Abstract
INTRODUCTION
Myotonic Dystrophy type 1 (DM1) is one of the most commonly inherited neuromuscular disorders in adults [1]. It shows autosomal dominant inheritance and demonstrates genetic anticipation in which successive generations will be affected earlier and more severely. DM1 is caused by a CTG trinucleotide expansion in chromosome 19q13.3 [1]. Although DM1 is primarily characterized by progressive muscle weakness and delayed muscle relaxation (myotonia), it has multisystemic manifestations which include cardiac arrhythmias, cataracts and insulin resistance [2].
Congenital myotonic dystrophy (CDM) is an especially dramatic form of DM1, in which the severity of clinical symptoms is maximal and onset occurs both neonatally and prenatally with polyhydramnios and reduced fetal movement. The incidence in Canada is reported as being 2.1/100000 [3]. When a child is diagnosed with CDM, approximately 60% of the time, they are the index case for their family [3]. The diagnosis of CDM often results in delayed development. Patients with CDM often present with respiratory failure requiring ventilation [4]. In addition, the other classic symptoms include: hypotonia, failure to thrive, feeding difficulties, weakness and clubfeet. In cases requiring prolonged ventilation, the mortality rate can be as high as 25% [5].
The pathophysiology of CDM is the result of an unstable trinucleotide CTG repeat expansion in the 3’ untranslated region of the Myotonic Dystrophy Protein Kinase (DMPK) gene [1]. The mutated mRNA forms a hairpin loop which cannot leave the nucleus in order to be translated, leading to downstream effects upon many other proteins. Normal CTG repeat sizes range from 3–35 [6]. Symptoms of DM1 are typically observed with repeat numbers greater than 50. The number of repeats is variable in affected patients with CDM but usually is greater than 500[6].
CDM is a severe condition that affects patients physically, cognitively, and socially. Children with CDM have many physical complications such as gastrointestinal issues, experience severe intellectual disability, and often require special assistance at school [5]. As a result of the global nature of the disorder, it can lead to a significant burden of care. In addition, parents may also be affected with symptoms of myotonic dystrophy, adding to the problems experienced by families with this condition. It has long been recognized that a high proportion of CDM children have developmental disability [7, 8], but rarely has this been documented in prospective manner, but some effort has been made to try to link this to changes on brain MRI [9] or repeat size [10] but the prognostic value of these biomarkers is not strong. Some of the common developmental problems that children affected with CDM and DM1 face by parent proxy report are communication issues, fatigue, and problems with using their hands and fingers and reported rates of cognitive impairment in this study for ADHD. Autism and intellectual disability in this cross sectional international study were markedly higher than in the general population (5).
A five year surveillance study was performed via the Canadian Pediatric Surveillance Program to determine the incidence, neonatal morbidity, and mortality of CDM in Canada. The second phase of the study was a cohort study of eligible incident cases of CDM in which the development, quality of life and medical morbidity was monitored through follow up questionnaires. In this article, the profile of developmental milestones in CDM patients will be presented and compared to the general population. The Health Related Quality of Life (HRQOL) of patients with CDM was examined over several years to demonstrate the impact CDM has upon the lives of patients’ and their families.
MATERIALS AND METHODS
Children affected with CDM were identified through the Canadian Pediatric Surveillance Program (CPSP) postnatally. The CPSP is a program which monitors rare diseases. The methods of the surveillance program have been reported in more detail in a previous article [3]. Physicians were initially sent a report from to fill out and return to the CPSP. Duplicate reports were identified, and all reports were sent to the primary investigator for review. Families with affected CDM children not identified via the CPSP could enroll as well. The inclusion criteria for participants were They must have had a confirmed diagnosis of DM1, The symptoms of DM1 were evident in the neonatal period (first month of life) as recognized by hypotonia, respiratory or feeding difficulties requiring admission to a NICU or other hospital ward for greater than 72 hours and The diagnosis was confirmed by genetic testing demonstrating an expanded trinucleotide CTG repeat >200 in the DMPK gene in the child or mother.
Enrollment packages containing letters of information and consent forms were sent to the reporting physician of patients that met all inclusion criteria. The participants’ guardian(s) all provided informed consent.
The participants’ families were contacted every 3 months for the first year, and then 6 months from age one to five by phone calls. Each time a follow up case report form was filled out by the study coordinator on any medical changes or complications, the development of language and motor skills, and schooling. Prenatal and neonatal symptoms experienced by members of the cohort have been listed in Table 1. Each element of development is listed in Tables 2 and 3. A standardized self-report developmental profile questionnaire was not included because the data on common developmental milestones was being obtained directly through phone interviews with the parents by the study coordinator, a method that was felt to be more consistent and clearer than a questionnaire. Phone calls were also thought to help in retaining higher numbers of participants throughout the study. In addition, parents affected by DM1 can find self-directed questionnaires difficult to complete so it was felt best to limit the questionnaires to HRQOL. Parents were mailed the Infant and Toddler QOL and PedsQL questionnaires and were required to complete them annually. Both questionnaires were found to be feasible, valid, and reliable, and therefore were considered appropriate to use in this study [11, 12]. At the time that this study was started, there was no disease specific HRQOL measure, so two generic measures were used. Since then, a parent proxy HRQOL measure for CDM, or childhood DM1 has been recently published [5].
