Identification and treatment of neurodevelopmental and mental disorders in boys and adults with Duchenne muscular dystrophy: a cohort study

Abstract

Background

Over the last few years, there has been increasing attention to the involvement of the central nervous system in Duchenne muscular dystrophy (DMD). The aim of this study was to assess the spectrum of neurodevelopmental and mental disorders and possible required intervention in our cohort of 264 boys and adults with DMD.

Methods

We retrospectively analysed clinical notes and psychological assessments, including routinely performed cognitive tests and clinical observations. Intelligence quotients and site of mutations were also noted.

Results

103/264 individuals (39%) had symptoms compatible with one of the following diagnoses: attention deficit hyperactivity disorder (ADHD) (n=26), autism spectrum disorder (ASD) (n=11), depressive mood/disruptive mood dysregulation disorder (n=27), anxiety disorder (n=17), obsessive-compulsive disorder (n=2), psychosis risk syndrome (n=7), and 13 had a more complex phenotype. ADHD and ASD were more frequent in infancy, emotional dysregulation during early adolescence, and psychosis and more severe phobias in older boys and adults. The risk of developing these disorders did not increase with the concomitant involvement of the dystrophin isoforms Dp140 and Dp71. Pharmacological treatment was suggested for 48 individuals but was started only in 24, as it was refused by the remaining 24 families.

Conclusions

Our findings confirm that neurodevelopmental and mental disorders are common in DMD and are likely to have a multifactorial nature. These findings support the need for disease-specific assessments and the need to increase awareness of the possible behavioural and social difficulties among families and healthcare professionals.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Over the last few years, there has been increasing attention to the possible role of different dystrophin isoforms in the developing and adult brain.

• Most studies have focused on cognitive aspects, and there is less evidence on other aspects of central nervous system involvement.

WHAT THIS STUDY ADDS

• Our findings expand the existing literature, reporting the spectrum of neurodevelopmental and mental disorders in Duchenne muscular dystrophy (DMD), identifying age-specific patterns and the lack of a consistent association with intellectual disability and brain dystrophin isoforms.

• We also report how pharmacological treatments, which were suggested in 46% of boys and adults with neurodevelopmental and mental disorders, were refused or postponed by nearly half of them.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These findings suggest that neurodevelopmental and mental disorders are common in DMD and highlight the need for disease-specific assessments.

• The scarce compliance to treatment in our cohort also highlights the need to increase awareness of the possible behavioural and social difficulties among families and healthcare professionals.

Introduction

Duchenne muscular dystrophy (DMD) is a disorder caused by mutations in the dystrophin gene, causing loss of dystrophin protein expression¹ responsible for progressive muscle degeneration with motor, respiratory and cardiac impairment. Over the last few years, there has been increasing attention to the role of different dystrophin isoforms in the brain. Most studies have focused on cognitive aspects, but there is evidence that neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD)² and autism spectrum disorder (ASD),³ or mental disorders, such as obsessive-compulsive disorder (OCD) or anxiety disorders (AD), are also frequent.⁴,⁷

The aim of this study was (1) To assess the spectrum of neurodevelopmental and mental disorders in our cohort of boys and young adults with DMD in relation to the involvement of brain dystrophin isoforms and (2) To evaluate the clinicians’ attitude to treatment and the rate of agreement from individuals and carers to start new psychopharmacological treatment.

Methods

This retrospective study included all the boys above the age of 6 years and male adults with a genetic diagnosis of DMD attending our centre. Written informed consent was obtained from all. The investigations were carried out following the revised Declaration of Helsinki.

We used a descriptive design, analysing data extracted from health records. As part of our clinical routine, all individuals have at least one assessment of cognitive abilities using the age-appropriate Wechsler scales. At the time of the cognitive assessment, all individuals also undergo a wider clinical assessment, observing possible neurodevelopmental and mental difficulties according to Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnostic criteria.

When available, we also reviewed other tests, such as the Conner’s Rating Scales (CRS-R) for ADHD, the Childhood Autism Rating Scale—second Edition Standard form (CARS2-ST) for ASD and the K-SADS.

