Blake, JC

Bugiardini, E

Hanna, MG

Holton, JL

Houlden, H

Lynch, DS

Matthews, E

Pittman, AM

Reilly, MM

Rossor, AM

Swash, M

Enrico Bugiardini

Alexander M. Rossor

David S. Lynch

Michael Swash

Alan M. Pittman

Julian C. Blake

Michael G. Hanna

Henry Houlden

Janice L. Holton

Mary M. Reilly

Emma Matthews

Crossref

Neurology Genetics

Homozygous mutation in <i>HSPB1</i> causing distal vacuolar myopathy and motor neuropathy

UCL Discovery

Clinical/ScientificNotesEnrico Bugiardini, MDAlexander M. Rossor,MRCPDavid S. Lynch, MRCPIMichael Swash, FRCPAlan M. Pittman, PhDJulian C. Blake, MRCPMichael G. Hanna, FRCPHenry Houlden, FRCPJanice L. Holton,FRCPathMary M. Reilly, FRCPIEmma Matthews, MRCPNeurol Genet2017;3:e168; doi: 10.1212/NXG.0000000000000168HOMOZYGOUS MUTATION IN HSPB1 CAUSINGDISTAL VACUOLAR MYOPATHY AND MOTORNEUROPATHYCase report. A 57-year-old woman, born to parentsof Gujarati Indian descent (figure, A), presented atage 19 with pain and stiffness in her calves and a ten-dency to trip. In her 20s, a formal neurologic exam-ination demonstrated predominantly distal lowerlimb weakness and normal upper limb musclestrength.1 Motor and sensory nerve conduction stud-ies were normal with the exception that no motorresponse was elicited from the extensor digitorumbrevis. Fibrillations and polyphasic action potentialswere present on EMG. The creatine kinase (CK) levelwas 1,452 IU/L. A quadriceps muscle biopsy wasperformed at age 27 from which images were availablein the records.1 At that time, muscle fiber diameterswere large ranging from 50 to 80 mm. Many of thefibers contained single or multiple unrimmed va-cuoles that appeared empty in the modified Gomoritrichrome preparation (figure, B.a). There was noincrease in endomysial connective tissue or evidenceof inflammation, necrosis, or regeneration. There wasno evidence of glycogen, increased lipid, or acid phos-phatase staining in the vacuoles (figure, B.b). TheATPase at pH 9.5 demonstrated that most of thevacuolated fibers were of type 2, and electron micros-copy showed electron-dense material within vacuoles(figure, B.c and d).1 The overall appearances werethose of a vacuolar myopathy without any featuressuggesting neurogenic change, and she was diagnosedwith a distal myopathy.1She re-presented at age 57 following the develop-ment of slowly progressive severe upper and lowerlimb weaknesses. On examination at age 57, therewas evidence of distal more than proximal upperlimb weakness affecting wrist extension (MedicalResearch Council [MRC] grade 41/5), fingerextension (4 1 5), first dorsal interossei (1/5),abductor pollicis brevis (3/5 right and 4/5 left),and abductor digiti minimi (3/5 right and 4/5 left).In the lower limbs, she had severe proximal weak-ness (grade 2/3) with no movement at the ankles.Sensory modalities were preserved except forreduced vibration sense at the ankles. She wasareflexic. Her CK level was 404 IU/L. Neurophys-iologic studies suggested an axonal motor neurop-athy. Sensory nerve action potentials were,nevertheless, at the lower limit of normal for ampli-tude in the lower limbs (right sural 6 mV, rightsuperficial peroneal 7 mV, and normal range .5 mV),and distal lower limb motor responses were absent.Needle EMG showed prominent chronic neuro-genic changes with large motor units recruiting inreduced numbers but at increased firing rates toa reduced interference pattern. This EMG patternwas most pronounced distally but evident proxi-mally in the upper and lower limbs. No low ampli-tude or brief polyphasic motor units were seen onany occasion at re-presentation. Muscle MRI wasperformed, showing widespread severe muscle fattyreplacement (figure, C).There was no relevant family