Global prevalence of intellectual developmental disorder in dystrophinopathies: A systematic review and meta‐analysis

Abstract

Aim To estimate the global prevalence of intellectual developmental disorder (IDD) and the IDD prevalence–genotype association in Becker muscular dystrophy (BMD) or Duchenne muscular dystrophy (DMD) according to the affected isoforms of the DMD gene: Dp427, Dp140, Dp71. Method Systematic searches in MEDLINE, Scopus, Web of Science, and the Cochrane Library were conducted from inception of each database to March 2022. Observational studies that determined the prevalence of IDD in the population with BMD or DMD were included. Meta‐analyses of IDD prevalence and prevalence ratios of the IDD–genotype association were conducted. Results Forty‐nine studies were included. The prevalence of IDD in BMD was 8.0% (95% confidence interval 5.0–11.0), and in DMD it was 22.0% (18.0–27.0). Meta‐analyses of IDD–genotype association showed a deleterious association between IDD and the number of isoforms affected in DMD, with a prevalence ratio = 0.43 (0.28–0.64) and 0.17 (0.09–0.34) for Dp140+/Dp71+ versus Dp140−/Dp71+ and Dp140+/Dp71+ versus Dp140−/Dp71− comparisons respectively. However, in BMD, there was no association for Dp140+/Dp71+ versus Dp140−/Dp71+. Interpretation There is a high prevalence of IDD in BMD and DMD. Moreover, the number of isoforms affected is strongly and negatively associated with the prevalence of IDD in DMD. What this paper adds The global prevalence of intellectual developmental disorder (IDD) was 8% in Becker muscular dystrophy and 22% in Duchenne muscular dystrophy (DMD). The global prevalence of IDD in DMD was 12%, 29%, and 84% in participants with Dp427−/Dp140+/Dp71+, Dp427−/Dp140−/Dp71+, and Dp427−/Dp140−/Dp71− genotypes respectively. In DMD, 12% and 22% of participants had abnormal performance IQ and verbal IQ values respectively.

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

“…These body-wide abnormalities include cardiomyopathy [ 294 , 295 , 296 ], respiratory failure [ 297 , 298 , 299 , 300 ], liver atrophy [ 301 , 302 ], renal failure [ 303 , 304 , 305 , 306 ], bladder dysfunction [ 307 , 308 , 309 , 310 ] and gastrointestinal complications [ 311 , 312 , 313 ], as well as bone fragility [ 314 ] and scoliosis [ 315 , 316 , 317 ]. A subset of Duchenne patients suffers from neurological deficiencies that manifest themselves as neurodevelopmental delays, emotional disturbances, mental retardation and behavioral problems [ 318 , 319 , 320 , 321 , 322 ]. The main non-skeletal muscle organ systems that are affected in dystrophinopathy include the following: Central nervous system: cognitive impairments, attention deficit, altered emotions, impaired language, memory deficiencies and altered coordination; Peripheral nervous system: abnormal transmission at nerve–muscle connections; Cardio-respiratory system: late-onset cardiomyopathy, cardio-respiratory syndrome, respiratory insufficiency; Liver: enlargement, steatosis, fibrosis, atrophy and ectopic fat deposition; Renal system: kidney failure, cardio-renal syndrome, hyperfiltration, hypertension and ectopic fat deposition; Bladder: dysfunction of the urinary tract and bladder; Bone: increased risk of bone fragility; Spine: high risk of development of scoliosis; Gastrointestinal system: delayed gastric emptying and pancreatic dysregulation; Immune system: hyperactivity causing chronic inflammation, spleen adaptations.…”

“…These body-wide abnormalities include cardiomyopathy [294][295][296], respiratory failure [297][298][299][300], liver atrophy [301,302], renal failure [303][304][305][306], bladder dysfunction [307][308][309][310] and gastrointestinal complications [311][312][313], as well as bone fragility [314] and scoliosis [315][316][317]. A subset of Duchenne patients suffers from neurological deficiencies that manifest themselves as neurodevelopmental delays, emotional disturbances, mental retardation and behavioral problems [318][319][320][321][322]. The main non-skeletal muscle organ systems that are affected in dystrophinopathy include the following:…”

Extracellular Matrix Proteomics: The mdx-4cv Mouse Diaphragm as a Surrogate for Studying Myofibrosis in Dystrophinopathy

“…Characteristic patterns of toe walking and difficulties with climbing stairs progress at more advanced stages of the disease towards respiratory insufficiency, cardiomyopathy, scoliosis, and severe limitations in general mobility [185][186][187][188][189][190], which eventually results in the loss of unassisted ambulation and upper body weakness [191]. Approximately one-fifth of Duchenne patients suffer from intellectual developmental disorder that can be associated with learning difficulties, behavioral deficits, emotional problems, attention deficits, impaired language and speech development, cognitive deficiencies, and mental retardation [192][193][194]. Of note, secondary multi-system abnormalities in dystrophinopathy negatively affect whole-body homeostasis, including the proper functioning of the kidneys, the bladder, the gastrointestinal tract, and the liver [19].…”

Difficulties in social cognitive functioning among pediatric patients with muscular dystrophies

“…A higher risk of co-occurrence of neurodevelopmental and psychiatric conditions in children and youth with MDs has also been reported compared with the general population ( Mohamadian et al, 2022 ). Additionally, patients with MDs have higher rates of internalizing symptoms (depression and anxiety), autism spectrum disorders (ASDs) and attention-deficit hyperactivity disorder (ADHD) ( Colvin et al, 2022 ; Mohamadian et al, 2022 ; Pascual-Morena et al, 2022 ).…”