We reviewed if there had been any past concern or referral for behavioural difficulties. Present or past history of psychopharmacology treatments was also noted, including the age when they were first prescribed. Signs and symptoms were classified into major diagnostic groups according to DSM-5 criteria: ASD, ADHD, OCD, AD, disruptive mood/dysregulation disorder (DM/DD). In subjects with a primary diagnosis, other signs, if present, were reported as comorbidities. Isolated intellectual disability (ID) or academic difficulties not associated with any social or behavioural difficulties were reported separately.

The cohort was subdivided into four groups according to the site of mutations and the number of dystrophin isoforms involved: group 1 (Dp427-, Dp140+) with mutations before exon 44, group 2 (Dp427-, Dp140-, Dp71+) with mutations after exon 51, group 3 (Dp427-, Dp140-, Dp71+) with mutations after exon 63 (Dp427-, Dp140-, Dp71-); group 4 was labelled as ‘uncertain’ as mutations between exons 45 and 50 have an indeterminate effect on Dp140 expression.

Statistical analysis

A Pearson’s χ² test was performed to assess possible associations between brain dystrophin isoforms and the prevalence of neurobehavioural findings (yes/no).

Results

Our cohort included all the 264 boys with DMD older than 6 years attending our unit (age range 6–38 years). On clinical assessment, 103 (39%) (50 ambulant and 53 non-ambulant) were found to have at least one neurodevelopmental or mental disorder diagnosis according to DSM-5 criteria⁸ associated with ID in 34 of the 103 (33%). Another 72 had ID or borderline cognitive function with academic difficulties not associated with neurodevelopmental and mental disorders. The remaining 89 had no clear signs of brain involvement. We report our findings subdivided according to the main diagnosis:

ADHD was identified in 26 individuals (9.8% of the total cohort), on the basis of clinical assessment using DSM-5 criteria. In 24/26, the diagnosis had already been suggested by the school or by the referring centres. In 18/26, CRS-Rs were available from parents and in 9 also from teachers, confirming the diagnosis in all the teacher responses (9/9) and in 12/18 parents’ responses.

In 11/26, ADHD had already been suspected at a younger age but could not be formally diagnosed, as both CRS-R and DSM criteria are available from the age of 6.

In 9/26, ADHD was associated with mild ID, and in 17, it was not. In five, there were also signs of other behavioural comorbidities (four with oppositional defiant disorder, one with ASD).

ASD was found in 11 individuals (4.2%) on clinical assessment. Other tests (Autism Diagnostic Observation Schedule (ADOS), CARS-2) were available for all and supported the diagnosis. The age when ASD was diagnosed ranged between 2 years and 9 years. In 6/11, ASD was associated with ID. In four, there were also signs of other behavioural comorbidities compatible with ADHD.

Depressive mood/disruptive mood dysregulation disorder was found in 27 individuals (10.2% of the total cohort) on clinical assessment. In 7/27, the onset or the worsening of the symptoms occurred around puberty in boys who complained about growth and pubertal delay.

In 9/27, emotional dysregulation was associated with ID. In three, there were also signs of other behavioural comorbidities compatible with ADHD that had been observed since school age.

Anxiety was found in 17 individuals (6.4% of the total cohort) on clinical assessment. In 4/17, the onset or the worsening of the symptoms occurred around puberty. In 7/17, anxiety was associated with ID. In three, there were also signs of other behavioural comorbidities compatible with ADHD that had been observed since school age. Four of the 17 individuals had separation anxiety (23.5%), 2 social anxiety (11.7%), 6 generalised anxiety or specific phobias (35.3%), and 5 (29.5%) had selective mutism.

OCD was found in two individuals (0.7% of the total cohort) on clinical assessment. In both cases, the worsening of the symptoms occurred around adolescence. Neither had ID.

Psychosis risk syndrome (PRS) was found in seven individuals (2.6% of the total cohort). In three out of seven, there were reports of early signs of depressive mood with emotional dysregulation, and in one out of seven, a diagnosis of ADHD at a younger age with clear psychotic symptoms becoming more obvious around puberty or in adulthood; one had a history of autistic traits with anxiety, one of anxiety and one of OCD symptoms. In two individuals, there were also persisting signs of anxiety. In three out of seven individuals, psychotic signs were associated with ID, and in four, they were not.