Infant and toddler quality of life questionnaire (ITQOL)
This tool is used to assess levels of health and wellbeing in children aged 2 months to 5 years. Parents rated their children’s HRQOL on nine dimensions: their children’s overall health, physical abilities, their satisfaction with their child’s overall growth and development, discomfort/pain, temperament and mood, overall behavior, getting along with others, health, and the impact of their child’s health on the parent.
PedsQL pediatric quality of life inventory questionnaire
Parents rated their children’s HRQOL life on four dimensions: physical, emotional, social, and school. The first three dimensions are the core dimensions of health as designated by the World Health Organization. Total HRQOL score was the averaged sum of all the dimensions. Psychosocial score was the averaged sum of emotional, social, and school scores.
The study was approved by the Health Sciences Research Ethics Board at Western University in London, Ontario. All parents and/or legal guardians of each child gave informed, signed consent prior to enrolment in the study.
RESULTS
At the time of the study there were 38 confirmed cases of CDM [3] but only 19 children were initially enrolled in the cohort. One family withdrew their child immediately, another one was withdrawn by their family at age 3.5 years. One child died from unknown complications of CDM in hospital. This child had been hospitalized immediately following birth until his death at 9 months of age. At birth, 47.1% of the cohort required assisted ventilation, 64.7% needed respiratory therapy, and 82.4% needed an NG tube to assist with feeding (Table 1). Ultimately there were eight males and eight females (N = 16) enrolled. The CTG repeat range was 700–2600 repeats, with the average being 1767. With the exception of one case that was paternally transmitted, the cases were all maternally transmitted.
Motor skills and language skills
Developmental milestones were achieved at later ages in CDM patients when compared to the general population [13] and females were generally more delayed than males for both motor and language skills (Tables 2 and 3). Almost all of the children were eventually able to walk independently, however this was not achieved until the age of 6.5 years for one of the children. Data on toilet training was only obtained for three of the children and was achieved at a similar age in both females and males (Table 2). In language skills, the ability to follow complex commands and to speak >10 words, showed the widest range of achievement (Fig. 2). The majority of skills in motor development showed wider ranges of achievement when compared to language skills (Figs. 1 and 2).
Health related quality of life scores
For the ITQOL questionnaire, physical scores were fairly consistent (Table 4). For the section comparing the child’s health to the last year, the data suggest that the first year the child’s health was the worst, but as they age their health improves. This is also reflected in the general health section where there is an overall increase in score as patients grow older (Table 4). At the age of 5, when compared to the previous year, there seems to be an improvement in behaviour and temperament which could be related to better scores for getting along with others and behaviour compared to others. Between the ages of 1 to 5, parents appeared to be more worried and anxious about their child’s condition but were less limited in the time that they had for their personal needs (Table 4). For PedsQL, the total QOL score remained fairly stable. Physical QOL scores were stable with the exception of age 5. In general, psychosocial scores were higher than physical scores, but decreased from ages 1 to 4, while remaining stable at age 5 (Table 5). Overall, the PedsQL scores seemed to be more divergent from the control population than the ITQOL scores (Tables 4 and 5).
DISCUSSION
The description of developmental milestones and HRQOL from a national prospective cohort of CDM patients is an important contribution to the understanding of this severe disorder. The findings in this study are consistent with the impression that the motor developmental profile for CDM shows a significant delay at first, then improvement in early childhood. As they age, these individuals with CDM will eventually develop the classical manifestations of DM1, which includes myotonia, muscle atrophy and cataracts [6]. Our study also supports past reports that the vast majority of children will acquire independent ambulation [14], since all but one of the patients were able to walk by themselves.
Developmental milestones
Typically developing males appear to reach standard motor milestones at a slightly earlier age than females [15]. This result was mirrored in the cohort, with boys achieving most of the motor milestones earlier. The only exception was dressing in which females achieved this milestone at an average age of 2 years and 10 months, and males accomplished later at 4 years and 2 months (Table 2). However, dressing also has a cognitive component that might factor into this discrepancy. At puberty, female performance in motor development tends to level off, while male performance continues to improve [15]. Future studies upon this cohort could examine the effect of puberty upon performance in motor skills.
Males were able to achieve certain language skills before females (Table 2). For example, the average age required to follow complex commands was greater than 2 in boys and greater than 3 in girls. This result contrasts with previously reported data on gender differences in verbal ability where a slight female superiority has been indicated [16].
