OBJETIVO: Fazer um levantamento da literatura médica destinada ao estudo das disfunções cognitivas nos pacientes com distrofia muscular de Duchenne, através da descrição dos marcos do desenvolvimento neuropsicomotor e dos testes psicométricos para quantificação da inteligência. FONTES DOS DADOS: Revisão não sistemática sobre os aspectos da cognição na distrofia muscular de Duchenne nas principais bases médicas científicas: MEDLINE, LILACS, Biblioteca Cochrane e SciELO. SÍNTESE DOS DADOS: Os pacientes com distrofia muscular de Duchenne apresentaram atraso para marcha e desenvolvimento da linguagem, os quais se correlacionaram a menores pontuações nos testes de inteligência no futuro. Há marcante disfunção nos subtestes das habilidades verbais. CONCLUSÕES: A média do coeficiente de inteligência encontra-se com um desvio padrão abaixo da média populacional. Quanto maior a disfunção cognitiva, piores serão os aspectos relacionados à morbidade e mortalidade na doença.
Distrofia muscular de Duchenne; retardo mental; atraso do desenvolvimento neuropsicomotor
OBJECTIVE: To survey the medical literature directed to the study of cognitive dysfunction in patients with Duchenne muscular dystrophy through description of the milestones of neurological development and psychometric tests for quantifying intelligence. SOURCES: Non-systematic review of aspects of cognition in Duchenne muscular dystrophy in the major medical scientific bases: MEDLINE, LILACS, SciELO and Cochrane Library. SUMMARY OF THE FINDINGS: Patients with Duchenne muscular dystrophy exhibited delay in walking and language development, which correlated with lower scores on future intelligence tests. There is marked impairment in the verbal subtests. CONCLUSIONS: Average IQ has standard deviation below the average of the population. The greater the cognitive impairment, the worse aspects related to morbidity and mortality in the disease will be.
Duchenne muscular dystrophy; mental retardation; delay milestones; neurological development delay
IMestranda, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. Neurologia Infantil, UFRJ, Rio de Janeiro, RJ, Brazil
IIProfessora associada, Departamento de Pediatria, UFRJ, Rio de Janeiro, RJ, Brazil
IIIProfessora adjunta, Departamento de Pediatria, UFRJ, Rio de Janeiro, RJ, Brazil
OBJECTIVE: To survey the medical literature directed to the study of cognitive dysfunction in patients with Duchenne muscular dystrophy through description of the milestones of neurological development and psychometric tests for quantifying intelligence.
SOURCES: Non-systematic review of aspects of cognition in Duchenne muscular dystrophy in the major medical scientific bases: MEDLINE, LILACS, SciELO and Cochrane Library.
SUMMARY OF THE FINDINGS: Patients with Duchenne muscular dystrophy exhibited delay in walking and language development, which correlated with lower scores on future intelligence tests. There is marked impairment in the verbal subtests.
CONCLUSIONS: Average IQ has standard deviation below the average of the population. The greater the cognitive impairment, the worse aspects related to morbidity and mortality in the disease will be.
Keywords: Duchenne muscular dystrophy, mental retardation, delay milestones, neurological development delay.