history. Her motherhas diabetes and her father a right above knee ampu-tation for peripheral vascular disease. Neither hadneurologic complaints. However, clinical examina-tion of both in their 80s revealed mild distal weakness(MRC grade 4/5) in the upper and lower limbs withareflexia. Pinprick sensation was reduced to the mid-forearm and foot in her mother. Her father hadreduced vibration sense to the left ankle. Neurophys-iologic testing was not possible in either.Targeted exome sequencing of the proband’sDNA using the Agilent Focused Exome kit identifieda homozygous variant (c.418C.G, p.Arg140Gly) inHSPB1, which was confirmed by Sanger sequencing.Both parents were heterozygous. We have reportedthis variant previously in heterozygous form in indi-viduals from 5 Indian Gujarati families with distalmotor neuropathy.2Discussion. Our patient presented at age 19 withclinical and biopsy features consistent with a distalmyopathy. Prominent vacuoles in type 2 fibers con-tained granular, electron-dense material (figure, B)that was interpreted to represent the product of myo-fibrillar degeneration.1 At presentation, neurophysio-logic studies did show fibrillations and polyphasicaction potentials. However, nerve conduction studieswere normal with the exception of 1 absent motornerve response, and overall, the clinical image was feltto represent a distal myopathy at this time. SubsequentNeurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 1neurophysiologic studies performed at age 57 follow-ing progressive limb weakness revealed an axonalmotor neuropathy. Although chronic end-stagemyopathy may have neurophysiologic features thatcan appear neurogenic, in this case, even the lessaffected proximal limb muscles failed to demonstrateany myopathic motor units or myopathic recruitment.HSPB1 is a small heat-shock protein highly ex-pressed in striated muscle with an important role inmaintaining myofibrillar structure during stressconditions.3Mutations in HSPB1, HSPB3, and HSPB8 areclassically associated with motor neuropathy.4 HSPB5(CRYAB) has been associated with a wide spectrum ofclinical manifestations including desmin-related myo-fibrillar myopathy. The protein position of theArg140Gly HSPB1 mutation in our case correspondsto the Arg120 HSPB5 residue mutated in this myop-athy (figure, D).4 Heterozygous mutations in HSPB8have recently been reported causing neuropathy anddistal myopathy with rimmed vacuoles and fibrillaraggregates in 2 families.5 Subsequently, distalmyopathy and neuronopathy have been attributedto an HSPB1 mutation in 1 family.6 We describea patient with a homozygous HSPB1 mutation alsopresenting with a distal vacuolar myopathy, motorneuropathy, and minimal sensory involvement, sup-porting the association of HSPB1mutations with thisphenotype. This expands the genetic testing indicatedin distal vacuolar myopathy.From the MRC Centre for Neuromuscular Diseases (E.B., A.M.R.,J.C.B., M.G.H., J.L.H., M.M.R., E.M.), UCL Institute of Neurol-ogy and National Hospital for Neurology and Neurosurgery; Depart-ment of Molecular Neuroscience (D.S.L., A.M.P., M.G.H., H.H.,J.L.H.), and Division of Neuropathology (J.L.H.), UCL Instituteof Neurology, London; Department of Neurology (M.S.), The RoyalLondon Hospital; and Department of Clinical Neurophysiology(J.C.B.), Norfolk and Norwich University Hospital, UK.Author contributions: Enrico Bugiardini: drafting and revising themanuscript, study concept, and interpretation of data. AlexanderM. Rossor: interpretation of data and revising the manuscript. DavidS. Lynch: acquisition of data and analysis of data. Michael Swash:interpretation of data and revising the manuscript. Alan M. Pittman:acquisition of data and analysis of