Cognitive functions in duchenne muscular dystrophy: A reappraisal and comparison with spinal muscular atrophy

doi:10.1016/S0960-8966(06)80008-8

Neuromuscular Disorders

Volume 2, Issues 5–6, 1992, Pages 371-378

https://doi.org/10.1016/S0960-8966(06)80008-8 Get rights and content

Abstract

In order to clarify cognitive functions in Duchenne muscular dystrophy (DMD), we performed a new controlled neuropsychological study. IQ (WISC-R), verbal skills (fluency, confrontation naming and syntax comprehension) and memory abilities (BEM) were studied in two matched groups; 24 DMD children and 17 spinal muscular atrophy (SMA) children aged 12–16 yr. A significant difference appeared between the DMD and SMA patients: only in the DMD group were there significant disabilities in certain specific functions and normal scores in others. Despite similar education, the DMD children more often had significantly greater learning disabilities. There were more DMD left-handers. Verbal IQ was significantly low whereas performance IQ was at a normal level. DMD children also performed poorly in reading tasks and in some memory functions such as story recall and verbal recognition. Specific cognitive disabilities in certain DMD children, not seen in SMA children, suggest a relationship with a DMD genetic disorder.

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The unconditioned fear response in vertebrates deficient in dystrophin
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Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat stimuli. Dystrophin-deficient animal models of DMD demonstrate enhanced stress reactivity that manifests as sustained periods of immobility. When the threat is repetitive or severe in nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it is apparent that enhanced sensitivity to stressful/threat stimuli in dystrophin-deficient vertebrates is a legitimate cause of concern for patients with DMD that could impact neurocognition and pathophysiology. This review discusses our current understanding of the mechanisms and consequences of the hypersensitive fear response in preclinical models of DMD and the potential challenges facing clinical translatability.
Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?
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There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5–17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.
Clinical study on cognitive impairment in Duchenne muscular dystrophy
2023, Neuromuscular Disorders
Our study aimed to explore the intellectual function of patients with Duchenne muscular dystrophy (DMD) in China and examine the correlation of full-scale intelligence quotient (FSIQ) with age, mutation locations, mutation class, and dystrophin isoforms. We assessed 64 boys with DMD using The Wechsler Intelligence Scales for Children-Fourth Edition and compared intellectual function at enrollment and follow-up in the 15 patients who completed the follow-up. Our findings confirm that boys with DMD may exhibit cognitive impairment, with the Working Memory Index being the most impaired. There was no significant correlation between FSIQ and age; however, a positive correlation was noted between age and the Verbal Comprehension Index. FSIQ was not associated with mutation class, the number of affected mutated exons, or mutation locations. However, there was a significant difference in FSIQ between the groups with intact and deficient Dp140. Fifteen participants adhered to glucocorticoid therapy throughout the two-year follow-up period, and eleven of them showed an improvement in FSIQ compared to their initial scores, with improvement ranging from 2 to 20. In conclusion, patients with the cumulative loss of isoforms in the brain are at a higher risk of cognitive deficits and may require early cognitive interventions.
Retinal dystrophins and the retinopathy of Duchenne muscular dystrophy
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Citation Excerpt :
Clinical cases of DMD/BMD have been reported since the eighteenth century, but it was only in the 1860s that the French neurologist Guillaume Benjamin Amand Duchenne de Boulogne (1806–1875) detailed muscle histology, clinical features and clinical progression of this disease (Duchenne, 1868) that has been later associated with his name (Emery and Emery, 1993; Jay and Vajsar, 2001). Duchenne also pointed for the first time to the presence of comorbidities in the central nervous system, which have been later shown to be independent from their motor handicap (e.g., Billard et al., 1992). Walton and Nattrass (1954) defined muscular dystrophies as diseases of hereditary origin, characterized by progressive atrophy and muscle weakness associated with the degeneration and necrosis of muscle fibers, increase in connective tissue, and fat infiltration of muscle tissues.
Duchenne muscular dystrophy (DMD) is caused by X-linked inherited or de novo DMD gene mutations predominantly affecting males who develop early-onset muscle degeneration, severely affecting their quality of life and leading to reduced life expectancy. DMD patients may also develop proliferative retinopathy, cataract, ERG abnormalities, altered contrast sensitivity, color vision losses, and elevated flash detection thresholds during dark adaptation. Depending on the position of the genetic alteration in the large DMD gene, it is associated with a lack of the full-length dystrophin protein possibly with an additional loss of one or several other dystrophins, which are normally transcribed from internal promoters in retina and crystalline lens. During the last decades, the properties of the dystrophins have been characterized in patients with different genetic alterations and in genetic mouse models of DMD. The complex expression pattern of the dystrophins in photoreceptors, Müller glial cells and astrocytes, likely influences synaptic transmission, ionic balance and vascular integrity of the retina. However, the specific function of each retinal dystrophin remains largely unknown. This review describes the current knowledge on dystrophin expression, the putative molecular, structural, and physiological properties of retinal dystrophins, and the main clinical implications associated with the loss of dystrophins in DMD patients and mouse models. Current data and working hypotheses warrant future research on retinal dystrophins to increase our understanding of dystrophin function in the central nervous system in general and to unveil new retinal mechanisms and therapeutic avenues for retinal diseases.
Synaptic alterations as a neurodevelopmental trait of Duchenne muscular dystrophy
2022, Neurobiology of Disease
Dystrophinopaties, e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy and X-linked dilated cardiomyopathy are inherited neuromuscular diseases, characterized by progressive muscular degeneration, which however associate with a significant impact on general system physiology. The more severe is the pathology and its diversified manifestations, the heavier are its effects on organs, systems, and tissues other than muscles (skeletal, cardiac and smooth muscles). All dystrophinopaties are characterized by mutations in a single gene located on the X chromosome encoding dystrophin (Dp427) and its shorter isoforms, but DMD is the most devasting: muscular degenerations manifests within the first 4 years of life, progressively affecting motility and other muscular functions, and leads to a fatal outcome between the 20s and 40s. To date, after years of studies on both DMD patients and animal models of the disease, it has been clearly demonstrated that a significant percentage of DMD patients are also afflicted by cognitive, neurological, and autonomic disorders, of varying degree of severity. The anatomical correlates underlying neural functional damages are established during embryonic development and the early stages of postnatal life, when brain circuits, sensory and motor connections are still maturing. The impact of the absence of Dp427 on the development, differentiation, and consolidation of specific cerebral circuits (hippocampus, cerebellum, prefrontal cortex, amygdala) is significant, and amplified by the frequent lack of one or more of its lower molecular mass isoforms. The most relevant aspect, which characterizes DMD-associated neurological disorders, is based on morpho-functional alterations of selective synaptic connections within the affected brain areas. This pathological feature correlates neurological conditions of DMD to other severe neurological disorders, such as schizophrenia, epilepsy and autistic spectrum disorders, among others. This review discusses the organization and the role of the dystrophin-dystroglycan complex in muscles and neurons, focusing on the neurological aspect of DMD and on the most relevant morphological and functional synaptic alterations, in both central and autonomic nervous systems, described in the pathology and its animal models.
Third case of Duchenne muscular dystrophy and West syndrome: Expanding the spectrum of the DMD neuropsychiatric phenotype
2021, Neuromuscular Disorders
Duchenne muscular dystrophy is an X-Linked neuromuscular disorder, and the most common muscular dystrophy. Neuropsychiatric phenotype associated to DMD gene mutations include now low IQ scores, epilepsy, autism, and attention deficit disorder. These have been observed with higher frequency in mutations that disrupt the short isoforms Dp71 and Dp140. West syndrome has been previously reported in two unrelated patients with Duchenne muscular dystrophy. Here, we report the third patient with West syndrome who had a novel hemizygous nonsense pathogenic variant in the exon 8 of the DMD gene c.811C>T, p.(Gln271*), suggesting West syndrome as part of the neuropsychiatric spectrum in Duchenne muscular dystrophy.