Duchenne muscular dystrophy (DMD) (Online Mendelian Inheritance in Man®, OMIM 310200) is a recessive hereditary disease, linked to the X chromosome, which affect skeletal muscles, heart and brain, with progressive evolution until death around the second decade, generally caused by cardiorespiratory events.1
DMD affects one in every 3,600 to 6,000 boys of live birth and it occurs as a result of mutations in the dystrophin gene (locus Xp21.2).2 Around 1/3 of all new cases diagnosed arise from "new" mutations.3,4 Dystrophin is a large structural protein (427 kDa) whose function is to connect the internal cytoskeleton of the skeletal fiber with the extracellular matrix proteins, stabilizing muscular contraction.5 In DMD, the protein is absent or dysfunctional, thus resulting in imbalance in the integrity of the lipid bilayer of the membrane, with influx of calcium and cellular necrosis.6,7
The disease is manifested early in childhood with delay in motor behavior. Motor weakness is more pronounced in the lower members and is expressed through difficulty in running, climbing stairs, jumping, walking on the tips of ones feet and frequent falls. Paresis is progressive until loss of walking ability at around 11-12 years old.8 Fibrosis of the heart muscle fibers occurs, resulting in dilated cardiomyopathy and disorders in rhythm and behavior after 10 years of age.9 Respiratory muscles are also affected, and after 10 years of age, development of restrictive ventilatory disorder is observed, with reduction of forced vital capacity from 8 to 12% a year.9,10 Scoliosis is present in practically all patients and increases after loss of walking ability, significantly contributing to reduction of respiratory vital capacity.11 Long bone fractures generally occur due to falls in 21-44% of the boys.12-14
In addition to motor delay, language delay is also observed. Mental retardation (MR) is a quite frequent aspect among boys with DMD, affecting around 30% of them. This prevalence is greater than that observed in the general population, in which MR rates of approximately 1% are observed. The average intelligence quotient (IQ) for patients with DMD is 85, in other words, below the IQ considered normal in the general population, which varies between 90 and 120. Generally, verbal IQ is more intensely affected than executive IQ. The seriousness of MR does not appear to be correlated with the intensity of muscle weakness. In addition to cognitive impairment, one also observes in this disease a greater frequency of psychiatric comorbidities, such as attention deficit disorder and hyperactivity.15
The present article seeks to survey the medical literature directed to the study of cognitive impairments in patients with DMD through description of the neurological development milestones and of the psychometric tests for quantification of intelligence. Thus, we intend to highlight the delay in acquisition of neurological skills, as well as lower intellectual performance in the psychometric tests in children who are carriers of this dystrophy, emphasizing the possible physiopathological explanations that determine greater probability of MR in a peripheral muscle type disease.
A non-systematic review was undertaken regarding cognition aspects in DMD in the major medical scientific bases: MEDLINE, LILACS, Cochrane Library and SciELO, searching keywords like intelligence, cognition, brain functioning, central nervous system, psychometric tests, neurological development scales, global development delay and mental retardation in Duchenne muscular dystrophy in Portuguese and English respective terminology. Due to the relative scarcity of scientific publications on the theme, bibliographical research was not limited by date. Only periodicals published in English or Portuguese were selected and those that were listed as available in the journals/magazines indexed to the CAPES periodical portal.
The intention was thus to describe the sequence of neurological development milestones and their cognitive aspects in children with DMD, establishing the discrepancies in the chronological ages for acquisition of motor, adaptive, personal-social and language skills. In addition, it will be possible to assess the differences of intellectual performance in the major psychometric tests applied to children with DMD when compared to healthy controls, as expected, given the greater prevalence of MR in this population.
Neurological development in DMD
Motor delay in DMD is an event well known by neurologists. Less known is the delay in acquisition of language skills in these children. These are intriguing clinical observations because, a priori, changes in higher cortical functions would not be expected in a peripheral muscle type disease.
In Table 1, which may be found at the end of this article, are summarized the diverse observations regarding how the neurological development stages in children with DMD are processed.
Cognitive development in DMD
Cognitive deficit in dystrophy is a known clinical aspect, even referred to by Duchenne in 1868 in the first clinical description of the disease. Although many researchers in past decades (Gowers, 1879; Morrow & Cohen, 1954; Whalton & Natrass, 1954; Sherwin & McCully, 1961; and Lincoln & Staples, 1977) have refuted the hypothesis of MR being a clinical manifestation associated with dystrophy, there is currently overwhelming evidence corroborating the incorporation of this finding to the semiological scenario of the disease.20
Cotton et al.21, Allen & Rodgin22, Karagan23, Leibowitz & Dubowitz25 and Prosser et al.25 observed that children with dystrophy exhibit a deficient intellectual profile. The average IQ in this group is less than the average in the general population, although the seriousness of this finding does not correlate with the intensity of muscle weakness or serum level of creatine phosphokinase.
In Table 2, we will be able to summarize the results of the diverse assessments and cognitive measures performed throughout the years on patients with dystrophy.
