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Workshop report| Volume 30, ISSUE 9, P782-794, September 2020

249th ENMC International Workshop: The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, The Netherlands, November 29th–December 1st 2019

Published:August 14, 2020DOI:https://doi.org/10.1016/j.nmd.2020.08.357

      Highlights

      • Overview of the multiple dystrophin isoforms expressed in the brain.
      • Large body of preclinical data and possibilities for postnatal dystrophin restoration.
      • Overview of neurocognitive and behavioral heterogeneity in DMD and BMD.
      • Neuromuscular specialists to also focus on early diagnosis and intervention for brain comorbidities.
      • Need to develop standard operation procedures for neurocognition and behavior assessment.

      Keywords

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      References

        • Birnkrant DJ
        • Bushby K
        • Bann CM
        • Apkon SD
        • Blackwell A
        • Colvin MK
        • et al.
        Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan.
        Lancet Neurol. 2018; 17: 445-455
        • Muntoni F
        • Torelli S
        • Ferlini A
        Dystrophin and mutations: one gene, several proteins, multiple phenotypes.
        Lancet Neurol. 2003; 2: 731-740
        • Nudel U
        • Zuk D
        • Einat P
        • Zeelon E
        • Levy Z
        • Neuman S
        • et al.
        Duchenne muscular dystrophy gene product is not identical in muscle and brain.
        Nature. 1989; 337: 76-78
        • Monaco AP
        • Neve RL
        • Colletti-Feener C
        • Bertelson CJ
        • Kurnit DM
        • Kunkel LM
        Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene.
        Nature. 1986; 323: 646-650
        • Gorecki DC
        • Monaco AP
        • Derry JM
        • Walker AP
        • Barnard EA
        • Barnard PJ
        Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters.
        Hum Mol Genet. 1992; 1: 505-510
        • D'Souza VN
        • Nguyen TM
        • Morris GE
        • Karges W
        • Pillers DA
        • Ray PN
        A novel dystrophin isoform is required for normal retinal electrophysiology.
        Hum Mol Genet. 1995; 4: 837-842
        • Lidov HG
        • Kunkel LM
        Dp140: alternatively spliced isoforms in brain and kidney.
        Genomics. 1997; 45: 132-139
        • Byers TJ
        • Lidov HG
        • Kunkel LM
        An alternative dystrophin transcript specific to peripheral nerve.
        Nat Genet. 1993; 4: 77-81
        • Austin RC
        • Howard PL
        • D'Souza VN
        • Klamut HJ
        • Ray PN
        Cloning and characterization of alternatively spliced isoforms of Dp71.
        Hum Mol Genet. 1995; 4: 1475-1483
        • Tinsley JM
        • Blake DJ
        • Davies KE
        Apo-dystrophin-3: a 2.2kb transcript from the DMD locus encoding the dystrophin glycoprotein binding site.
        Hum Mol Genet. 1993; 2: 521-524
        • Fratter C
        • Dalgleish R
        • Allen SK
        • Santos R
        • Abbs S
        • Tuffery-Giraud S
        • et al.
        EMQN best practice guidelines for genetic testing in dystrophinopathies.
        Eur J Hum Genet. 2020;
        • Gazzoli I
        • Pulyakhina I
        • Verwey NE
        • Ariyurek Y
        • Laros JF
        • t Hoen PA
        • et al.
        Non-sequential and multi-step splicing of the dystrophin transcript.
        RNA Biol. 2016; 13: 290-305
        • Lidov HG
        • Selig S
        • Kunkel LM
        Dp140: a novel 140kDa CNS transcript from the dystrophin locus.
        Hum Mol Genet. 1995; 4: 329-335
        • Spitali P
        • van den Bergen JC
        • Verhaart IE
        • Wokke B
        • Janson AA
        • van den Eijnde R
        • et al.
        DMD transcript imbalance determines dystrophin levels.
        FASEB J. 2013; 27: 4909-4916
        • Gherardi S
        • Bovolenta M
        • Passarelli C
        • Falzarano MS
        • Pigini P
        • Scotton C
        • et al.
        Transcriptional and epigenetic analyses of the DMD locus reveal novel cisacting DNA elements that govern muscle dystrophin expression.
        Biochim Biophys Acta Gene Regul Mech. 2017; 1860: 1138-1147
        • Gallia GL
        • Zhang M
        • Ning Y
        • Haffner MC
        • Batista D
        • Binder ZA
        • et al.
        Genomic analysis identifies frequent deletions of Dystrophin in olfactory neuroblastoma.
        Nat Commun. 2018; 9: 5410
        • Doorenweerd N
        • Mahfouz A
        • van Putten M
        • Kaliyaperumal R
        • PAC TH
        • Hendriksen JGM
        • et al.
        Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.