Another 13 individuals (4.9% of the total cohort) had a more complex phenotype characterised by multiple neurobehavioural difficulties associated with moderate/severe intellectual disability (MS-ID) with IQ less than 50, both present since early childhood (figure 1).

Figure 1. Distribution of neurodevelopmental and mental disorders in the total cohort. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; CNS central nervous system.

Neurodevelopmental and mental disorders and brain dystrophin isoforms

91 of the 264 had involvement of Dp427 only (group 1), 39 had concomitant involvement of Dp140 (group 2); 12 had involvement of all three isoforms (group 3) and 122 were in the uncertain group (figure 2).

Figure 2. Distribution of ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; PRS, psychosis risk syndrome in the groups subdivided according to mutations.

There was no significant difference in the presence of neurodevelopmental and mental disorders across the four groups (figure 3, table 1).

Figure 3. Distribution of mutation groups in boys and adults with neurodevelopmental, behavioural and emotional disorders. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; PRS, psychosis risk syndrome.

Table 1. Distribution of neurobehavioural findings according to mutations groups and IQ levels.

	Mutation group 1 (Dp427- Dp140+, Dp71+) (n=92)				Mutation group 2 (Dp427- Dp140-, Dp71+) (n=41)				Mutation group 3 (Dp427-, Dp140-, D71-) (n=11)				Mutation group 4 (uncertain) (n=122)
	Total	IQ≥85	IQ 70–84	IQ<70	Total	IQ≥85	IQ 70–84	IQ<70	Total	IQ≥85	IQ 70–84	IQ<70	Total	IQ≥85	IQ 70–84	IQ<70
ADHD (n=26)	11	1	4	6	5	1	2	2	2	0	1	1	8	3	2	3
ASD (n=11)	3	0	1	2	2	1	0	1	1	0	0	1	5	2	1	2
DM/DMDD (n=27)	7	3	3	1	7	2	1	4	1	0	0	1	12	6	3	3
Anxiety (n=17)	7	3	2	2	2	2	0	0	0	0	0	0	8	3	0	5
OCD (n=2)	0	0	0	0	0	0	0	0	0	0	0	0	2	1	1	0
PRS (n=7)	2	0	1	1	2	0	1	1	0	0	0	0	3	1	1	1
‘Complex’ phenotype (n=13)	4	0	0	4	2	0	0	2	1	0	0	1	6	0	0	6
Total (n=103)	34	7	11	16	20	6	4	10	5	0	1	4	44	16	8	20

ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; PRS, psychosis risk syndrome.

Using a Pearson’s χ² test, the association between brain dystrophin isoforms and the prevalence of neurobehavioural findings was not significant, χ² (3, n=266)=1.87, p=0.60.

Treatments

All the 103 cases with neurodevelopmental and mental disorders were referred for neurobehavioural or educational therapies. Additionally, 47/103 individuals received an indication for pharmacological treatment. In all 47, the initial diagnosis, based on clinical assessment by the psychologist and the psychiatrist, was supported by the assessments described in the previous section. All pharmacological interventions were conducted either within the scope of nationally approved labelling or, where such approval was absent, in accordance with recognised standards of good clinical practice, as substantiated by international scientific literature and clinical expertise.⁹,¹¹

The pharmacological treatment was initiated in 23/47 in whom it was proposed (49%), while it was refused by the remaining 24 families.

Of the 26 individuals with ADHD, 11 received an indication to treatment with methylphenidate, but this was refused by the family in 6/11. In all the five who were treated, there was an improvement in the behavioural pattern.

Of the 27 individuals with DM/DD, 17 received an indication to treatment with mood stabiliser, antipsychotics or antidepressants (lamotrigine, aripiprazole, paroxetine, duloxetine, mirtazapine), but in 11, the treatment was refused. In the six who were treated, there was some improvement of the symptoms.

Of the 17 individuals with anxiety, 6 received an indication to treatment with Selective Serotonin Reuptake Inhibitor (SSRI) or aripiprazole, but in 2/6, the treatment was refused. In all the four who were treated, there was some improvement of the symptoms.

Both individuals diagnosed with OCD received an indication to treatment with SSRI that was accepted by their families.