Throughout history, the major focuses of research regarding the physiopathology of DMD were directed to the study of muscular-skeletal impairment. Even now, little is known about the psychocognitive manifestations of the disease and its etiopathogenic bases. Nevertheless, considering that an extensive share of children with DMD have MR, it is important to gather the results of scientific literature regarding this topic to better understand what deficits these are and the best strategy for dealing with them.
According to Haggerty, intelligence includes "sensation, perception, association, memory, imagination, discrimination, judgment and reasoning."34,35 It is a challenge to discern the beginning of intelligence. It is believed that its development after birth begins in the nursing child with substitution of reflex and involuntary responses to the outside environment for more elaborate sensory motor skills. At the beginning of the past century, authors such as Bowlby (1951), Kirman (1953) and Bailey (1933) believed that the diagnosis of MR through neuropsychological tests could not be performed in children under 2 years of age. On the other hand, Gesell, in 1943, believed that practically all cases of cognitive deficiency could indeed be identified already in the first year of life, in the event that there was neurological delay. Global delay of the four behavioral areas of neurodevelopment (motor, adaptive, personal-social and language) is correlated with low scores on future intelligence tests.36 In 1983, Kaminer verified that a large majority of children with MR began walking only at 17 months, thus corroborating the associative correlation between MR and neurological delay. Other studies, such as Matsuishi in 1984, also found the same associative correlation.37,38
The American Association of Mental Retardation (AAMR) defines MR as intellectual disability associated with two or more of the following adaptive skills: communication, independence at home, interaction with the community, caring for ones own health and safety, leisure, caring for ones own hygiene, self-direction, academic functions and work functions. These clinically diagnosed criteria of MR must be present before 18 years of age. To assess the level of intelligence, clinical criteria are necessary regarding adaptive behavior of the individual in relation to his environment and pyschometric criteria (through tests or scales).39
Intellectual functions are generally tested by means of IQ tests for children above 5 years of age. A score lower than 68 on the Stanford-Binet scale or below 70 on the Wechsler test defines the presence of intellectual impairment.40 In 1968, the World Health Organization (WHO) introduced the four levels of MR, which are currently in effect in manual and statistical diagnosis of mental disorders (DSM-IV):
Profound MR: IQ below 20-25;
Serious MR: IQ from 20-25 and 35-40;
Moderate MR: IQ from 35-40 and 50-55;
Slight MR: IQ from 50-55 up to 70.
IQ considered as normal in the general population ranges from a score of 90 to 120. Graphic representation of the general IQ follows a normal or Gaussian distribution pattern; in other words, approximately 95% of the population has scores from 90 to 120, 2.5% below 90 (cognitive impairment) and 2.5% above 120 (cognitive superiority). Those whose acquired score is from 71 to 84 are called individuals with borderline IQ. From the functional point of view, individuals with slight and moderate MR would then be seen as "educable;" those with serious MR would be called "trainable;" and those with profound MR would be "dependents."39
In contrast with the high prevalence of MR among patients with DMD, it is estimated that in the general population these rates are from 1 to 3%, a bit more frequent in the male group, at a proportion between men and women of 1.3 and 1.9:1.41
Neurological delay in DMD
With follow-up of the cohort of 22 patients with DMD made by Parsons et al., motor and language delay was verified both through the Denver scales and the Griffiths scale.18
According to assessment of 130 patients with DMD made by Cyrulnik et al., children with dystrophy sat, crawled, stood and walked later when compared to healthy controls. Likewise, beginning of first words and construction of verbal sentences were observed at a later age. On the other hand, this same analysis did not show differences in ages for acquisition of bladder and bowel control between both groups. Another important finding was that children with DMD, and who had delay in speech, had worse performance on vocabulary tests when compared with those that did not have a history of delay in language. Comparative analysis between children with DMD with and without motor delay also showed differences; in other words, those that acquired walking skills in a later period exhibited less cognitive performance on reasoning tests. The etiopathological hypothesis raised by this group was that the same brain area responsible for learning and motor cerebellum coordination also participates in cognitive abilities. In fact, studies with tomography through emission of positrons in patients with DMD reveal that the cerebellum an area rich in dystrophin has low energetic metabolism of glucose, a finding that partially sustains the previous hypothesis.19
