Congenital and infantile myotonic dystrophy

Congenital and infantile myotonic dystrophy

Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V...

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Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 144

Congenital and infantile myotonic dystrophy BERNARD ECHENNE1* AND GUILLAUME BASSEZ2 Neuromuscular Illness Reference Center, Pediatric Neurology Service, Hoˆpital Gui de Chauliac, Universit de Montpellier I, Montpellier, France and Sherbrooke University, Sherbrooke, Canada

1

2

Neuromuscular Illness Reference Center, CHU Henri Mondor and Inserm U955, Universit Paris 12, Paris, France

INTRODUCTION Myotonic dystrophy (DM) includes DM1 (myotonic dystrophy type 1 or Steinert’s disease) and DM2 (myotonic dystrophy type 2). Both DM types share autosomal dominant inheritance, muscle weakness, myotonia, posterior capsular cataracts, and multiorgan involvement of heart, brain, and endocrine system (Ashizawa et al., 2000). However, the two disorders also have distinctive clinical features and one of the major differences is the scarcity of neonatal/childhood forms in DM2, of which only two cases have been reported so far in the literature; one of these patients had reduced intrauterine movements and muscle hypotonia after birth (Kruse et al., 2008), the second had only congenital talipes equinovarus without any other clinical sign (Renard et al., 2010). The clinical spectrum of DM1 is extremely wide and diverse and age of onset may vary from the prenatal/neonatal period to the last decades of adulthood. Different classifications exist, based on the age of onset. In fact, DM may begin at any age, and no absolute distinction exists between the different clinical forms which rather form a continuum, with extreme variability in clinical manifestations and evolution from one patient to another, even in a particular family (Machuca-Tzili et al., 2005; Echenne et al., 2008). It should be noted that although myotonic dystrophy has been present in the literature since the beginning of the twentieth century, congenital and infantile forms were not described as specific DM1 clinical entities until 1960 and 1991, respectively. Genetically, DM1 is an autosomal dominant disease which belongs to the group of disorders caused by expansion of a trinucleotide repeat. The mutation is a noncoding CTG triplet repeat tract in the 30 -UTR region

of the myotonin protein kinase gene (DMPK) on chromosome 19 (19q13) (Guida et al., 1995; Cheng et al., 1996). DM1 is characterized by anticipation, which is defined by increasing severity and earlier onset of the disease phenotype in successive generations related to the intergenerational expansion of the repeat size (Harley et al., 1992; Harper et al., 1992).

CLASSIFICATION DM1 in children can be classified as follows, keeping in mind that many overlaps occur between these clinical forms: ● ●

congenital forms (CDM1) characterized by neonatal manifestations with various degree of severity other childhood forms: infantile, late-infantile, and juvenile.

Congenital forms (CDM1) Transmission occurs almost exclusively via the mother. A severe form and a milder form can be distinguished.

CDM1 SEVERE FORM This clinical subgroup may be viewed as the most severe end of the clinical spectrum. Often preceded by polyhydramnios, reduced fetal movements, and preterm delivery, these patients present at birth with difficulties breathing and feeding, which cause respiratory distress that needs assisted ventilation, marked generalized hypotonia and hyporeflexia (Fig. 144.1). Most children have facial weakness, and often characteristic tentshaped upper lips and a carp mouth. They often – but not always – present with arthrogryposis and/or clubfeet.

*Correspondence to: Professor Bernard Echenne, Centre de Re´fe´rence des Maladies Neuromusculaires, Service de Neurope´diatrie, Hoˆpital Gui de Chauliac, 34295 Montpellier, France. E-mail: [email protected]

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Fig. 144.1. Severe congenital neonatal form with respiratory distress and arthrogryposis syndrome.

CDM1 MILDER FORM In these patients, gestational age is normal and polyhydramnios infrequent. Feeding and swallowing difficulties, generalized hypotonia, and arthrogryposis are the main clinical features, without respiratory distress. Bilateral isolated clubfeet could be the first isolated sign of the disease.

EVOLUTION OF CDM (SEVERE OR LESS SEVERE) Mortality in CDM1 during the neonatal period has been estimated at between 30% and 40% of patients (Reardon et al., 1993; Roig et al., 1994; Campbell et al., 2004). Some children who survive may die later from sudden infant death syndrome, or from respiratory failure (Hageman et al., 1993; Dubowitz, 1995). In severely affected patients surviving the neonatal period, as in less severely affected patients, the disease course is very much the same: the most constant feature is mental delay, preceded by speech and language delay, that exists in all cases and progressively worsens after several years of evolution. In these forms, signs of central nervous system (CNS) dysfunction predominate, with mental deficiency and/or psychiatric disturbances that tend to be underestimated (Echenne et al., 2008; Ekstr€ om et al., 2008). A specific facial dysmorphic appearance is another frequent finding that worsens through time: facial weakness with hypomimia, slight ptosis, open mouth and tented upper lip, and temporal muscle atrophy. Motor development is delayed in most cases, the children becoming ambulant after the age of 2 years. But in terms of muscular weakness and the development of myotonic syndrome, disease progression is markedly variable from one patient to another. In some cases, a rapid worsening of muscle weakness may occur between the ages of 15 and 20, leading to the loss of ambulation.