data. Julian C. Blake: interpretationof data and revising the manuscript. Michael G. Hanna: revising themanuscript and study concept. Henry Houlden: revising the manuscriptand study concept. Janice L. Holton: interpretation of data and revisingFigure Clinical-pathologic features of patient homozygous for the HSPB1 p.Arg140Gly mutation and protein conservation between species(A) Family pedigree: an arrow indicates the proband; half-filled indicates distal weakness in parents who were heterozygous for p.Arg140Gly mutation. (B)Biopsy of the quadriceps muscle performed at age 27; (B.a) modified Gomori trichrome staining shows variation in fiber diameter and prominent vacuoleswithin many muscle fibers, arrows; (B.b) Periodic acid–Schiff preparation showed no evidence of glycogen accumulation within vacuoles (arrows); (B.c)ATPase pH 9.5 demonstrates that vacuoles are predominantly in darkly stained type 2 fibers, arrows; and (B.d) ultrastructural examination of the musclerevealed electron-dense material within vacuoles (arrows). (C) Muscle MRI demonstrating severe widespread fatty infiltration of pelvic, thigh, and calfmuscles with relative sparing of the adductor longus (red arrows). (D) Conservation of HSPB1 and HSPB5 (CRYAB) amino acid sequence between species.The Arg140 residue in HSPB1 is well conserved and corresponds to the position of Arg120 in the CRYAB gene.2 Neurology: Geneticsthe manuscript. Mary M. Reilly: revising the manuscript and studyconcept. Emma Matthews: drafting and revising the manuscript, studyconcept, and interpretation of data.Study funding: The research leading to these results has receivedfunding from the European Community’s Seventh Framework Pro-gramme (FP7/2007–2013) under grant agreement no. 2012-305121 “Integrated European–omics research project for diagnosisand therapy in rare neuromuscular and neurodegenerative diseases(NEUROMICS).” This work is also supported by a Medical ResearchCouncil Centre grant and Wellcome Trust grant on Synaptopathies.Part of this work was undertaken at University College LondonHospitals/University College London, which received a proportion offunding from the Department of Health’s National Institute forHealth Research Biomedical Research Centres’ funding scheme.Disclosure: E. Bugiardini reports no disclosures. A.M. Rossor isfunded by a Wellcome Trust Postdoctoral Fellowship for Clinicians(110043/Z/15/Z). D.S. Lynch reports no disclosures. M. Swash hasreceived speaker honoraria for lectures and educational activities notfunded by industry; has served on the editorial boards of variousscientific and medical journals; has held patents regarding electronicmeasuring devices; receives royalties from the publication of severalbooks; has served as Chief Medical Officer for Swiss Re Life andHealth; serves on the Board of Directors for MedHand AB Stockholmand Malvern Arts Press; has served as an advisor to Best Doctors Inc.,Europe (receives compensation); holds stock/stock options in Med-Hand AB Stockholm; and serves as an expert witness for legal pro-ceedings. A.M. Pittman and J.C. Blake report no disclosures.M.G. Hanna is supported by a Medical Research Council Centregrant, the National Centre for Research Resources, the Myositis SupportGroup, and the National Highly Specialised Service (HSS) Depart-ment of Health UK and has been a consultant for Novartis. H. Houl-den has received research support from the Medical Research Council(MRC) UK, The BRT, The MDA USA, Muscular Dystrophy UK,Ataxia UK, Muscular Dystrophy UK, Rosetrees Trust, The WellcomeTrust, and the National Institute for Health (NIHR) UCL/UCLH BRC. J.L. Holton has received travel funding fromMerck Serono; has served on the editorial board of Neuropathol-ogy