All seven individuals diagnosed with PRS received an indication to treatment with antipsychotics (risperidone, olanzapine) or, when depressive features were prominent, with antidepressants (sertraline or escitalopram), but in 2/7 the treatment was refused. In the five who received treatment, there was some improvement of the symptoms that was more obvious in the ones with acute onset of symptoms.

In the 13 individuals with a more global involvement, 5 received an indication to treatment (antipsychotics), but in 3/5, the treatment was refused by the family.

Discussion

A few papers have recently reported the profile of neurodevelopmental and mental disorders in DMD.^{3 4 6 12 13} Although the most recent care recommendations suggest the routine use of tools aimed at identifying psychosocial adjustments,¹⁴ this is not always performed in clinical practice, and the literature on this topic is scanty. Even less has been reported on the pharmacological approach.^{4 15 16}

In our study, neurodevelopmental and mental disorders were found in over a third of our cohort. If we also include isolated intellectual disabilities or academic difficulties (27%), the rate of abnormal findings rises to 66%, similar to a previous cohort study reporting that over 70% had at least one abnormal sign.⁴ Our findings also confirm the previous observation that neurodevelopmental and mental disorders were not always associated with concomitant ID.²,⁴

The access to both paediatric and adult cohorts allowed us to identify different patterns of disorders in relation to age. ADHD and ASD were generally identified in ambulant school-aged children between the age of 6 years and 11 years. Anxiety and depression with emotional dysregulation, in contrast, were more often first identified in teenage boys before the age of 18 years, often after loss of ambulation. More severe phobias and psychotic breaks were more frequent in non-ambulant young adults

Although the age-related distribution of these diagnoses in DMD follows to some extent what is observed in the general population, their frequency in DMD was much higher and is likely to be due to a multifactorial aetiology, including genetic factors, with the involvement of different brain dystrophin isoforms.

Brain dystrophin isoform Dp427, expressed both in muscle and brain, is involved in all DMD individuals, irrespective of the site of mutations. In our cohort, the risk of neurodevelopmental and mental disorders did not appear to consistently increase with the concomitant involvement of Dp140 and Dp71, which has been associated with an increased risk for ID and^{4 5 17} speech delay.¹⁸ The involvement of Dp427, therefore, appears to be already a risk factor for increased frequency of the neurodevelopmental and mental disorders assessed in our cohort. Animal models, cell culture and human studies suggest that Dp427 is predominantly expressed in cortical neurons and hippocampus.¹⁹ More specifically, the localisation of Dp427 to the synaptic membrane in neurons, causing GABAergic inhibitory synapses dysfunction in the cortex, amygdala, hippocampus and parahippocampal gyrus (known to be implicated in the pathogenesis of ASD²⁰ and depression), is therefore likely to play a role in the neuropsychiatric phenotypes.²¹

Dp140 and Dp71, both largely expressed in fetal brain and strongly involved in cognitive aspects, have been predominantly associated with glutamergic functionality, with Dp71 also having a role in aquaporin 4 localisation in endothelial cells.²² The lack of correlation between the neurodevelopmental and mental comorbidities with Dp140 and Dp71 appears to suggest that these isoforms may play a minor role in these disorders.

These findings expand previous data from our group and others reporting the lack of a clear correlation between the number of brain dystrophin isoforms and ADHD,² social behaviour³ and anxiety.²¹ Our findings could not be easily correlated with the previous study also investigating neurodevelopmental and mental disorders as there was a different subdivision of the mutations (<30, 31–62, >62).⁴

The lack of a consistent correlation between patterns of social and behavioural issues with the site of mutation led us to speculate a possible concomitant role of environmental and psychosocial factors such as burden of the disease or use of steroids, which are known to have an impact on behaviour²³ and on other relevant aspects. In our cohort, anxiety and depression with emotional dysregulation were more common in teenagers who had steroid-induced delayed puberty and growth. Steroids are routinely assumed since the age of 4–5 years and most of the boys with DMD are below the third centile for height and have delayed puberty. In seven boys who developed depression with emotional dysregulation or anxiety, the boys or their parents underlined that short stature and delayed puberty was a major issue at school and in social life, in some cases associated with teasing or bullying, social withdrawal and anger. Phobias and psychotic breaks, in contrast, were more often found in young adults needing more cardiorespiratory support or following acute episodes requiring admissions. Most of them already had a history of milder signs of anxiety occurring at younger ages.