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^*: This study is dedicated to the memory of J. L. Signoret, the leading force in our work in this field.

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Cognitive functions in duchenne muscular dystrophy: A reappraisal and comparison with spinal muscular atrophy*

Abstract

Cell

Dev Med Child Neurol

Absence of genetic heterogeneity in Duchenne Muscular Dystrophy shown by a linkage study using two cloned DNA sequences

J Med Genet

Gene deletions in X-linked muscular dystrophy

Am J Hum Genet

Localization and cloning of Xp 21 deletion breakpoints involved in muscular dystrophy

Hum Genet

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Recherches sur la paralysie musculaire pseudo-hypertrophique, ou paralysie myosclérosique

Arch Gén Méd

Duchenne's muscular dystrophy

Arch Neurol

The assessment of intelligence in boys with Duchenne muscular dystrophy

Rehabil Lit

Neuropsychological performance of children with Duchenne muscular dystrophy and spinal muscle atrophy

Dev Med Child Neurol

Mental retardation in association with progressive muscular dystrophy

Am J Dis Child

Intellectual functioning in childhood progressive muscular dystrophy

Pediatrics

The genetic relationship of progressive muscular dystrophy (Duchenne type) and mental retardation

Dev Med Child Neurol

Intellectual impairment in muscular dystrophy

Arch Dis Child

Downward shift IQ in persons with Duchenne muscular dystrophy compared to those with spinal muscular atrophy

Am J Ment Retard

Intellectual function in Muscular Dystrophies

Eur Arch Psychiatr Neurol Sci

Intellectual functioning in Duchenne muscular dystrophy

Dev Med Child Neurol

Mental retardation in patients with Duchenne progressive muscular dystrophy

J Neurosci

Intellect and behaviour in Duchenne muscular dystrophy

Dev Med Child Neurol

Similarity of IQ of siblings with Duchenne Muscular Dystrophy

Am J Ment Retard

Early verbal disability in children with Duchenne muscular dystrophy

Dev Med Child Neurol

Serial position memory of boys with Duchenne Muscular Dystrophy

Dev Med Child Neurol

Mental retardation in Duchenne Muscular Dystrophy in man

The psychological factors in muscular dystrophy

J Child Psychiatr

Reaction observed in boys of various ages (10–14) to a crippling, progressive, and fatal illness (muscular dystrophy)

J Chronic Dis

Three cognitive functioning and neurological deficit: Duchenne muscular dystrophy and celebral palsy

Aust Psychologist

Autosomal dominant spinal muscle atrophy. A clinical and genetic study

J Neurol Sci

Progressive muscular atrophies clinical aspects of spinal muscular atrophy