Applied Neurobiology; has been an employee of UniversityCollege London; and has received research support from Alz-heimer’s Research Trust, the Margaret Watson Memorial TrustGrant from The Sarah Matheson Trust, Action MedicalResearch, Brain Net Europe: Support for the Queen SquareBrain Bank for Neurological Disorders, the Sarah MathesonTrust, Myositis Support Group, the Multiple System AtrophyTrust, Michael J Fox Foundation for Parkinson’s Research,Alzheimer’s Research UK, MSA Coalition, King Baudouin Foun-dation Sophia Fund, and Medical Research Council. M.M. Reillyreceives support from the Medical Research Council (MRC), MRCCentre grant (G0601943), and the National Institutes of NeurologicalDiseases and Stroke and office of Rare Diseases (U54NS065712); hasserved on the editorial boards of Brain, Neuromuscular Disorders;Journal of the Peripheral Nervous System; and JNNP; has beena consultant for Servier, Acceleron, and Alnylam; and has receivedresearch support from Wellcome Trust, UCL CBRC, Ipsen, MuscularDystrophy Association (US), Muscular dystrophy campaign grants,CLH/UCL Comprehensive Biomedical Research Centre, and CRDC.E. Matthews is funded by a postdoctoral fellowship from the NIHR andhas received research support from the Brain Research Trust and theMuscular Dystrophy Campaign. Go to Neurology.org/ng for full disclo-sure forms. The Article Processing Charge was funded by the authors.This is an open access article distributed under the terms of theCreative Commons Attribution License 4.0 (CC BY), which permitsunrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.Received April 10, 2017. Accepted in final form April 24, 2017.Correspondence to Dr. Matthews: emma.matthews@ucl.ac.uk1. Swash M, Schwarz MS, Thompson A, Cox E, Gray A. Distalmyopathy with focal granular degenerative change in vacuo-lated type 2 fibers. Clin Neuropathol 1988;7:249–253.2. Rossor AM, Morrow JM, Polke JM, et al. Pilot phenotypeand natural history study of hereditary neuropathies causedby mutations in the HSPB1 gene. Neuromuscul Disord2017;27:50–56.3. Sugiyama Y, Suzuki A, Kishikawa M, et al. Muscle developsa specific form of small heat shock protein complex com-posed of MKBP/HSPB2 and HSPB3 during myogenic dif-ferentiation. J Biol Chem 2000;275:1095–1104.4. Benndorf R, Martin JL, Kosakovsky Pond SL, Wertheim JO.Neuropathy- and myopathy-associated mutations in humansmall heat shock proteins: characteristics and evolutionaryhistory of the mutation sites. Mutat Res Rev Mutat Res2014;76:15–30.5. Ghaoui R, Palmio J, Brewer J, et al. Mutations in HSPB8causing a new phenotype of distal myopathy and motorneuropathy. Neurology 2016;86:391–398.6. Lewis-Smith DJ, Duff J, Pyle A, et al. NovelHSPB1 mutation causes both motor neuronopathyand distal myopathy. Neurol Genet 2016;2:e110.doi: 10.1212/NXG.0000000000000110.Neurology: Genetics 3DOI 10.1212/NXG.00000000000001682017;3; Neurol Genet Enrico Bugiardini, Alexander M. Rossor, David S. Lynch, et al. neuropathy causing distal vacuolar myopathy and motorHSPB1Homozygous mutation in This information is current as of July 6, 2017ServicesUpdated Information & http://ng.neurology.org/content/3/4/e168.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/3/4/e168.full.html##ref-list-1This article cites 6 articles, 2 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/peripheral_neuropathyPeripheral neuropathy http://ng.neurology.org//cgi/collection/muscle_diseaseMuscle disease http://ng.neurology.org//cgi/collection/all_neuromuscular_diseaseAll Neuromuscular Disease http://ng.neurology.org//cgi/collection/all_geneticsAll Geneticsfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2017 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