In addition, the severity of neonatal symptoms could also be a factor in determining how patients develop. In this cohort, more females required assisted ventilation than males, but the average duration of ventilation was greater for males due to one patient requiring 64 days of ventilation (Table 1). More females experienced prenatal symptoms of CDM than males which could have also had an impact upon their development.
CDM is associated with cognitive impairment, primarily due to static encephalopathy and possibly structural brain differences [10] including ventriculomegaly. The degree of cognitive impairment has been reported to be correlated with the extent of ventricular dilation [17]. In a study of brain structures in patients with CDM, macrocephaly was found alongside ventricular dilation in 8 out of 14 patients [18]. A characteristic feature in CDM is T2 hyperintense signals in the white matter [19]. White matter lesions are correlated with ventriculomegaly [19].
Speech is delayed in CDM patients not only as a result of primary cognitive and language deficits but also as a repercussion of hypotonia and weakness in facial muscles. Therefore it is necessary for speech to be monitored in CDM patients, and timely introduction of speech therapy as required. As CDM is a multisystemic condition, a variety of supportive therapies are needed such as physical, occupational, and speech therapy. A multidisciplinary clinic which offers neurological, orthopedic and child development services can aid in managing CDM.
Health related quality of life
Many of the instruments used to measure QOL assume that absence of ill-being means the presence of wellbeing. Therefore it is important to recognize this assumption when examining the results of these questionnaires. There are limitations to using questionnaires, such as the PEDSQL as an HRQOL measure for patients with CDM since the generic nature of the questions excludes many of the issues which may be relevant to CDM patients and families. The results in this study are parents’ proxy reports of their child’s QOL. Parent proxy reports are necessary at these young ages.
Of the two questionnaires used in this study, ITQOL has a more holistic outlook, as it asks more specific questions in each dimension, and has more dimensions as well. ITQOL also looks at how the parent is coping with their child’s condition. This is especially important, since CDM is an inherited condition and parents may be suffering from symptoms themselves. Pain is also included as a separate category, whereas it is included in physical functioning in PedsQL. It has many sections that compare the child to others, such as behaviour. There is also a domain which observes how health has changed compared to the previous year.
There are some inconsistencies between the parents’ ratings between the two questionnaires. For example, physical abilities appeared to improve in ITQOL between ages 4 and 5, but the physical score decreased in PedsQL (Tables 4 and 5). This could be attributed to different questions asked and small sample size at the 5 year mark. As stated previously, pain is included in physical scores in PedsQL, as is low energy levels, which could have contributed to a lower score in this section. Of the two instruments, ITQOL has parent satisfaction with child’s development as a separate category, illustrating the impact that development has upon quality of life. In this cohort, satisfaction with child’s development remained consistent between all ages and was only slightly lower than that of the control result (Table 4).
In the literature, a common finding is that physical functioning does not correlate with emotional/social functioning [20]. In many motor diseases, the physical limitations may be greater than the emotional and social problems that accompany the condition. However, in this study, psychosocial HRQOL scores tended to worsen as children aged (Table 5). This result can be attributed to the condition of CDM in which cognitive and developmental disability plays a substantial role particularly as the child ages, physical functioning improves, and the cognitive and social differences from typically developing children becomes more evident.
When compared to the general population in literature, for ITQOL, the cohort scores were lower in every dimension except for Families Getting Along (Table 4) at age 2 [11]. Future studies could perhaps examine in greater detail the impact that a chronic condition such as CDM has upon family dynamics. The cohort scores for the PedsQL questionnaire were lower than that of the average population [12]. However it cannot be concluded if these differences are statistically and clinically significant.
Limitations for this study include that the data was collected by phone interviews, there were no concurrent controls, and that the control values are taken from literature making statistical comparisons not optimal. As well, it may have been of benefit to formally assess development and cognition with a validated parent report measure. The greatest limitation however, is that the sample size is small, so the data may not be representative and it is difficult to make any statistical conclusions. Despite these limitations, this study takes into account patients from all over Canada, and has been consistent in obtaining follow ups of patients every 6 months, and plans to do so until the age of 18 years.
The concept of health related QOL is complex and there are several aspects by which people assess their overall well-being, including physical, emotional and social aspects. In order to properly treat a disorder it is essential to focus on all these characteristics. Instruments such as the PedsQL aim to gain multidimensional perspective of health and have a variety of applications, such as use during clinical trials, in population surveys, and in screening for psychosocial issues that might occur during patient care. The process of determining QOL is dependent upon a number of factors which includes development. The evaluation of developmental milestones continues to be important when assessing children’s growth. Patients with CDM are developmentally delayed when compared to the general population, but will show improvement in motor and language skills early in life. Future studies upon this cohort can continue to monitor patients’ progress and to observe if continued therapy (speech, PT, OT etc.) has an impact on development.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Footnotes
ACKNOWLEDGMENTS
We would like to thank the families participating in this study. Also much appreciation to Michael Miller for his statistical advice. This study was funded by the William Singeris National Centre for Myotonic Dystrophy Research.