EARLY DEVELOPMENT OF BOYS WITH DUCHENNE MUSCULAR DYSTROPHV

R. A. Smith J. R . Sibert P. S. Harper

There are no prospective studies of the early development of boys with Duchenne muscular dystrophy (DMD), mainly be- cause of lateness of diagnosis in most cases (Crisp et al. 1982, O’Brien et al. 1983). Delay in early motor development has been reported: among 130 boys with DMD the median age at walking was 18.3 months (Gardner-Medwin et al. 1978); 56 per cent of 114 cases were not walking by 18 months and 25 per cent did not walk until two years (Emery 1986). Dubowitz (1965) reported locomotor delay in 27 cases, with seven not sitting until later than nine months, 13 not standing until 14 months and 15 not walking until later than 18 months. Based on the obser- vations that age at learning to walk was not correlated with age at inability to walk, and on the negative correlation between WISC verbal IQ and age at independent walking, Gardner-Medwin (1982) proposed that delayed walking in DMD may be more closely related to IQ than to the severity of muscle disease. Dubowitz (1 965) reported that only 25 per cent of boys labelled as having ‘sub- normal’ intelligence had normal early milestones of development. Most of this information has been obtained retro- spectively, however, with problems of recall bias, and there is very little infor- mation on other areas of development.

There are many studies on the assess-

ment of intelligence of older boys with DMD, most of the larger studies reporting intellectual impairment, with an average IQ one standard deviation below the mean (Cohen et al. 1968, Kozicka el al. 1971, Florek and Karolak 1977, Dubowitz 1979, Leibowitz and Dubowitz 1981). but with no progressive deterioration with age (Cohen et al. 1968, Leibowitz and Dubo- witz 1981). Decreased performance on verbal tasks has been reported, especially

B early on and mainly of verbal expression (Marsh and Munsat 1974, Lincoln and Staples 1977, Karagan and Zellweger s Dubowitz 1981, Kaplan el al. 1986). Not all authors are in agreement with these 6 s findings, however (Sherwin and McCully 1961, Black 1973, Mearig 1979). More e s 2 recent work has concentrated on assessing

3 fewer subjects in more detail. Detailed s, neuropsychological usessment of older

boys has revealed deficits in memory a s function and reading ability (Whelan

8 1987, Andersen el al. 1988, Dorman et al. 1988). None of the studies has concen- s trated on assessing the abilities of young boys with DMD under the age of five years.

I t has been shown that at 48 months, E4 maternal IQ and home environment could explain 29 per cent of the variation in IQ of normal children (Yeates et a/. 1983). d The Seattle longitudinal study (Bee et al. 1982) showed that home environment, as

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measured by the Home Inventory, cor- related with the child’s Stanford-Binet IQ when both were measured at 48 months. Therefore any study of child development should include some assessment of maternal intelligence and home environ- ment, and not just social class.

We have performed a prospective developmental study of 33 young boys with DMD, using standardised develop- mental assessments, and have attempted to assess the variables that may influence their developmental abilities.

Subjects All boys aged under 72 months with confirmed DMD were ascertained from the DMD register based on the Institute of Medical Genetics, Cardiff. This group was supplemented by writing to clinical geneticists in England, asking for details of young boys with DMD. A letter was sent to each family identified, inviting participation in the study. The cut-off of six years was chosen to include a range of ages and to include some boys diagnosed later. It was considered that a group consisting solely of boys diagnosed early on clinical grounds would not be repre- sentative of the disease as it presents in the population.

Thirty-three boys were ascertained from 31 families. The average age at entry to the study was 3.4 years (range 0.83 to 6.67, SD 1-59 years). 19 were from Wales and 14 were from various regions of England. They formed a heterogeneous group with regard to method of diagnosis: 12 were diagnosed in the asymptomatic phase purely because of a positive family history, nine presented with locomotor problems and 12 were diagnosed because of developmental delay. All affected males had very raised levels of serum creatine kinase, 24 had the diagnosis confirmed by muscle biopsy and the remaining nine had an affected relative who had had a confirmatory muscle biopsy. In none of the families was the pattern of disease suggestive of Becker muscular dystrophy.

