Developmental Milestones and Quality of Life Assessment in a Congenital Myotonic Dystrophy Cohort

Prasad, Madhavi; Hicks, Rhiannon; MacKay, Melissa; Nguyen, Cuong; Campbell, Craig

doi:10.3233/jnd-160165

Cited by 9 publications

(5 citation statements)

References 18 publications

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“…and 6‐min walk test) compared with healthy individuals; however, by the age of 12–14 years, they have outcomes that are similar to those of healthy controls . Although most patients with CDM have a global developmental delay, the vast majority achieve ambulation at a mean age of 2.4 years, varying from 1.2 to 3.9 years . The pathophysiology suggests that CDM may be a disorder of muscle immaturity, with the splicing dysfunction forcing proteins into more fetal isoforms .…”

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“…3 Although most patients with CDM have a global developmental delay, the vast majority achieve ambulation at a mean age of 2.4 years, varying from 1.2 to 3.9 years. 4 The pathophysiology suggests that CDM may be a disorder of muscle immaturity, with the splicing dysfunction forcing proteins into more fetal isoforms. 5 Both clinical observation and the pathophysiology suggest that one might see a gradual improvement in muscle mass (relative to their peers) as the child ages.…”

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Body composition in patients with congenital myotonic dystrophy

et al. 2019

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Introduction Congenital myotonic dystrophy (CDM) is a rare neuromuscular disorder characterized by severe hypotonia and muscle weakness at birth that tends to improve with age. Understanding lean body and bone mass in this population has important research and clinical implications. The main objective of this study was to determine whether older children with CDM had muscle mass similar to healthy controls. Methods Thirty‐five patients with CDM (3‐13 years old) were enrolled. We analyzed lean body mass (LBM) and bone mineral content using the mechanostat framework, which allows calculation of z‐scores for sex, age, and height. Results All patients had low LBM z‐scores (muscle mass); however, higher LBM z‐score was positively correlated with age (r = 0.45, P = 0.006), showing that it is closer to normal in older patients. Discussion Unlike other neuromuscular diseases, older children with CDM have a muscle mass closer to age‐matched controls, consistent with the clinical profile of increasing strength in childhood. Muscle Nerve 60: 176–179, 2019

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Body composition in patients with congenital myotonic dystrophy

et al. 2019

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“…The mortality rate at birth is high. For the children that pass the critical neonatal period, the developmental profile (especially motor and language skills) improved in early childhood and apparently faster in boys (Prasad et al, 2016). However, moderate to severe intellectual disabilities, reduced IQ-values, speech and language delay, deficit in visuospatial and/or visuo-constructive skills, attention deficit with or without hyperactivity disorder (ADHD), autism spectrum disorder, problems with communication and social anxiety have been reported by several authors in DM1 childhood patients (Angeard et al, 2007, 2011; Meola and Sansone, 2007; Ekström et al, 2008, 2009; Douniol et al, 2009, 2012).…”

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confidence: 99%

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

Gourdon

Meola

2017

Front. Cell. Neurosci.

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Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments.

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“…[16][17][18][19] CNS manifestations severely compromise DM patients' capability of handling complex tasks and their quality of life 2,5,20 ; either in congenital, infantile and adolescent DM patients 5 who show learning disability, autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) or excessive daytime sleepiness, depression, apathy, dysexecutive syndrome, social avoidance, and fatigue in adult DM1 and DM2. 5,21 Although advances in magnetic resonance (MR) brain imaging on DM patients and microstructural analysis in mouse models have been achieved in the past few years, [22][23][24][25][26] there is still a huge gap between DM brain phenotypes and the misregulations of gene expression. In particular, it remains unclear how dysfunctions in MBNL-mediated splicing cause DM CNS phenotypes and affect neuronal microstructures.…”

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confidence: 99%

Muscleblind‐like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development

Huang

Lee

Lin

et al. 2023

Neuropathology Appl Neurobio

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Aims Muscleblind‐like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models. Methods To create Mbnl2 knockout neurons, cDNA encoding Cre‐recombinase was delivered into neural progenitors of Mbnl2flox/flox mouse brains by in utero electroporation. The morphologies and dynamics of dendritic spines were monitored by confocal and two‐photon microscopy in brain slices and live animals from the neonatal period into adulthood. To investigate the underlying molecular mechanism, we further detected the changes in the splicing and molecular interactions of proteins associated with spinogenesis. Results We found that Mbnl2 knockout in cortical neurons decreased dendritic spine density and dynamics in adolescent mice. Mbnl2 ablation caused the adducin 1 (ADD1) isoform to switch from adult to fetal with a frameshift, and the truncated ADD1 failed to interact with alpha‐II spectrin (SPTAN1), a critical protein for spinogenesis. In addition, expression of ADD1 adult isoform compensated for the reduced dendritic spine density in cortical neurons deprived of MBNL2. Conclusion MBNL2 plays a critical role in maintaining the dynamics and homeostasis of dendritic spines in the developing brain. Mis‐splicing of downstream ADD1 may account for the alterations and contribute to the DM brain pathogenesis.

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Developmental Milestones and Quality of Life Assessment in a Congenital Myotonic Dystrophy Cohort

Abstract: Understanding developmental milestones and quality of life are important parameters when judging a child's overall health. For CDM patients delineating developmental milestones and QOL have important clinical care and research implications.

Cited by 9 publications

References 18 publications

Body composition in patients with congenital myotonic dystrophy

Body composition in patients with congenital myotonic dystrophy

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

Muscleblind‐like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development

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