While there is increasing evidence, also from animal models, of the involvement of specific neurotransmitters and neural networks as the primary mechanism underlying many of these symptoms, especially for anxiety, fear response and other neurobehavioural symptoms,²¹ it is likely that environmental and psychosocial factors may also play an additional role.

A better understanding of the mechanisms underlying these difficulties has also increased awareness of the need to treat them.

All the 103 boys and adults with a neurodevelopmental and mental disorder were referred for neurobehavioural and educational therapies. When this approach was felt to be only partially helping, drugs were prescribed in 47 of them. Although there is evidence from the literature that pharmacological treatment may have limited value, in agreement with a recent study suggesting a possible role of psychopharmaceutical treatment for neurobehavioural problems in DMD,¹⁶ this was considered in these selected cases. The age when treatment was thought to be needed reflected the age-related pattern of occurrence of the individual diagnosis. It is of note that in nearly half of the cases in whom treatment was suggested, this was never initiated, and in others, it only started when the clinical signs became more severe.

The relatively high number of families declining pharmacological therapy is likely to be due to multiple factors, including concerns about side effects and, in some cases, may reflect challenges in recognising behavioural and emotional symptoms, especially when these overlap with physical disability progression. In our cohort, the most frequent mental disorders such as anxiety, depressive mood or withdrawal often occurred around puberty, at the time of the loss of ambulation, and the families often interpreted these emotional changes as related to disease progression. While this observation is based on our clinical experience, it remains a hypothesis that warrants confirmation through systematic, prospective studies. These findings are in keeping with other studies also suggesting possible lack of concordance between self-reported, parental recognition and clinical observation of psychiatric symptoms, especially in the context of chronic disorders, as parents may interpret emotional or behavioural signs as contextually justified, delaying acceptance of treatment.²⁴,²⁹ The high number of refusals from the families may also lead to questioning the validity of the clinical diagnosis. However, it is unlikely that the discordance between clinicians and parents may result from challenges in the clinical diagnosis process, as in all cases the diagnosis, based on the DSM-5 criteria, was achieved independently by both a psychologist and a psychiatrist and, when available, was also confirmed by school reports. Furthermore, the prevalence of neurodevelopmental and mental disorders in our cohort is similar, if not lower, to that reported in other DMD cohort studies.⁴

It should also be mentioned that the parents’ responses were based on questionnaires that are screening and not diagnostic tools and, as recently suggested, may not be entirely feasible for DMD.³⁰ Work is in process to explore if these signs and symptoms could be better captured by using disease-specific screening questionnaires that are increasingly becoming available.^{31 32}

Despite being a cohort study including both boys and adults routinely assessed in our centre, the retrospective design of the study has several limitations, as the assessments were not systematically performed at the same age. Furthermore, longitudinal data were only available in a limited number of cases, not allowing us to fully appreciate possible developmental trajectories that could only be established from the clinical history. All patients who received treatment had an improvement of symptoms that could be observed on follow-up clinical assessments. Although these findings are limited by the lack of a standardised structured follow-up, both clinicians and families agreed on the positive trend observed following treatment, in agreement with a similar trend observed in a recent large study in boys with DMD and young adults.¹⁶

Even with these limitations, our findings confirm that neurodevelopmental and mental disorders are common in DMD with some age-related patterns that are likely to have a multifactorial nature, including genetic, environmental and psychosocial factors. These findings highlight the need for a more systematic routine assessment of these aspects, as suggested by the recent care recommendations.¹⁴ Systematic, prospective studies, also including comparative analyses with other conditions involving chronic disability and with non-motor impaired populations, will help to better understand to which extent DMD may have specific patterns of brain involvement possibly related to involvement of brain dystrophin isoforms and to validate these impressions, informing targeted clinical recommendations. Finally, our findings highlight not only the need for better identification and treatment of psychiatric comorbidities in DMD, but also the importance of supporting both clinicians and families in recognising these challenges, particularly in a setting where the severity of physical disability often dominates attention, and awareness of emotional and behavioural issues is only recently emerging within the scientific and clinical communities.

Data availability statement

Data are available upon reasonable request.