A control group of normal boys matched for age was ascertained from the Cardiff birth register, with a mean age of 3 - 5 years (range 1-67 to 6-83, S D 1.55 years).

Method All boys were assessed with the Griffiths Mental Development Scales (GMDS) (Griffiths 1970). Reynell Developmental Language Scales (RDLS) (Reynell and Huntley 1985) and the British Picture Vocabulary Scales (BPVS) (Dunn et al. 1982), using three evaluations at six- monthly intervals over a one-year period. All the assessments were performed by R.A.S. in the patient’s home. At the second visit an assessment of the home environment was made, using the Home Observation for Measurement of the Environment (HOME) (Caldwell and Bradley 1984), an assessment of maternal intelligence was made, using the AH4 test of intelligence (Heim 1970), and the child’s behaviour was assessed with a behaviour screening questionnaire (BSQ) (Richman and Graham 1971).

Assessments The GMDS are a widely used set of six subscales, including locomotor, personal/ social, hearing and speech, eye/hand co- ordination, performance and practical reasoning. They give detail on develop- mental abilities and an over-all profile of scores. They are suitable up to the age of eight years and can be used to test serially over long periods. The scores are given as a mental age in months, based on scored items; when divided by the actual age, they give a quotient for each subscale. The general quotient is the mean of the subscale quotients. The current mean for the Griffiths scales is 110, as the standard- isation is somewhat out of date (Hanson et al. 1985). The scales were included in the study as they are the standard British developmental scales.

The RDLS have recently been revised and updated and are used to assess expressive language and verbal compre- hension. They cover the age-range one to six years and give scores as an equivalent age, with a standard deviation score for each scale. These scales were included as a general test of language ability.

The BPVS are designed to measure a subject’s receptive vocabulary for standard English. The age-range is from 2% to 18 years. This is a recent and fully standard- ised British modification of the Peabody Picture Vocabulary Test. Performance can

be expressed as a standard deviation score or an age-equivalent score.

The AH^ is an intelligence test consisting of two parts, the first testing verbal and number skills and the second testing dia- grammatic skills. It is a short (20-minute) test which can easily be administered in the home. A raw score is used, not a quotient. The mean score in a normative series is 75.23, with a standard deviation of 14.58.

The HOME inventory is a 75-item questionnaire which gives information on the variables that may influence child development. There are three scales, appropriate for children up to three years, from three to six years, and over six years. As the ranges of raw scores obtained on these scales differ, in this study they have been transformed to a percentage of rhe maximum raw score attainable (HOME%). This scale is standardised on an American sample and there is no British equivalent.

The BSQ is of proven validity and reliability and consists of a semi-structured interview. Parents are asked to describe 12 types of behaviour, each of which is coded 0, 1 or 2 according to pre-established criteria. A cut-off value of 11 is taken to indicate the possibility of behaviour problems. The scale is intended to cover the age range 2% to 3% years, but in this study the scale was applied to all children under the age of five; it would not be appropriate for older children.

The data were analysed using x2 , unpaired t test, two-way analysis of variance and Pearson product moment correlation coefficients.

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Assessment 1 2 3 ' 1 2 3 DMD group Control group

Fig. I . General developmental quotients on the Griffiths Mental Development Scales for DMD and control groups.

TABLE I Social class distribution

Social class Control DMD

1 2 3N 3M 4

5 Unclassifiable

Total

2 7

6 0 I 0 5

21

2 5

10 I 4

2 9

33

Results All 33 boys with DMD were assessed on all scales twice, and 31 three times. 21 control boys were assessed on all scales twice, and 20 three times.

Table I shows the social class distri- bution of the two groups; xz analysis revealed no significant difference between groups. Mean age at first assessment was 3.4 years (range 0.83 to 6.67, SD 1.59) for the affected group and 3.5 years for the control group (range 1.67 to 6.83, SD 1 *59).