        Sci Rep. 2017; 7: 12575
        • Doorenweerd N
        • Straathof CS
        • Dumas EM
        • Spitali P
        • Ginjaar IB
        • Wokke BH
        • et al.
        Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy.
        Ann Neurol. 2014; 76: 403-411
        • Aranmolate A
        • Tse N
        • Colognato H
        Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy.
        BMC Neurosci. 2017; 18: 63
        • Patel AM
        • Wierda K
        • Thorrez L
        • van Putten M
        • De Smedt J
        • Ribeiro L
        • et al.
        Dystrophin deficiency leads to dysfunctional glutamate clearance in iPSC derived astrocytes.
        Transl Psychiatry. 2019; 9: 200
        • Hellebrekers DMJ
        • Doorenweerd N
        • Sweere DJJ
        • van Kuijk SMJ
        • Aartsma-Rus AM
        • Klinkenberg S
        • et al.
        Longitudinal follow-up of verbal span and processing speed in Duchenne muscular dystrophy.
        Eur J Paediatr Neurol. 2020; 25: 120-126
        • Waite A
        • Brown SC
        • Blake DJ
        The dystrophin-glycoprotein complex in brain development and disease.
        Trends Neurosci. 2012; 35: 487-496
        • Sekiguchi M
        • Zushida K
        • Yoshida M
        • Maekawa M
        • Kamichi S
        • Yoshida M
        • et al.
        A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice.
        Brain. 2009; 132: 124-135
        • Vaillend C
        • Chaussenot R
        Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice.
        Hum Mol Genet. 2017; 26: 1041-1055
        • Miranda R
        • Sebrie C
        • Degrouard J
        • Gillet B
        • Jaillard D
        • Laroche S
        • et al.
        Reorganization of inhibitory synapses and increased PSD length of perforated excitatory synapses in hippocampal area CA1 of dystrophin-deficient mdx mice.
        Cereb Cortex. 2009; 19: 876-888
        • Dallerac G
        • Perronnet C
        • Chagneau C
        • Leblanc-Veyrac P
        • Samson-Desvignes N
        • Peltekian E
        • et al.
        Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse.
        Neurobiol Dis. 2011; 43: 635-641
        • Goyenvalle A
        • Griffith G
        • Babbs A
        • El Andaloussi S
        • Ezzat K
        • Avril A
        • et al.
        Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers.
        Nat Med. 2015; 21: 270-275
        • Vaillend C
        • Perronnet C
        • Ros C
        • Gruszczynski C
        • Goyenvalle A
        • Laroche S
        • et al.
        Rescue of a dystrophin-like protein by exon skipping in vivo restores GABAA-receptor clustering in the hippocampus of the mdx mouse.
        Mol Ther. 2010; 18: 1683-1688
        • Daoud F
        • Candelario-Martinez A
        • Billard JM
        • Avital A
        • Khelfaoui M
        • Rozenvald Y
        • et al.
        Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions.
        PLoS One. 2008; 4: e6574
        • Chaussenot R
        • Amar M
        • Fossier P
        • Vaillend C
        Dp71-Dystrophin Deficiency Alters Prefrontal Cortex Excitation-Inhibition Balance and Executive Functions.
        Mol Neurobiol. 2019; 56: 2670-2684
        • Ricotti V
        • Mandy WP
        • Scoto M
        • Pane M
        • Deconinck N
        • Messina S
        • et al.
        Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations.
        Dev Med Child Neurol. 2016; 58: 77-84
        • Miranda R
        • Nudel U
        • Laroche S
        • Vaillend C
        Altered presynaptic ultrastructure in excitatory hippocampal synapses of mice lacking dystrophins Dp427 or Dp71.
        Neurobiol Dis. 2011; 43: 134-141
        • Remmelink E
        • Aartsma-Rus A
        • Smit AB
        • Verhage M
        • Loos M
        • van Putten M
        Cognitive flexibility deficits in a mouse model for the absence of full-length dystrophin.
        Genes Brain Behav. 2016; 15: 558-567
        • Miranda R
        • Laroche S
        • Vaillend C
        Reduced neuronal density in the CA1 anterodorsal hippocampus of the mdx mouse.
        Neuromuscul Disord. 2016; 26: 775-781
        • Relizani K
        • Griffith G
        • Echevarria L
        • Zarrouki F
        • Facchinetti P
        • Vaillend C
        • et al.
        Efficacy and safety profile of tricyclo-DNA antisense oligonucleotides in Duchenne muscular dystrophy mouse model.
        Mol Ther Nucleic Acids. 2017; 8: 144-157
        • Aupy P
        • Zarrouki F
        • Sandro Q
        • Gastaldi C
        • Buclez PO
        • Mamchaoui K
        • et al.
        Long-term efficacy of AAV9-U7snRNA-mediated exon 51 skipping in mdx52 Mice.
