.J.T.), Helsinki University Hospital; and Department of Pathology (L.M.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 () p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance.

Methods: An index patient with autopsy-proven ALS was discovered to have the p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data.

Results: Seven screened patients (1.5%) were found to carry the heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare and mutations. One patient was compound heterozygous for p.Ala90Val and p.Asp91Ala.

Conclusions: Our data suggest that the penetrance of p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the founder mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481226PMC
June 2019

A novel COL6A2 mutation causing late-onset limb-girdle muscular dystrophy.

J Neurol 2019 Jul 8;266(7):1649-1654. Epub 2019 Apr 8.

Neuromuscular Research Center, Department of Neurology, Tampere University and University Hospital, Tampere, Finland.

Limb-girdle muscular dystrophies (LGMD) are genetic disorders characterized by weakness of predominantly proximal limb and trunk muscles due to progressive loss of muscle tissue. Collagen VI-related muscular dystrophies usually display more generalized muscle involvement combined with contractures and/or hyperlaxity of distal finger joints. LGMD-like phenotype of collagenopathy has only rarely been described and as reported is usually of childhood onset. We identified a Finnish family with COL6A2-related LGMD with autosomal dominant inheritance and very late onset at 40-60 years of age. Since the mutation was previously unreported, the pathognomonic findings on muscle MRI were the decisive clue for the correct diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-019-09307-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586699PMC
July 2019

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions.

Nat Commun 2019 03 27;10(1):1396. Epub 2019 Mar 27.

Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, 6000, WA, Australia.

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437160PMC
March 2019

Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations.

Ann Neurol 2019 06 3;85(6):899-906. Epub 2019 Apr 3.

Folkhälsan Research Center, Helsinki, Finland.

Objective: To clinically and pathologically characterize a cohort of patients presenting with a novel form of distal myopathy and to identify the genetic cause of this new muscular dystrophy.

Methods: We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles.

Results: In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant.

Interpretation: ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy. ANN NEUROL 2019;85:899-906.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25470DOI Listing
June 2019

An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy.

Neurology 2019 04 6;92(14):e1600-e1609. Epub 2019 Mar 6.

From the Neuromuscular Research Center (M. Jokela, S.L., J.P., B.U.), Department of Neurology, University Hospital and University of Tampere; Division of Clinical Neurosciences (M. Jokela), Department of Neurology, Turku University Hospital and University of Turku; Kiinamyllynkatu 4-8 (M. Jokela), Turku, Finland; Unità Operativa Complessa di Neurologia (G.T.), Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Folkhälsan Institute of Genetics and Department of Medical Genetics (A.V., P.-H.J., S.V., M. Johari, M.S.), Haartman Institute, University of Helsinki, Finland; Institute of Pediatric Neurology (E.M., M.P.), Catholic University School of Medicine, Rome, Italy; Department of Pathology (S.H.), Fimlab Laboratories, Tampere University Hospital, Finland; Metabolic and Neuromuscular Unit (M.D.), Meyer Hospital, Florence, Italy; Department of Pediatric Neurology (P.I.), Children's Hospital, University of Helsinki and Helsinki University Hospital; Department of Neurology (P.H.), Kuopio University Hospital and University of Eastern Finland; and Department of Neurology (B.U.), Vasa Central Hospital, Finland.

Objective: To identify the genetic defect causing a distal calf myopathy with cores.

Methods: Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.

Results: A novel deletion-insertion mutation in ryanodine receptor 1 () was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique -mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.

Conclusions: Our findings expand the spectrum of -related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007246DOI Listing
April 2019

Clinical Reasoning: A 54-year-old man with dyspnea and muscle weakness.

Neurology 2019 03;92(10):e1136-e1140

From the Departments of Neurology (A.C., M.S., L.B., F.P., L.L.C., R.R.) and Respiratory Medicine (E.B.), Hospital Británico de Buenos Aires, Argentina; Folkhälsan Institute of Genetics (B.U.), Helsinki University; Tampere Neuromuscular Center (B.U.), Tampere University and University Hospital; and Neurology Department (B.U.), Vaasa Central Hospital, Vaasa, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007040DOI Listing
March 2019

Myasthenic congenital myopathy from recessive mutations at a single residue in Na1.4.

Neurology 2019 03 1;92(13):e1405-e1415. Epub 2019 Mar 1.

From the Departments of Physiology (N.E., M.Q., S.C.C.) and Neurology (P.B.S.), David Geffen School of Medicine at UCLA; Molecular and Cellular Integrative Physiology Program at UCLA (N.E., S.C.C.), Los Angeles, CA; Tampere Neuromuscular Center (J.P., T.S., B.U.), Tampere University and University Hospital, Finland; MRC Centre for Neuromuscular Diseases (M.S.C., M.G.H., R.M.), Department of Neuromuscular Disease, UCL Institute of Neurology, London, UK; Folkhälsan Genetic Institute (B.U.), Helsinki; and Neurology Department (B.U.), Vasa Central Hospital, Finland.

Objective: To identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, .

Methods: A combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and oocytes.

Results: Missense mutations of the same residue in the skeletal muscle sodium channel, R1460 of Na1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes.

Conclusions: Novel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453767PMC
March 2019