The results on all three assessment scales for each visit are shown in Tables I1 and 111. All scales were administered to

each boy, but some of the DMD and control boys were unable to complete items on the practical reasoning subscale, which starts at two years. The distribution of general developmental quotients on the GMDS for each assessment for both groups is shown in Figure 1; the distri- bution is normal for both groups. 521

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TABLE II GMDS, RDLS and BPVS assessments for DMD group

Assessment I 2 3 N Mean (SO) N Mean (SO) N Mean (SO)

GMDS Locomotor Personal/social Hearing speech Eyelhand co-ordination Performance Practical reasoning General quotient RDLS VCA-EQ (yrs) VCA-SS EL-EQ (yrs)

BPVS BPVS-EQ (yrs)

EL-SS

BPVS-SS

33 65 33 81 33 77 33 82 33 88 20 86 33 79

31 2.20 31 -1.53 31 2.02 31 -1.74

18 2-66 17 78

(13.7) (16.8) (19.1) (16.2) (15.5) (21.3) (14.3)

(1.58) (1.03) (1.59) (1.11)

(1-52) (16.7)

33 58 (14.0) 31 52 (10.8) 33 78 (17.1) 31 77 (18.6) 33 76 119.9) 31 77 122.8) 33 81 ii7.4j 31 79 (19.7j 33 87 (15.0) 31 88 (19.5) 22 80 (27.8) 24 79 (23.7) 33 77 (14.4) 31 75 (14.9)

33 2.53 (1.88) 28 2.84 (1.8) 32 -1.41 (1.25) 26 -1 .44 (1.38) 33 2.32 (1.42) 28 2.59 (1.61) 32 -1.76 (1.04) 26 -1.54 (1.21)

18 3-28 (1.68) 22 3.40 (1.78) 20 81 (16.2) 22 84 (14.3)

TABLE 111 GMDS, RDLS and BPVS assessments for control group

Assessment I 2 3 N Mean (SO) N Mean (SO) N Mean (SO)

GMDS Locomotor PersonaVsocial Hearinglspeec h Eyelhand co-ordination Performance Practical reasoning General quotient RDLS VCA-EQ (yrs)

EL-EQ (yrs)

BP VS EQ AGE (yrs) ss

VCA-SS

EL-SS

21 21 21 21 21 17 21

21 21 21 21

14 12

112 110 110 108 116 I12 111

3.2 0.15 2-9

- 0.38

4.13 I03

(8.7) 21 116.4) 21 (ws j 21 (11.6) 21 (17.9) 21 (17.oj 21 (12.4) 21

(1.70) 20 (0.87) 20 (1.53) 20 (0.82) 20

113 109 111 105 I I5 I12 111

3.8 0.36 3.4

- 0.07

3.95 102

(10.8) 20 111 (14.6) 20 110 (16.9) 20 116 (10.8) 20 106 (17.9) 20 115 (17.7) 20 109 (12.56) 20 111

(1.61) I5 3-62 ( I .05) I5 0.24 ( I -62) I5 3.39 (0.87) I5 0.01

(1.82) 20 4.38 (8 * 74) 18 103

(11.00) (13.5) (17.2) (12.8) (13.1) (14.6) (11.9)

(1.39) (1.11) ( I -28) ( I *08)

(1.77) (12.84)

522

The DMD group had low mean scores on all subscales, with the lowest scores on the locomotor and speech subscales. Language developmental delay was con- firmed on the RDLS and BPVS, with mean standard deviation scores below - 1 - 5 on both subscales of the RDLS, and a mean standardised score of 78 for BPVS (BPVS- ss). The mean standard score on the expressive language scale (EL-SS) was lower than on the verbal comprehension scale (VCA-SS). There was a highly statisti- cally significant difference (p < 0.001)

between the DMD group and the control group on all subscales of all three developmental assessments at each visit.

