Early neurodevelopmental assessment in Duchenne muscular dystrophy

Pane, Marika; Scalise, Roberta; Berardinelli, Angela; D'Angelo, Maria Grazia; Ricotti, Valeria; Alfieri, Paolo; Moroni, Isabella; Hartley, Louise; Pera, Maria Carmela; Baranello, Giovanni; Catteruccia, Michela; Casalino, Tiziana; Romeo, Domenico M.; Graziano, Alessandra; Gandioli, Claudia; Bianco, F.; Mazzone, Elena; Lombardo, Maria; Scoto, Mariacristina; Sivo, Serena; Palermo, Concetta; Gualandi, Francesca; Sormani, Maria Pia; Ferlini, Alessandra; Bertini, Enrico; Muntoni, Francesco; Mercuri, Eugenio

doi:10.1016/j.nmd.2013.02.012

Cited by 70 publications

(63 citation statements)

References 17 publications

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“…The relationship between the isoforms that are affected and the cognitive profile is further supported by the higher incidence of neurodevelopmental disorders in patients missing Dp140 compared to patients missing only Dp427 5,26 . This group distinction was already detectable below the age of four, as assessed with developmental quotients 8 . Finally, imaging has shown reduced grey matter volume and altered white matter microstructure compared to age-matched healthy controls, which was also more profound in patients missing Dp140 27 .…”

Section: 4mentioning

confidence: 88%

“…Unfortunately, there are no longitudinal studies that investigate whether the cognitive pathology in DMD is progressive. Developmental delay was reported below the age of four and more cerebral atrophy was seen in men with DMD compared to boys, which may indicate progression with age 8,9 . However, normalization of IQ values in older patients has also been suggested 1 .…”

Section: 4mentioning

confidence: 98%

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Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Doorenweerd

Mahfouz

Putten

et al. 2017

Neuromuscular Disorders

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Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked genetic neuromuscular disorders characterized by severe and progressive muscle weakness. Mutations in the DMD gene result in absent/non-functional muscle dystrophin protein in DMD and shortened/partially functional protein in BMD.In addition to skeletal muscle pathology, DMD is characterized by cognitive and behavioural problems with 30% of boys with DMD showing cognitive impairment (IQ < 70) 1 and 40% having reading deficits similar to those observed in patients with phonological dyslexia 2-4 . Moreover, there is a higher incidence of attention-deficit/ hyperactivity disorder (ADHD) (32%), anxiety disorder (27%), autism spectrum disorders (ASD) (15%), epilepsy (6.3%), and obsessive-compulsive disorder (OCD) (4.8%) in patients with DMD [5][6][7] . The progressive nature of the

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Section: 4mentioning

confidence: 88%

Section: 4mentioning

confidence: 98%

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Doorenweerd

Mahfouz

Putten

et al. 2017

Neuromuscular Disorders

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“…Indeed, Dp140 has been amply localised in glial cells, 44 and disruption of this isoform in mutations affecting exons 45-62, has been implicated with cognitive impairment, higher incidence of ADHD and delayed milestones. 13,14,45 Mutations affecting Dp71, a brain isoform implicated in transmembrane permeability, 46 although rare, are recognised in association with severe cognitive impairment. 13,47 The two boys with Dp71 mutations, indeed, had the most severe profile with ASD and profound speech delay.…”

Section: Ocular and Neurodevelopmental Features Of Dmd V Ricotti Et Almentioning

confidence: 99%

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Ricotti

Jägle²,

Theodorou

et al. 2015

Eur J Hum Genet

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Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly 'negative' scotopic ERGs (a:b ratios 41). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.

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“…The locomotor quotient of the Griffith’s scales decreases in young boys with DMD 8 . Recently, the Griffith’s motor scales and the Bayley-III have been shown to have a negative correlation with age in young boys with DMD 9,10 . Pane et al also demonstrated that those boys whose dystrophin mutations disrupt the promoter of the predominant dystrophin brain isoform were more likely to have deficits in language and cognition 9 .…”

Section: Introductionmentioning

confidence: 99%

One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

Connolly

Florence

Cradock

et al. 2014

Pediatric Neurology

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BACKGROUND The pathogenesis of Duchenne muscular dystrophy starts prior to birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here we report six and twelve month follow-up of two subsets of these boys. PATIENTS Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and six months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, six, and twelve months. RESULTS Gross motor scores were lower at baseline compared to published controls (6.2 ± 1.7; normal 10 ± 3; p<.0001), and showed a further declining trend to 5.7 ± 1.7 (p =.20) at six months. Repeated measures analysis of the 12 boys followed for 12 months showed that gross motor scores, again low at baseline (6.6 ± 1.7; p<.0001), declined at six months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (p=0.11). Cognitive and language scores were lower at baseline compared to normal children (range p=.002 to p<0.0001) and did not change significantly at 6 or 12 months (range p=.89 to p=.09). Fine motor skills, also low at baseline, improved over one year (p=.05). CONCLUSION Development can reliably be measured in infants and young boys with DMD across time using the Bayley-III. Power calculations using these data show that motor development may be used as an outcome measure.

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Early neurodevelopmental assessment in Duchenne muscular dystrophy

Cited by 70 publications

References 17 publications

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

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