Homozygous mutation in HSPB1 causing distal vacuolar myopathy and motor neuropathy

St George's Online Research Archive

Clinical/ScientificNotesEnrico Bugiardini, MDAlexander M. Rossor,MRCPDavid S. Lynch, MRCPIMichael Swash, FRCPAlan M. Pittman, PhDJulian C. Blake, MRCPMichael G. Hanna, FRCPHenry Houlden, FRCPJanice L. Holton,FRCPathMary M. Reilly, FRCPIEmma Matthews, MRCPNeurol Genet2017;3:e168; doi: 10.1212/NXG.0000000000000168HOMOZYGOUS MUTATION IN HSPB1 CAUSINGDISTAL VACUOLAR MYOPATHY AND MOTORNEUROPATHYCase report. A 57-year-old woman, born to parentsof Gujarati Indian descent (figure, A), presented atage 19 with pain and stiffness in her calves and a ten-dency to trip. In her 20s, a formal neurologic exam-ination demonstrated predominantly distal lowerlimb weakness and normal upper limb musclestrength.1 Motor and sensory nerve conduction stud-ies were normal with the exception that no motorresponse was elicited from the extensor digitorumbrevis. Fibrillations and polyphasic action potentialswere present on EMG. The creatine kinase (CK) levelwas 1,452 IU/L. A quadriceps muscle biopsy wasperformed at age 27 from which images were availablein the records.1 At that time, muscle fiber diameterswere large ranging from 50 to 80 mm. Many of thefibers contained single or multiple unrimmed va-cuoles that appeared empty in the modified Gomoritrichrome preparation (figure, B.a). There was noincrease in endomysial connective tissue or evidenceof inflammation, necrosis, or regeneration. There wasno evidence of glycogen, increased lipid, or acid phos-phatase staining in the vacuoles (figure, B.b). TheATPase at pH 9.5 demonstrated that most of thevacuolated fibers were of type 2, and electron micros-copy showed electron-dense material within vacuoles(figure, B.c and d).1 The overall appearances werethose of a vacuolar myopathy without any featuressuggesting neurogenic change, and she was diagnosedwith a distal myopathy.1She re-presented at age 57 following the develop-ment of slowly progressive severe upper and lowerlimb weaknesses. On examination at age 57, therewas evidence of distal more than proximal upperlimb weakness affecting wrist extension (MedicalResearch Council [MRC] grade 41/5), fingerextension (4 1 5), first dorsal interossei (1/5),abductor pollicis brevis (3/5 right and 4/5 left),and abductor digiti minimi (3/5 right and 4/5 left).In the lower limbs, she had severe proximal weak-ness (grade 2/3) with no movement at the ankles.Sensory modalities were preserved except forreduced vibration sense at the ankles. She wasareflexic. Her CK level was 404 IU/L. Neurophys-iologic studies suggested an axonal motor neurop-athy. Sensory nerve action potentials were,nevertheless, at the lower limit of normal for ampli-tude in the lower limbs (right sural 6 mV, rightsuperficial peroneal 7 mV, and normal range .5 mV),and distal lower limb motor responses were absent.Needle EMG showed prominent chronic neuro-genic changes with large motor units recruiting inreduced numbers but at increased firing rates toa reduced interference pattern. This EMG patternwas most pronounced distally but evident proxi-mally in the upper and lower limbs. No low ampli-tude or brief polyphasic motor units were seen onany occasion at re-presentation. Muscle MRI wasperformed, showing widespread severe muscle fattyreplacement (figure, C).There was no relevant family history. Her motherhas diabetes and her father a right above knee ampu-tation for peripheral vascular disease. Neither hadneurologic complaints. However, clinical examina-tion of both in their 80s revealed mild distal weakness(MRC grade 4/5) in the upper and lower limbs withareflexia. Pinprick sensation was reduced to the mid-forearm and foot in her mother. Her father hadreduced vibration sense to the left ankle. Neurophys-iologic testing was not possible in either.Targeted exome sequencing of the proband’sDNA using the Agilent Focused Exome kit identifieda homozygous variant (c.418C.G, p.Arg140Gly) inHSPB1, which was confirmed by Sanger sequencing.Both parents were heterozygous. We have reportedthis variant previously in heterozygous form in indi-viduals from 5 Indian Gujarati families with distalmotor neuropathy.2Discussion. Our patient presented at age 19 withclinical and biopsy features consistent with a distalmyopathy. Prominent vacuoles in type 2 fibers con-tained granular, electron-dense material (figure, B)that was interpreted to represent the product of myo-fibrillar degeneration.1 At presentation, neurophysio-logic studies did show fibrillations and polyphasicaction potentials. However, nerve conduction studieswere normal with the exception