Cognitive impairment in DMD
According to results from Prosser et al. During application of the Wechsler Intelligence Scale for Children, Wechsler Intelligence Scale for Adults and Stanford-Binet scale in children with DMD, a reduction of intellectuality was observed in this group, a non-progressive loss with the passage of years and without correlation to the seriousness or stage of the disease. Socio-economic conditions were not determinant for MR, because a normal IQ was observed in the healthy siblings of these patients. This group of scholars did not observe significant differences in the verbal and executive IQ scores.25
On the other hand, in 1974, Marsh & Munsat, upon studying 34 boys with DMD, found a lower score on verbal IQ when compared to executive IQ. Nevertheless, in spite of the verbal IQ deficit not being progressive with the passage of years, executive IQ deteriorates to the extent that muscular weakness is accentuated, because most subtests depend on manual agility.26
According to the extensive meta-analysis performed by Cotton et al., 30% of the patients with DMD have MR, with the great majority (79%) being classified as slight. It was also observed that the deficit is greater for verbal mastery than for executive mastery, with the major difficulties being found for functions like naming, verbal fluency, expressive and receptive language, reading and verbal learning.21
Hinton et al., upon assessing 41 children with DMD, observed that there is worse performance in DMD in mathematical abilities, with attention and memory deficit. However, in tests of visual-spatial capacity, individuals with DMD had performance similar to that of their controls, indicating that the visual learning of these children is better than the verbal. In addition to Hinton, other authors had already described worse verbal IQ scores in children with DMD, such as Billard et al., in 1992; Ogasawara, in 1989; and Whelan, in 1987. It has been suggested that dystrophin may perform a stabilizing role in neurons, similar to their function in the muscle cell, thus contributing to the integrity of the synapses. Dystrophin is located in the dendrites and tends to aggregate in the postsynaptic densities, suggesting its possible role in interneuronal transmission.27
Wicksell et al. found statistically significant differences between memory scores (short and long term), learning and executive capacity in comparison of children with DMD and their respective controls.28
In 2004, Hinton et al. deepened analysis of academic abilities of individuals with dystrophy to test the suspicion that immediate verbal memory deficit would be the principal core of all the other school disabilities. The results obtained during analysis of 26 patients were similar to those found in 2001; in other words, worse performance in all academic areas in the affected group, especially mathematics. In fact, children with dystrophy had poor performance in all the tests which depended on listening to information or a sequence of commands to be executed. Thus, this led to the conclusion that limited immediate memory storage capacity is the central cause of academic disabilities. Dyslexia was not ascribed as the etiology of the literacy difficulties of these children, as other authors suggested in the past (Billard et al. in 1992, Dorman et al. in 1988). It is believed that the worse results in the framework of phonological decodification found in other studies are also derived from a greater deficiency, which is found in the immediate verbal memory.29
In 2007, this same group sought to assess the verbal and memory functions in dystrophy. After the performance of specific language tests, they concluded that the disease in a specific way affects language competencies: children with DMD have greater difficulties in tests of remembering sentences. For them, DMD does not globally affect all verbal abilities. Only immediate memory is found to be impaired, with the processes of consolidation and recovery of information intact.30
Cyrulnik et al., upon studying 20 children with DMD, observed that there was global delay in neurodevelopment, as well as deficit of attention/memory, receptive and expressive language, visual-spatial capacity and fine motor control, as well as in social abilities, approximately one standard deviation below that expected.19 This same author had already described 1 year before that children with DMD that exhibit motor delay and delay in language milestones in the first years of life will have worse performance on intelligence tests after 4 years of age and greater cognitive deficit.19
While some authors like Hinton et al.27 and Cyrulnik et al.31 observed worse scores for verbal IQ if compared to executive IQ in DMD, the group of Donders & Taneja32 found lower performance in both tests. Taneja et al. observed impairment of visual memory and non-verbal executive functions, just as Wicksell et al. in 2004.28