Analysis with two-way analysis of variance failed to detect any significant difference within groups between assess- ments, except for the locomotor scale of the GMDS in the DMD group, which showed a significant (p<O-OOl) decrease over the year.

Table IV gives the mean maternal AH^ score, the mean BSQ scale and the mean percentage score on the HOME inventory

TABLE IV Comparison of AH4, BSQ and Home% between DMD and control groups

Control DMD N Mean (SO) N Mean (SD) t

B ~~~~~~ ~~~

AH4 21 87.1 (16.3) 31 80.3 (17.3) 1 . 5 HOMEOlo 21 81-2 (8-7) 33 76.8 (10.3) 0.67

BSQ 16 4.37 (2.3) 27 7.89 (3.6) 4*37***

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TABLE V Correlations between maternal AH4, BSQ, HOME%, Locomotor subscale (A), age and quotients for DMD group

SU bscale N AH4 BSQ HOME% A Age

Locomotor 33 - 0.05 -0-12 - 0.57'' Personal/social 33 0.09

Hearinglspeech 33 0.13 - 0*5O** Eyelhand co-ordination 33 0.11 0.54.' Performance 33 0.11 -0.36 Practical reasoning 22 0.29 - 0.48. General quotient 33 0.12 -0.53.. RDLS VCA-SS 32 - 0.01 -0*50** EL-SS 32 - 0.08 -0.55..

0.14 - -0.830.. -0.18 0.33 - 0.06 -0.23 0.23 0.08 -0.11 0.29 0.01 - 0.07 0.28 0.07 -0.11 0.11 0.07

0.16 0*42* -0.10

- 0.24 0.01 0.21 -0.21 0.36. -0.13

BPVS BPVS-SS 20 0.37 -0.35 -0.18 0.22 0.02

TABLE VI Correlation coefficients between maternal AH4, BSQ, HOME%, Locomotor, age and subscale quotients for control group

SU bscale N AH4 A BSQ HOME%

-0.39 0.25 -0.31 0.36 - 0.09 0.16 - 0.38 0 . 3 7 -0.16 0.57. - 0.33 0.54. -0.18 0.43

Age

0.03 0.09 0.05 0.09

-0.35 -0.11 - 0.09

Locomotor Personal/social Hearinglspeec h Eyelhand co-ordination Performance Practical reasoning General quotient

21 21

0.35 0.48* 0.44.

- 0.78++* 0.35 0.48. 0.47. 0*61** 0.64'.

21 21 21

0.38 0.45.

21 21

0.50. 0.46.

RDLS VCA-SS EL-SS

0,42 0.40

0.10 0.34 -0.22 0.58..

0.28 0.31

20 20

0.06 0.08

BP VS BPVS-SS 14 0.40 -0.14 -0.08 0.33 0.36

523

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for both groups. Five of the control and six of the DMD group were over the age of five, so the BSQ was not administered. There was no significant difference between the HOME percentage score and AH^ score for both groups; however, there was a highly statistically significant difference in mean BSQ scores between the groups. More importantly, none of the control group children had BSQ scores over the cut-off limit of 11, whereas seven (26 per cent) of the DMD group did.

Pearson product movement correlations were calculated between the subscale scores and the AH4, BSQ, HOME%, age and locomotor subscale scores (Tables V and VI). These correlations were based on results obtained on the middle visit.

For the control group, there were no significant correlations between the BSQ and subscale scores. There were moder- ately positive correlations between AH4 and the personal/social, hearing and speech, performance, practical reasoning and general quotients of the GMDS and standard score of the BPVS (BPVS-SS). There were also moderately positive cor- relations between HOME% and perfor- mance, practical reasoning on the GMDS, and expressive language subscales of the RDLS. There were no correlations with age cross-sectionally. There were strong correlations between the locomotor sub- scale score and the other subscale scores of the Griffiths scales, but not with the language subscales.

For the DMD group, there were no significant correlations with AH4 or HOME%. The correlations of locomotor subscale with the other subscales were not as strong as for the control group. The locomotor subscale was strongly negatively correlated with age cross-sectionally. The BSQ scores strongly negatively correlated with all the scales, except the locomotor scale, performance scale and the BPVS-Ss.