More frequently, however, the muscular weakness remains slight during childhood without significant motor handicap until the appearance of a degenerative process during the third or the fourth decade of life, similar to the dystrophic pattern of the adult form. The occurrence of clinical myotonia, a specific sign of the disease, is most often delayed after 10 years of age. All patients exhibit difficulties with fine motor skills, and when they reach adolescence or adulthood, motor and executive dyspraxia are a constant feature. It must be emphasized that despite congenital onset, some complications are rarely seen, such as diabetes mellitus and cardiac disorders, which appear later, into the third decade of life.

Other childhood forms: infantile and juvenile DM1 These children experience a normal neonatal period and the age of occurrence of the first clinical signs is variable. Patients with patent symptoms occurring during the first decade will be assigned to infantile DM1 whereas children with onset between 10 and 20 years of age will be classified as a juvenile form of DM1. The assignment is often retrospective, and approximate in many cases. Importantly, these childhood forms can be equally maternally or paternally inherited (French national DM registry, unpublished data). Moderate motor delay with hypotonia and delayed milestones may occur infrequently. Speech and language delays, noted as school difficulties from the time they started school, are often the nonspecific initial signs of the disease, related to the mental dysfunction observed in the vast majority of these patients. This highlights a very important and recently underlined fact: these childhood forms of DM1 have to be considered rather as a CNS disease than a muscular or systemic disease (Echenne et al., 2008; Ekstr€om et al., 2008). Another key point is the existence of a continuum between the severe CDM1 variant, the less severe CDM1 form, and the juvenile form. The first clinical signs, the age of onset, the chronology of clinical manifestations that progressively appear as the disease advances, as well as the intensity or severity of symptoms, vary considerably from one patient to another. The range of CTG repeat expansion may collectively distinguish these forms but overlaps limit its predictive use in a given patient. Further studies are needed to determine if progression of dysfunction of various organs may be correlated or independent in patients.

FIRST CLINICAL SIGNS The first clinical signs can occur at any age. The most frequently seen are signs of CNS dysfunction:













CONGENITAL AND INFANTILE MYOTONIC DYSTROPHY 1389 The large majority of patients demonstrate severe or moderate mental delay or deficiency, or borderline normal intellectual level. Most require special education. School difficulties, including speech and language delay that slowly worsens after several years of evolution, are the most frequent findings. In some patients, a decrease of intellectual abilities may be observed over time, as has been seen in some adult patients (Modoni et al., 2004; Echenne et al., 2008). No correlation has been found between motor and mental dysfunction, which is global, affecting both verbal and nonverbal abilities. However, some authors highlight the possibility of borderline or normal intellectual levels, with more specific dysfunctions, affecting attention/memory and/or visuospatial and visuo-constructive skills, especially in case of smaller CTG expansion and paternal transmission (Angeard et al., 2007). Psychopathological manifestations may be observed at any age in the evolution of the disease. They are found in more than 50% of patients (Steyaert et al., 1997; Goossens et al., 2000). They include not just learning difficulties, but also attention deficit disorders, hyperactivity, Tourette syndrome, conduct disorders, aggressiveness and opposition. Anxiety disorders and depression are frequently Fig. 144.2. Typical dysmorphic facial appearance in a seen (Steyaert et al., 2000). More recently, autistic 16-year-old adolescent in whom disease started during the first spectrum disorders have been reported that may months of life with hypotonia and delayed milestones. The concern up to 49% of patients. Autistic disorders dysmorphic signs appeared progressively after 6 years of age. were considered as a common first diagnosis in 35% of these children (Ekstr€ om et al., 2008). Language and speech defects are a constant feature develops during the second decade of life and throughout the course of the disease, occurring as worsens rapidly, leading to loss of ambulation within the first sign in some cases, or appearing later, with a few years. Nevertheless, muscle weakness most slow worsening evolving to dysarthria and a dysphooften remains mild, or even absent, and does not nic voice. lead to a real handicap during childhood or adolesYoung patients with DM1 often experience fatigue cence. If present, the typical adult DM1 muscle and daytime somnolence that contribute to the weakness pattern, that is, a predominant distal limb impairment of academic performance. Fatigue is weakness with an ascending course, may be found. related to sleep abnormalities consisting of periodic However, in many children proximal muscles can limb movements and/or sleep apnea syndrome causalso be affected, as well as the axial musculature ing fragmentation of sleep (Quera Salva et al., 2006). (Kroksmark et al., 2005). The typical facial dysmorphic appearance (Fig. 144.2) ● Most children with either severe or mild CDM1 have becomes evident at various ages during the first feet deformities, which can also affect some of the decade of life, or sometimes only in adolescence. children with later onset form. Joint stiffness, clubThe characteristics are the same as those in the severe feet or equinovarus talipes are frequent in the neoyoung adult form: open mouth, tented upper lip and natal form; but contractures (hips, feet) may carp mouth, facial weakness, slight ptosis, temporal appear later in the disease course. Spinal deformimuscle atrophy. All these signs worsen with time. ties, when present, usually – but not always – have Muscular weakness and myopathic signs can appear an early onset and include thoracolumbar scoliosis at various ages, but can be lacking right up into adult as well as kyphoscoliosis (Kroksmark et al., 2005). age, and it has to be emphasized that muscular signs Developmental equinus and equinovarus exclusive are not the main feature in the great majority of DM1 of clubfoot may affect some children, requiring surchildren. In some patients, however, muscle wasting gery in most cases (Canavese and Sussman, 2009).