In 2009, the group of Wingeier et al. found the same IQ average in DMD as that already established in the literature, in other words, a score of 88 (borderline intelligence). In this analysis, around 24% of the sample fit into the assessment of slight MR (IQ < 70). Total loss or impairment of the Dp140 dystrophin isoform seems to be more strongly correlated with intellectual loss in boys with dystrophy.33
According to the proposed review, we observed that the IQ of patients with DMD is found to be around one standard deviation below the average considered as normal, and that the distribution of this score in the group also follows a normal or Gaussian pattern.21
Difficulties in the verbal subtests applied to patients with DMD are evident, as referred to by various authors: repeating the story (Billard et al., 1992; Hinton et al., 2000, 2001; Wicksell et al., 2004), repeating the sentence (Billard et al., 1992; Hinton et al., 2007), remembering digits (Billard et al., 1998; Hinton et al., 2000, 2001; Ogasawara, 1989; Wicksell et al., 2004) and digit scale (Anderson et al., 1988; Billard et al., 1998; Dorman et al., 1988; Hinton et al., 2000, 2001, 2004.; Sollee et al., 1985; Ogasawara, 1989; Whelan, 1987; Wicksell et al., 2004). These problems in verbal functions may be derived from failures in speech and language processing and reading, as many authors affirm. According to Cyrulnik et al., neurodevelopment and psychocognition impairment observed in dystrophy result from complete or partial absence of dystrophin in the central nervous system. This protein is found in the post-synaptic neuronal terminals of the cortex, hippocampus and cerebellum, areas intensely involved with reasoning and learning.42
Nevertheless, we observed that in spite of the 143 years that have passed since the first clinical description of the disease made by Duchenne and of the extensive technical-scientific biological advances, currently many questions still remain to be answered regarding brain functioning in DMD.
There are few publications directed to the chronological sequencing of the neurological development milestones in dystrophy, for the purpose of establishing the average time for acquisition of each one of the specific behaviors. Krajewska, in 1977, observed that 58% of the patients with DMD acquired walking ability only at 19 months, on average.16 It is known that children with DMD develop more slowly, as highlighted by Smith et al. in 199017, with delay not being only observed in motor skill, as would be expected in a peripheral muscle disease. Around 60% of the patients with DMD acquired walking ability only at 19 months, on average. Delay in language and personal-social abilities is the precursor of low intellectual performance and behavioral difficulties in the future.
Just as for other diseases that are affected by intellectual deficit, neuropediatricians lack psychometric assessment instruments with simple and practical applicability in day to day life to "quantify" the degree of this deficiency. The Gesell scale for assessment of neurological development is widely spread throughout the pediatrics scene and enjoys recognition and prestige in the area. Nevertheless, its use is restricted up to 5 years of age. As of school age, there is a lack of a cognitive assessment method for application in the medical appointment. The Wechsler and Stanford-Binet scales in spite of being complete and extensive are long and exclusive to the field of neuropsychology and, for that reason, are not used in routine medical semiology. Therefore, childhood neurology makes use of clinical definitions established by the WHO to diagnose and measure MR.
The observation that children with DMD that exhibit motor and language delay are precisely those that will develop diverse academic difficulties in the future in the most varied domains of cognition leads to the observation that the low intellectual performance of this group is not only due to motor disability and emotional disorders, but principally to early changes in the central nervous system. This reflects the need for creation of strategies for early pedagogical and speech and language stimulation for the group of children with DMD and neurological delay, because school difficulties will already be foreseen.
For teachers and educators, it is important to know that, contrary to the progressive nature of the muscular weakness, the intellectual deficit is not accentuated with the passage of time. Even those who are more limited from the motor skills point of view are capable of exercising their higher functions. As suggested by Hinton et al., some teaching strategies may be useful for minimizing the short term memory deficit in these patients, such as: use of direct and short phrases, dividing up of commands, repetition of information and use of visual resources in the pedagogical process.