of 1 absent motornerve response, and overall, the clinical image was feltto represent a distal myopathy at this time. SubsequentNeurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 1neurophysiologic studies performed at age 57 follow-ing progressive limb weakness revealed an axonalmotor neuropathy. Although chronic end-stagemyopathy may have neurophysiologic features thatcan appear neurogenic, in this case, even the lessaffected proximal limb muscles failed to demonstrateany myopathic motor units or myopathic recruitment.HSPB1 is a small heat-shock protein highly ex-pressed in striated muscle with an important role inmaintaining myofibrillar structure during stressconditions.3Mutations in HSPB1, HSPB3, and HSPB8 areclassically associated with motor neuropathy.4 HSPB5(CRYAB) has been associated with a wide spectrum ofclinical manifestations including desmin-related myo-fibrillar myopathy. The protein position of theArg140Gly HSPB1 mutation in our case correspondsto the Arg120 HSPB5 residue mutated in this myop-athy (figure, D).4 Heterozygous mutations in HSPB8have recently been reported causing neuropathy anddistal myopathy with rimmed vacuoles and fibrillaraggregates in 2 families.5 Subsequently, distalmyopathy and neuronopathy have been attributedto an HSPB1 mutation in 1 family.6 We describea patient with a homozygous HSPB1 mutation alsopresenting with a distal vacuolar myopathy, motorneuropathy, and minimal sensory involvement, sup-porting the association of HSPB1mutations with thisphenotype. This expands the genetic testing indicatedin distal vacuolar myopathy.From the MRC Centre for Neuromuscular Diseases (E.B., A.M.R.,J.C.B., M.G.H., J.L.H., M.M.R., E.M.), UCL Institute of Neurol-ogy and National Hospital for Neurology and Neurosurgery; Depart-ment of Molecular Neuroscience (D.S.L., A.M.P., M.G.H., H.H.,J.L.H.), and Division of Neuropathology (J.L.H.), UCL Instituteof Neurology, London; Department of Neurology (M.S.), The RoyalLondon Hospital; and Department of Clinical Neurophysiology(J.C.B.), Norfolk and Norwich University Hospital, UK.Author contributions: Enrico Bugiardini: drafting and revising themanuscript, study concept, and interpretation of data. AlexanderM. Rossor: interpretation of data and revising the manuscript. DavidS. Lynch: acquisition of data and analysis of data. Michael Swash:interpretation of data and revising the manuscript. Alan M. Pittman:acquisition of data and analysis of data. Julian C. Blake: interpretationof data and revising the manuscript. Michael G. Hanna: revising themanuscript and study concept. Henry Houlden: revising the manuscriptand study concept. Janice L. Holton: interpretation of data and revisingFigure Clinical-pathologic features of patient homozygous for the HSPB1 p.Arg140Gly mutation and protein conservation between species(A) Family pedigree: an arrow indicates the proband; half-filled indicates distal weakness in parents who were heterozygous for p.Arg140Gly mutation. (B)Biopsy of the quadriceps muscle performed at age 27; (B.a) modified Gomori trichrome staining shows variation in fiber diameter and prominent vacuoleswithin many muscle fibers, arrows; (B.b) Periodic acid–Schiff preparation showed no evidence of glycogen accumulation within vacuoles (arrows); (B.c)ATPase pH 9.5 demonstrates that vacuoles are predominantly in darkly stained type 2 fibers, arrows; and (B.d) ultrastructural examination of the musclerevealed electron-dense material within vacuoles (arrows). (C) Muscle MRI demonstrating severe widespread fatty infiltration of pelvic, thigh, and calfmuscles with relative sparing of the adductor longus (red arrows). (D) Conservation of HSPB1 and HSPB5 (CRYAB) amino acid sequence between species.The Arg140 residue in HSPB1 is well conserved and corresponds to the position of Arg120 in the CRYAB gene.2 Neurology: Geneticsthe manuscript. Mary M. Reilly: revising the manuscript and studyconcept. Emma Matthews: drafting and revising the manuscript, studyconcept, and interpretation of data.Study funding: The research leading to these results has receivedfunding from the European Community’s Seventh Framework Pro-gramme (FP7/2007–2013) under grant agreement no. 2012-305121 “Integrated European–omics research project for diagnosisand therapy in rare neuromuscular and neurodegenerative diseases(NEUROMICS).” This work is also supported by a Medical ResearchCouncil Centre grant and Wellcome Trust grant on Synaptopathies.Part of this work was undertaken at University College LondonHospitals/University College London, which received a proportion offunding from the Department of Health’s National Institute forHealth Research