Discussion The method of ascertainment ensures that our study group is representative of boys with DhlD detected at an early age. The age-range allows the use of the same developmental scales for all the boys, allowing comparison between and within groups.

This study demonstrates that boys with

DMD are significantly developmentally delayed. The scores on all scales are distributed approximately normally, but are not incompatible with a bimodal distribution. However, the study was not designed to answer this question and the numbers of boys are too small to allow statistical support for this hypothesis. The pattern is of global delay, with more severe delay in the locomotor and language areas. There was no difference between scores for the subgroups of DMD boys diagnosed early because of a positive family history and those diagnosed early because of developmental delay or poor locomotor function (Smith et al. 1989).

Prospective and cross-sectional analysis of the quotients against age showed that, with the exception of locomotor function, the quotients were generally static. Devel- opmental achievements actually were improving over time for most scales, but remained delayed to the same degree; therefore the quotients stayed the same. The exception was the locomotor subscale of the GMDS, which showed a progressive deterioration in quotient score, indicating a progressive loss of ability relative to age norms. The quotients did not change over time significantly for the control group, indicting that there was no significant learning effect from repeating the tests. However, one would expect any such effect to be too small to give rise to a statistically significant trend.

The significant correlations between maternal intelligence, home environment scores and subscale scores for the controls are to be expeoted. The same correlations for the DMD group are not statistically significant. There was also no significant difference between the two groups for maternal intelligence, home environment and social class. These findings, there- fore, suggest that the difference in developmental abilities between the two groups cannot be adequately explained by differences in social class, maternal in- telligence or home environment, as measured by the items in this study.

The correlations between the locomotor subscale and the other scales of the GMDS for the normal group are significant for most of the scales and may be explained by the preponderance of items relying on movement to score the item in several

of the subscales. The corresponding correlations in the DMD group are weaker, suggesting that decreased muscle activity may partly explain the deficiency on the other scales.

The lower scores on the expressive language scale could possibly be explained by decreased function of the muscles controlling speech. A clinical impression when performing this study was that many of the boys with DMD had problems with articulation, even when their speech content was good. However, it is not the full explanation, as there were marked discrepancies on the RDLS and the BPVS, which require little muscle function to score items. Also scores on the perform- ance scale were decreased. This is mainly an assessment of fine motor control of distal muscles, and would not be expected to be significantly affected by the disease at an early age, as the major effect initially in DMD is on the proximal muscles.

The low scores on the language scales, and probably the majority of delay on the GMDs, were probably related more to a deficit of central nervous system function than to muscle weakness, especially as these deficits are present early on in the disease, before any definite muscle weak- ness is apparent, and therefore before any secondary effects from poor locomotor function.

Recently there have been great advances in the understanding of the molecular biology of DMD. The gene has been cloned and the protein product dystrophin identified (Hoffman er al. 1987). Nude1 er al. (1989) have shown that the dystrophin gene is expressed in cultured brain cells; this finding may help to explain the central nervous system defect in DMD.

The significantly higher mean score on the behaviour screening questionnaire for the DMD group implies that there is a higher prevalence of behaviour problems in this group. This is supported by the number of boys above the cut-off point

on the questionnaire indicative of possible emotional problems. The scores on the BSQ correlated strongly with subscale scores on the GMDS, suggesting that the behaviour problems may have been secondary to the developmental delay, rather than an inherent part of DMD. A higher prevalence of behaviour problems in boys with mental retardation is well known (Rutter el al. 1970). Behaviour and psychiatric problems have been reported in older boys with DMD (Leibowitz and Dubowitz 1981, Fitzpatrick et al. 1986).

