Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS

Gourdon, Geneviève; Meola, Giovanni

doi:10.3389/fncel.2017.00101

Cited by 78 publications

(80 citation statements)

References 148 publications

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“…An array of both peripheral nervous system and CNS abnormalities have been reported in both DM1 and DM2. The manifestations of CNS impairment in the myotonic dystrophies may be 1 of the most important yet poorly understood aspects of the disease and were recently reviewed in detail by Gourdon and Meola [33]. Commonly reported CNS-related symptoms include fatigue, apathy, and cognitive difficulties.…”

Section: Other Neurological Manifestationsmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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Section: Other Neurological Manifestationsmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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“…1 The disease leads to significant physical impairment, which in combination with the neuropsychological impacts of the condition, results in severely restricted social participation. [2][3][4][5][6] No curative treatment exists, and evidence for the efficacy of rehabilitative approaches is largely lacking, resulting in considerable unmet need for treatment that aims to improve health status. 7 A DM1-specific model of factors determining health status was empirically derived from the findings of our longitudinal study.…”

Section: Introductionmentioning

confidence: 99%

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial

Okkersen¹,

Jimenez-Moreno²,

Wenninger³

et al. 2018

The Lancet Neurology

106

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“…DM1 and DM2 patients show a similar but not identical spectrum of clinical symptoms including muscular weakness and wasting, myotonia, cataracts, cardiac symptoms, and CNS involvement with cognitive impairment, depression, and daytime sleepiness (3). So far, a congenital or childhood form presenting with more severe and widespread neuropsychiatric symptoms including mental retardation, attention deficit with or without hyperactivity disorder (ADHD), autism spectrum disorder and others (4,5) has been reported in DM1 only.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Iron Accumulation in Deep Gray Matter in Myotonic Dystrophy Type 1 and 2 Using Quantitative Susceptibility Mapping and R2* Relaxometry: A Magnetic Resonance Imaging Study at 3 Tesla

et al. 2019

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Quantitative mapping of the magnetic susceptibility and the effective transverse relaxation rate (R2 * ) are suitable to assess the iron content in distinct brain regions. In this prospective, explorative study the iron accumulation in deep gray matter nuclei (DGM) in myotonic dystrophy type 1 (DM1) and 2 (DM2) and its clinical and neuro-cognitive relevance using susceptibility and R2 * mapping was examined. Twelve classical DM1, four childhood-onset DM1 (DM1 c.o. ), twelve DM2 patients and twenty-nine matched healthy controls underwent MRI at 3 Tesla, neurological and neuro-cognitive tests. Susceptibility, R2 * and volumes were determined for eleven DGM structures and compared between patients and controls. Twelve classical DM1, four childhood-onset DM1, and 12 DM2 patients as well as 29 matched healthy controls underwent MRI at 3 Tesla, and neurological and neuro-cognitive tests. Susceptibility, R2 * and volumes were determined for 11 DGM structures and compared between patients and controls. Iron accumulation in DGM reflected by R2 * or susceptibility was found in the putamen and accumbens of DM1 and in DM2, but was more widespread in DM1 (caudate, pallidum, hippocampus, subthalamic nucleus, thalamus, and substantia nigra). Opposed changes of R2 * or susceptibility were detected in caudate, putamen and accumbens in the childhood-onset DM1 patients compared to classical DM1. R2 * or susceptibility alterations in DGM were significantly associated with clinical symptoms including muscular weakness (DM1), daytime sleepiness (DM1), depression (DM2), and with specific cognitive deficits in DM1 and DM2.Keywords: myotonic dystrophy type 1, DM1, myotonic dystrophy type 2, DM2, R2 * relaxometry, quantitative susceptibility mapping, iron, deep gray matter Ates et al. QSM/R2 * in Myotonic Dystrophy

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Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS

Cited by 78 publications

References 148 publications

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial

Characterization of Iron Accumulation in Deep Gray Matter in Myotonic Dystrophy Type 1 and 2 Using Quantitative Susceptibility Mapping and R2* Relaxometry: A Magnetic Resonance Imaging Study at 3 Tesla

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