        Mol Ther Methods Clin Dev. 2020; 17: 1037-1047
        • Bagdatlioglu E
        • Porcari P
        • Greally E
        • Blamire AM
        • Straub VW
        Cognitive impairment appears progressive in the mdx mouse.
        Neuromuscul Disord. 2020; 30: 368-388
        • Ennaceur A
        • Delacour J.
        A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data.
        Behav Brain Res. 1988; 31: 47-59
        • Cotton S
        • Voudouris NJ
        • Greenwood KM
        Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients.
        Dev Med Child Neurol. 2001; 43: 497-501
        • Doorenweerd N
        Combining genetics, neuropsychology and neuroimaging to improve understanding of brain involvement in Duchenne muscular dystrophy - a narrative review.
        Neuromuscul Disord. 2020; 30: 437-442
        • Thangarajh M
        • Spurney CF
        • Gordish-Dressman H
        • Clemens PR
        • Hoffman EP
        • McDonald CM
        • et al.
        Neurodevelopmental needs in young boys with duchenne muscular dystrophy (DMD): observations from the cooperative international neuromuscular research group (CINRG) DMD natural history study (DNHS).
        PLoS Curr. 2018; 10
        • Thangarajh M
        • Kaat AJ
        • Bibat G
        • Mansour J
        • Summerton K
        • Gioia A
        • et al.
        The NIH toolbox for cognitive surveillance in Duchenne muscular dystrophy.
        Ann Clin Transl Neurol. 2019; 6: 1696-1706
        • Soim A
        • Lamb M
        • Campbell K
        • Pandya S
        • Peay H
        • Howard Jr JF
        • et al.
        A cross-sectional study of school experiences of boys with Duchenne and Becker muscular dystrophy.
        Phys Disabil Educ Relat Serv. 2016; 35: 1-22
        • Miller G
        • Tunnecliffe M
        • Douglas PS
        IQ, prognosis and Duchenne muscular dystrophy.
        Brain Dev. 1985; 7: 7-9
        • Hellebrekers DMJ
        • Lionarons JM
        • Faber CG
        • Klinkenberg S
        • Vles JSH
        • Hendriksen JGM
        Instruments for the assessment of behavioral and psychosocial functioning in Duchenne and Becker muscular dystrophy; a systematic review of the literature.
        J Pediatr Psychol. 2019; 44: 1205-1223
        • Hendriksen RGF
        • Vles JSH
        • Aalbers MW
        • Chin RFM
        • Hendriksen JGM
        Brain-related comorbidities in boys and men with Duchenne muscular dystrophy: a descriptive study.
        Eur J Paediatr Neurol. 2018; 22: 488-497
        • Birnkrant DJ
        • Bushby K
        • Bann CM
        • Apkon SD
        • Blackwell A
        • Brumbaugh D
        • et al.
        Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management.
        Lancet Neurol. 2018; 17: 251-267
        • Hinton VJ
        • De Vivo DC
        • Nereo NE
        • Goldstein E
        • Stern Y
        Poor verbal working memory across intellectual level in boys with Duchenne dystrophy.
        Neurology. 2000; 54: 2127-2132
        • Rahbek J
        • Werge B
        • Madsen A
        • Marquardt J
        • Steffensen BF
        • Jeppesen J
        Adult life with Duchenne muscular dystrophy: observations among an emerging and unforeseen patient population.
        Pediatr Rehabil. 2005; 8: 17-28
        • Lindberg U
        • Kruuse C
        • Witting N
        • Jorgensen SL
        • Vissing J
        • Rostrup E
        • et al.
        Altered somatosensory neurovascular response in patients with Becker muscular dystrophy.
        Brain Behav. 2018; 8: e00985
        • Lindberg U
        • Witting N
        • Jorgensen SL
        • Vissing J
        • Rostrup E
        • Larsson HB
        • et al.
        Effects of sildenafil on cerebrovascular reactivity in patients with Becker muscular dystrophy.
        Neurotherapeutics. 2017; 14: 182-190
        • Witting N
        • Kruuse C
        • Nyhuus B
        • Prahm KP
        • Citirak G
        • Lundgaard SJ
        • et al.
        Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy.
        Ann Neurol. 2014; 76: 550-557
        • Lionarons JM
        • Hellebrekers DMJ
        • Klinkenberg S
        • Faber CG
        • Vles JSH
        • Hendriksen JGM
        Methylphenidate use in males with Duchenne muscular dystrophy and a comorbid attention-deficit hyperactivity disorder.
        Eur J Paediatr Neurol. 2019; 23: 152-157
        • Hendriksen JG
        • Klinkenberg S
        • Collin P
        • Wong B
        • Niks EH
        • Vles JS
        Diagnosis and treatment of obsessive compulsive behavior in a boy with Duchenne muscular dystrophy and autism spectrum disorder: a case report.
        Neuromuscul Disord. 2016; 26: 659-661