The findings in this study have impli- cations for management. Young children with DMD do have significant problems before the muscle weakness is a clinical problem. This is a difficult period for the parents, who not only have to come to terms with a possibly recent diagnosis, but also will need help in the form of a devel- opmental stimulation programme, possibly including speech therapists and clinical psychologists if the behaviour problems are significant. The prevalence of develop- mental delay has important implications for improving early diagnosis; the diag- nosis of DMD should be excluded at initial presentation of young boys with unex- plained developmental delay, to enable possible prevention of secondary cases (Smith et al. 1989). Accepted for publication 24th August 1989.

Acknowledgements This study was supported by grants from the muscular dystrophy groups of Great Britain and Northern Ireland and America. We are grateful for the help given by Dr. S. Wallace, Dr. Reeta Bidder and Dr. R. G. Newcombe, and to the consultants who provided patients for the study.

Authors’ Appointments *R. A. Smith, Research Registrar; P. S. Harper, Professor and Consultant in Medical Genetics; Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN. J. R. Sibert, Consultant Paediatrician. Department of Child Health, University of Wales College of Medicine.

*Correspondence to first author.

SUMMARY Thirty-three boys with Duchenne muscular dystrophy (DMD) and a mean age of 3 .4 years were assessed with the Griffiths Developmental Scales, the Reynell Language Scales and the British Picture Vocabulary Scales a t six-monthly intervals over a one-year period. The boys showed developmental delay, which was most severe in the locomotor and language areas. The locomotor quotients deteriorated over time, but the other quotients did not. Maternal intelligence, home environment and social class had little effect on the aetiology of the developmental delay, and the behavioural problems seen in young boys with DMD may be secondary 10 it.

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RBSUMB Ddveloppement prdcoce d’une myopathie de Duchenne Trente-trois garcons avec myopathie de Duchenne (DMD) et un Lge moyen de troisans quatre mois ont ktk examinks aux Echelles de Dkveloppement de Griffiths, aux Echelles de Langage de Reynell et B la British Picture Vocabulary Scales ii six mois d’intervalle sur une pkriode d’un an. Les garcons prksentaient un retard de dkveloppement particulikrement marque pour la locomotion et le langage. Les quotients de locomotion se dktkrioraient en fontion du temps mais pas les autres quotients. L’intelligence maternelle, I’environnement B la maison et la classe sociale avaient peu d’effets sur I’ktiologie du retard de dkveloppement et les problkmes comportementaux observes chez les jeunes ghyons avec DMD peuvent &re secondaires B ce retard.

ZUSAMMENFASSUNG Friihentwicklung bei Kindern mit Duchenne’scher Uuskeldystrophie 33 Jungen mit Duchenne’scher Muskeldystrophie (DMD) wurden im mittleren Alter von 3.4 Jahren mit den Griffith Developmental Scales, den Reynell Language Scales und British Picture Vocabulary Scales uber einen Zeitraum von einem Jahr, in Intervallen von sechs Monaten untersucht. Die Jungen zeigten eine Entwicklungsverzogerung, die in den lokomotorischen und sprachlichen Bereichen am ausgepragtesten war. Mutterliche Intelligent, hausliches Umfeld und Sozialschicht hatten einen geringen Einflul3 auf die Atiologie der Entwicklungsverzogerung, und die Verhaltensprobleme, die bei den Jungen rnit DMD auffielen, sind moglicherweise davon abhangig.

RESUMEN Desarrollo precoz en la distroJ7a muscular de Duchenne Treinta y tres nifios con distrofia muscular de Duchenne (DMD) de una edad promedio de 3.4 afios fueron evaluados con las Griffiths Developmental Scales, las Reynell Language Scales y las British Picture Vocabulary Scales a intervalos de seis meses durante un period0 de un afio. Los nifios mostraron un retraso de desarrollo que era mAs grave en las Areas locomotora y del lenguaje. Los cocientes locomotores se deterioraron con tiempo pero 10s otros cocientes no. La inteligencia materna, el ambiente del hogar y la clase social tenian poco efecto en la etiologia del retraso del desarrollo y 10s problemas conductuales vistos en muchachos j6venes con DMD pueden ser secundarios a este retraso.

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