In the same way, a lack of studies is observed with greater samples of patients directed at analysis of possible associations between the neurological delay and MR with a worse clinical evolution. According to Mochizuki et al., in 2008, in accordance with the analysis of 194 patients with DMD, 38% exhibited slight MR, and this group began walking in a later period (average of 18.6 months), lost walking ability earlier (average of 10.2 years), needed ventilatory support (average of 19.9 years old) and nutritional support (average of 24.5 years old) earlier and died earlier (25 years) than the group with DMD without RM. Therefore, the care and treatment for patients with DMD and MR must be more meticulous than that for those with DMD and without MR.43
If there is, in fact, a statistically significant correlation between MR and a worse prognosis in DMD, both in the aspects of morbidity and mortality, it is necessary that the diagnosis of cognitive deficit be made early. The objective of this detection in the initial phases is installing speech and language rehabilitation already in lactation and pre-school to improve the quality of life of the children and their families.
- 1. Yiu EM, Kornberg AJ. Duchenne muscular dystrophy. Neurol India.2008;56:236-47.
- 2. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77-93.
- 3. Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 2004;5:872-6.
- 4. Koenig M, Hoffman EP, Bertelson CJ, Monaco EP, Feener C, Kunkel LM. Complete cloning of the Ducehnne muscular dystrophy (DMD) cDNA and preliminary genomic organization of DMD gene in normal and affected individual. Cell. 1987 Jul 31;50(3):509-17.
- 5. Barbujani G, Russo A, Danieli GA, Spiegler AW, Borkowska J, Petrusewicz IH. Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases. Hum Genet. 1990;84:522-6.
- 6. Hoffman EP, Dressman D. Molecular pathophysiology and targeted therapeutics for muscular dystrophy. Trends Pharmacol Sci. 2001 Sep;22(9):465-70.
- 7. Wrogemann K, Pena SD. Mitochondrial calcium overload: a general mechanism for cell-necrosis in muscle diseases. Lancet. 1976;1:672-4.
- 8. Roses AD, Herbstreight MH, Appel SH. Membrane protein kinase alteration in Duchenne muscular dystrophy. Nature. 1975;254:350-1.
- 9. Jones H, De Vivo DC, Darras BT. Neuromuscular disorders of infancy, childhood and adolescence. A clinician approach. Oxford: Butterworth-Heinemann; 2003.
- 10. Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol. 1990;26:271-7.
- 11. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2001;164:2191-4.
- 12. Ragette R, Mellies U, Schwake C, Voit T, Teschler H. Patterns and predictors of sleep disorders breathing in primary myopathies. Thorax. 2002;57:724-8.
- 13. McDonald DG, Kinale M, Gallagher AC, Mercuri E, Muntoni F, Roper H, et al. Fracture prevalence in Duchenne muscular dystrophy. Dev Med Child Neurol. 2002;44:695-8.
- 14. Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthop. 2000;20:71-4
- 15. Anderson JL, Head SI, Rae C, Morley JW. Brain Function in Duchenne muscular dystrophy. Brain 2002; 125:4-13.
- 16. Krajewska G. Motor development in children with muscular dystrophy of the Duchenne type. Neurol Neurochir Pol. 1977;11:647-51.
- 17. Smith RA, Sibert JR, Harper PS. Early development of boys with Duchenne muscular dystrophy. Dev Med Child Neurol. 1990;32:519-27.
- 18. Parsons EP, Clarke AJ, Bradley DM. Developmental progress in Duchenne muscular dystrophy: lessons for earlier detection. Eur J Paediatr Neurol. 2004;8:145-53.
- 19. Cyrulnik S, Fee RJ, De Vivo DC, Goldstein E, Hinton V. Delayed developmental language milestones in children with Duchennes muscular dystrophy. J Pediatr. 2007;150:474-8.
- 20. Anderson JL, Head SI, Rae C, Morley JW. Brain function in Duchenne muscular dystrofy. Brain 2002;125:4-13.
- 21. Cotton S, Voudouris NJ, Greenwood KM. Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. Dev Med Child Neurol. 2001;43:497-501.
- 22. Allen JE, Rodgin DW. Mental retardation in association with progressive muscular dystrophy. Am J Dis Child 1960;100:208-11.