Biomedical Research Centres’ funding scheme.Disclosure: E. Bugiardini reports no disclosures. A.M. Rossor isfunded by a Wellcome Trust Postdoctoral Fellowship for Clinicians(110043/Z/15/Z). D.S. Lynch reports no disclosures. M. Swash hasreceived speaker honoraria for lectures and educational activities notfunded by industry; has served on the editorial boards of variousscientific and medical journals; has held patents regarding electronicmeasuring devices; receives royalties from the publication of severalbooks; has served as Chief Medical Officer for Swiss Re Life andHealth; serves on the Board of Directors for MedHand AB Stockholmand Malvern Arts Press; has served as an advisor to Best Doctors Inc.,Europe (receives compensation); holds stock/stock options in Med-Hand AB Stockholm; and serves as an expert witness for legal pro-ceedings. A.M. Pittman and J.C. Blake report no disclosures.M.G. Hanna is supported by a Medical Research Council Centregrant, the National Centre for Research Resources, the Myositis SupportGroup, and the National Highly Specialised Service (HSS) Depart-ment of Health UK and has been a consultant for Novartis. H. Houl-den has received research support from the Medical Research Council(MRC) UK, The BRT, The MDA USA, Muscular Dystrophy UK,Ataxia UK, Muscular Dystrophy UK, Rosetrees Trust, The WellcomeTrust, and the National Institute for Health (NIHR) UCL/UCLH BRC. J.L. Holton has received travel funding fromMerck Serono; has served on the editorial board of Neuropathol-ogy Applied Neurobiology; has been an employee of UniversityCollege London; and has received research support from Alz-heimer’s Research Trust, the Margaret Watson Memorial TrustGrant from The Sarah Matheson Trust, Action MedicalResearch, Brain Net Europe: Support for the Queen SquareBrain Bank for Neurological Disorders, the Sarah MathesonTrust, Myositis Support Group, the Multiple System AtrophyTrust, Michael J Fox Foundation for Parkinson’s Research,Alzheimer’s Research UK, MSA Coalition, King Baudouin Foun-dation Sophia Fund, and Medical Research Council. M.M. Reillyreceives support from the Medical Research Council (MRC), MRCCentre grant (G0601943), and the National Institutes of NeurologicalDiseases and Stroke and office of Rare Diseases (U54NS065712); hasserved on the editorial boards of Brain, Neuromuscular Disorders;Journal of the Peripheral Nervous System; and JNNP; has beena consultant for Servier, Acceleron, and Alnylam; and has receivedresearch support from Wellcome Trust, UCL CBRC, Ipsen, MuscularDystrophy Association (US), Muscular dystrophy campaign grants,CLH/UCL Comprehensive Biomedical Research Centre, and CRDC.E. Matthews is funded by a postdoctoral fellowship from the NIHR andhas received research support from the Brain Research Trust and theMuscular Dystrophy Campaign. Go to Neurology.org/ng for full disclo-sure forms. The Article Processing Charge was funded by the authors.This is an open access article distributed under the terms of theCreative Commons Attribution License 4.0 (CC BY), which permitsunrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.Received April 10, 2017. Accepted in final form April 24, 2017.Correspondence to Dr. Matthews: emma.matthews@ucl.ac.uk1. Swash M, Schwarz MS, Thompson A, Cox E, Gray A. Distalmyopathy with focal granular degenerative change in vacuo-lated type 2 fibers. Clin Neuropathol 1988;7:249–253.2. Rossor AM, Morrow JM, Polke JM, et al. Pilot phenotypeand natural history study of hereditary neuropathies causedby mutations in the HSPB1 gene. Neuromuscul Disord2017;27:50–56.3. Sugiyama Y, Suzuki A, Kishikawa M, et al. Muscle developsa specific form of small heat shock protein complex com-posed of MKBP/HSPB2 and HSPB3 during myogenic dif-ferentiation. J Biol Chem 2000;275:1095–1104.4. Benndorf R, Martin JL, Kosakovsky Pond SL, Wertheim JO.Neuropathy- and myopathy-associated mutations in humansmall heat shock proteins: characteristics and evolutionaryhistory of the mutation sites. Mutat Res Rev Mutat Res2014;76:15–30.5. Ghaoui R, Palmio J, Brewer J, et al. Mutations in HSPB8causing a new phenotype of distal myopathy and motorneuropathy. Neurology 2016;86:391–398.6. Lewis-Smith DJ, Duff J, Pyle A, et al. NovelHSPB1 mutation causes both motor neuronopathyand distal myopathy. Neurol Genet 2016;2:e110.doi: 10.1212/NXG.0000000000000110.Neurology: Genetics 3

Homozygous mutation in HSPB1 causing distal vacuolar myopathy and motor neuropathy.

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Homozygous mutation in HSPB1 causing distal vacuolar myopathy and motor neuropathy.

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