New Insights about Congential Myotonic Dystrophy

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This is a copy of the article from J of Pediatrics MArch 16, 2013

The myotonic dystrophies have been called the most “diverse diseases known in medicine,”1 and in many respects, the broad spectrum of manifestations observed in myotonic dystrophy type 1 (DM1) are most evident when an undiagnosed and mildly affected mother gives birth to a severely affected child. DM1 results from an unstable trinucleotide repeat expansion (CTG) in the dystrophia myotonica-protein kinase gene (DMPK), located on chromosome 19q13.3.2, 3, 4

Congenital myotonic dystrophy (CDM) often presents as the index case in a family affected by DM1, and the diagnosis is made within the first few hours and days after birth. Neonatal symptoms can be life- threatening and include respiratory failure, feeding difficulties, hypotonia, and muscle weakness.5, 6, 7 The childhood years may bring marked dysarthria, intellectual impairment, and features of autistic spectrum disorders.8, 9, 10 Mothers of patients with CDM often have a diagnosis of DM1 established when their child is diagnosed. These mothers often have mild facial or distal muscle weakness, mild myotonia, and other multisystem manifestations, such as cataracts. Both diagnoses (CDM and adult DM1) can usher in a whirlwind of short- and long-term medical, psychosocial, and economic complications and decisions. Unfortunately, to date, limited empirical information is available to inform care providers, patients, and their family members about the prevalence and natural history of CDM.

In this issue of The Journal, Campbell et al11 provide important results to advance our knowledge of CDM and facilitate better clinical care of our youngest patients. Campbell et al define CDM as symptoms of myotonic dystrophy in the newborn period (<30 days after birth) and hospitalization for more than 72 hours, along with an abnormal cardiotocography repeat length >200. This repeat length may expand unpredictably from generation to generation, with the largest repeat expansions thought to result during passage from mother to child, occasionally reaching a length exceeding 2000 repeats.

Campbell et al used the Canadian Pediatric Surveillance Program (CPSP) to collect information on the number of CDM cases reported by pediatricians across Canada. The CPSP currently collects data from “over 2,500 pediatricians and pediatric subspecialists each month to monitor rare diseases and conditions in Canadian children” (http://www.cpsp.cps.ca/). On receipt of new cases of CDM, pediatricians were sent a sent a more detailed questionnaire on CDM for completion. The surveillance for this study was carried out between 2005 and 2010, with an average response rate of 80% over this period.

Overall, 121 cases of CDM were reported, and 38 patients met the inclusion and exclusion criteria of the study. Campbell et al calculated the prevalence of CDM in Canada as approximately 1/48 000 live births using incident reports and overall birth data from Canada’s central statistical office. They also analyzed the number of DM1 genetic tests performed by regional laboratories during the reporting period on children aged <3 years. In general, the number of genetic tests from regional laboratories matched the incidence rates observed in the CPSP. The matching results from the CPSP and regional genetic laboratories help validate the estimated prevalence of CDM in Canada. The authors’ findings are further strengthened by their use of the CPSP. The CPSP is highly cost-effective and has facilitated studies to monitor trends in disease incidence, improved public health policy, and built a robust network of clinical researchers.12

Analysis of regional prevalence rates of both adult DM1 and CDM in Canada and comparisons with international studies are important future research opportunities. As noted by Campbell et al, the high prevalence and awareness of DM1 in Quebec13 present challenges to precisely defining the prevalence of DM1 and CDM in Canada. The authors’ reported incidence rates of CDM in Canada are lower than those reported from previous studies in Sweden, Spain, and Britain, although the latter studies were not population-based.6, 14, 15 It will be interesting to see how Campbell et al’s results compare with future findings of the Muscular Dystrophy Surveillance Tracking and Research Network sponsored by the Centers of Disease Control and Prevention, which involves population-based surveillance of Duchenne and Becker muscular dystrophy in 4 US states16 and a planned extension to other dystrophies, including DM1.