- 23. Karagan NJ. Intellectual functioning in Duchenne muscular dystrophy: a review. Psychol Bull. 1979;86:250-9.
- 24. Leibowitz D, Dubowitz V. Intellect and behavior in Duchenne muscular dystrophy. Dev Med Child Neurol. 1981;23:577-90.
- 25. Prosser EJ, Murphy EG, Thompson MW. Intelligence and the gene for Duchenne muscular dystrophy. ArchDisChld. 1969;44:221-30.
- 26. Marsh GG, Munsat TL. Evidence for early impairment of verbal intelligence in Duchenne muscular dystrophy. Arch Dis Child. 1974;49:118-22.
- 27. Hinton VJ, De Vivo DC, Nereo NE, Goldstein E, Stern Y. Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy. J IntNeuropsychol Soc. 2001;7:45-54.
- 28. Wicksell RK, Kihlgren M, Melin L, Eeg-Olofsson O. Specific cognitive deficits are common in children with Duchenne muscular dystrophy. Dev Med Child Neurol. 2004;46:154-9.
- 29. Hinton V J, De Vivo DC, Fee R, Goldstein E, Stern Y. Investigation of poor academic achievement in children with Duchenne muscular dystrophy. Learn Disabil Res Pract. 2004;19:146-54.
- 30. Hinton VJ, Fee RJ, Goldstein EM, De Vivo DC. Verbal and memory skills in males with Duchenne muscular dystrophy. Dev Med Child Neurol. 2007;49:123-8.
- 31. Cyrulnik SE, Fee RJ, Batchelder A, Kiefel J, Goldstein E, Hinton VJ. Cognitive and adaptive deficits in young children with Duchenne muscular dystrophy (DMD). J Int Neuropsychol Soc. 2008;14:853-61.
- 32. Donders J, Taneja C. Neurobehavioral characteristics of children with Duchenne muscular dystrophy. Child Neuropsychol. 2009;15:295-304. Epub 2009 Jan 22.
- 33. Wingeier K, Giger E, Strozzi S, Kreis R, Joncourt F, Conrad B, Gallati S, Steinlin M. Neuropsychological impairments and the impact of dystrophin mutations on general cognitive functioning of patients with Duchenne muscular dystrophy. J ClinNeurosci. 2009;18:90-5. Epub 2009 Nov 24.
- 34. Burt C. Experimental tests of general intelligence. Br J Psychol. 1909;3:94-177.
- 35. Spearman C. "Intelligence" tests. Eugen Rev. 1939;30:249-54.
- 36. Illingworth, RS. Mental retardation in the infant and pre-school child; diagnosis and treatment. Br Med J. 1955 Jul 2;2(4930):1-7.
- 37. Kaminer RK, Jedrysek E. Age of walking and mental retardation. Am J Public Health. 1983;73:1094-6.
- 38. Matsuishi T. Possible risk factors and signs of mental retardation (MR) - comparative study of mentally retarded and normal children. Kurume Med J. 1984;31:301-7.
- 39. World Health Organization. ICD-10 Guide for mental retardation. Division of Mental Health and Prevention of Substance Abuse. Geneva; 1996.
- 40. Lemay JF, Herbert AR, Dewey DM, Innes AM. A rational approach to the child with mental retardation for the paediatrician. Paediatr Child Health. 2003;8:345-56.
- 41. Croen LA, Grether JK, Selvin S. The epidemiology of mental retardation of unknown cause. Pediatrics. 2001;107:e86.
- 42. Cyrulnik SE, Hinton VJ. Duchenne muscular dystrophy: A cerebellar disorder? Neurosci Biobehav Rev. 2008;32:486-96.
- 43. Mochizuki H, Miyatake S, Suzuki M, Shigeyama T, Yatabe K, Ogata K, et al. Mental retardation and lifetime events of Duchenne muscular dystrophy in Japan. Intern Med. 2008;47:1207-10.
Publication in this collection
12 Mar 2012
Date of issue
09 Aug 2011
23 Aug 2011