An important foundation of this article is Campbell et al’s statement of a clear definition of CDM. Such a specific definition strengthens their findings and facilitates future clinical studies to identify and monitor patients with CDM longitudinally. The authors acknowledge the challenges and the need to develop stringent clinical definitions of CDM, realizing the high likelihood that some children and infants with milder symptoms were not ascertained in this study. The authors also note that many asymptomatic or mildly affected neonates may undergo genetic testing if their parents have confirmed adult-onset DM1. Children developing symptoms in later infancy or early childhood (<5 years) often parallel the course of those with congenital onset. The present study, with its strict definition of CDM, may exclude children with mild symptoms.

Clinically, this report provides important data on the multisystem manifestations that occur and are severe in CDM. Almost 80% of the patients with CDM (30 of 38) experienced feeding difficulties that led to either nasogastric tube placement or, in 6 cases, gastric tube placement. The findings highlight the frequency of and variation in gastrointestinal symptoms, in particular the high prevalence of gastroesophageal reflux, in agreement with previous results from this group in an analysis of data from our US National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members.17 Gastroesophageal reflux was reported by 19% of patients with CDM in the US Registry, compared with 21% in the present study. Additional studies are warranted to examine the severity of gastroesophageal reflux, its possible contribution to pulmonary atelectasis, and possible management strategies.

As Campbell et al note, respiratory insufficiency and ventilator dependency remain critical issues in the neonatal period. Supporting earlier work,7 this article reports that 71% of the patients required respiratory support. For those patients requiring mechanical ventilation, the mean duration of ventilation was 104 days. This complication was directly related to the overall mortality of the cases surveyed, through primary respiratory complications, or indirectly related, by influencing clinical decisions. In support of this group’s earlier work, the vast majority of the children demonstrated improved respiratory status to the point of no longer requiring ventilatory support. Although earlier work suggested otherwise, current evidence suggests that duration of ventilation should not dissuade clinicians and parents from continuing care.

Indeed, discussion of goals of care of neonates with CDM has become even more challenging in view of this more recent information. Some significant psychosocial factors may influence parents’ decisions, particularly in index cases. From the clinician’s standpoint, it is challenging to base prognosis on length of cardiotocography repeats in the DMPK gene or on ventilator dependence. In our clinical experience, and as noted by Campbell et al, the majority of neonates with CDM show varying degrees of improvement throughout childhood and only later in adolescence begin to develop typical features of adult-onset DM1. Qualitatively, many of the children and parents report that dysarthria, intellectual impairment, and gastrointestinal symptoms remain significant symptoms throughout childhood; however, many of these parents report a meaningful quality of life nonetheess. The present study and ongoing long-term studies will provide important data to facilitate clinical care.

Many groups are currently developing clinical care guidelines for the myotonic dystrophies. Our colleagues in Quebec, for example, have recently published health guidelines for adult DM1, proposing an integrated care program that involves family, clinicians, decision makers, and community organizations to address the most disabling symptoms of DM1.18, 19 In addition, the American Academy of Neurology is currently developing evidence-based guidelines for the clinical management of DM1. For each affected system, a panel of neurologists and other experts are reviewing relevant literature and providing useful recommendations based on clinical experience where substantial information is not available. They are also addressing urgent needs for future research, with the goal to publish guidelines in 2013.

Another opportunity that merits mention is newborn screening for DM1. There are a high number of index cases in the neonatal period with overall mortality of the disease, including preventable cardiac and respiratory complications. Opportunities for newborn screening are encouraged by the development of promising therapeutic agents for DM1, including the recent discovery in a mouse model of DM1 of treatment that reverses myotonia and muscle fiber alterations.20 Given the severity of CDM, but acknowledging its natural history of improving during childhood, there is realistic hope that patients with CDM may benefit significantly from new experimental therapies. Newborn screening also can provide guidance for undiagnosed parents about future reproductive choices and facilitate preemptive clinical care and monitoring for complications of DM1, as well as specific treatments.

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