1390 B. ECHENNE AND G. BASSEZ Cataracts have occurred sometimes around 10 years myotonia through a mother’s handshake, in case of susof age, but are rarely symptomatic in childhood. pected CDM1). Lens opacities are typically of small size, multicolor, Neuroimaging studies are important: cerebral CT posterior capsular leading to a pattern nearly pathoscan or, better, cerebral MRI may give normal results gnomonic of DM disorder. or show abnormalities. The incidence of these abnormal● Gastrointestinal tract involvement may occur at difities remains unknown up to now, since no extensive ferent ages. Abdominal symptoms are prevalent as study has been performed in childhood. Abnormal the consequence of smooth musculature involveresults, however, seem frequent (Regev et al., 1987; ment leading to gastroparesis. Other signs are Bachman et al., 1996; Di Costanzo et al., 2008), although encopresis, fecal incontinence, anal dilatation mimthe pathophysiology remains poorly understood: venicking sexual abuse, and intestinal pseudo-occlusion tricular dilatation, diffuse cerebral atrophy, wide (Reardon et al., 1993). Virchow-Robin spaces, and subcortical white matter ● Heart involvement, most common in adult DM1 abnormalities may occur. Hyperintense white matter patients, consists of conduction disturbances that lesions are found on T2-weighted images in more than may worsen over time and may result in sudden half the adult patients and also in children. The occurdeath. Atrial flutter and left ventricular diastolic rence and severity of lobar, temporal, and/or periventrifunction abnormalities may be seen. Disabling carcular lesions in DM1 patients appears strictly linked to diac dysfunction or arrhythmias are rare events in the positivity of family history for the respective types childhood, the abnormalities remaining silent or disof lesions, whatever the length of CTG amplification crete. However, severe conduction defects, atrial or (Di Costanzo et al., 2008). Sometimes, more severe lesions ventricular tachyarrhythmia, important factors assomay be found, such as neuronal heterotopy, and periciated with sudden death in adults, can be diagnosed ventricular leukomalacia (Tanabe et al., 1992; Hageman in childhood (Bassez et al., 2004). Heart involvement et al., 1993; Di Costanzo et al., 2002). A developmental is mainly observed during the second decade, leadmechanism is suspected but not demonstrated. ing to palpitations or syncope, although sudden death has been exceptionally reported in childhood. PATHOPHYSIOLOGY Interestingly, in adolescents with DM1, many arrhythmic events appear to be exercise-related. This In DM1, the gene mutation involves a microsatellite is in accordance with the mild degree of myopathic motif (CTG) that is transcribed into RNA but not transsigns in some of these patients and the recent findlated. Therefore, the resulting DMPK protein level is ings prompt the inclusion of an exercise stress test poorly decreased and haploinsufficiency does not cause for young adults who want to practice sports. the vast panel of disease manifestations. The peculiar ● As compared to the adult form of the disease, endoand complex molecular mechanisms of DM1 results crinopathy is rarely documented in childhood DM1 from a toxic gain of function at the RNA level. Indeed, patients. Puberty seems to occur normally but testicexpansion of a CUG repeats tract located in the DMPK ular atrophy in early-onset cases may be observed. transcript alters its normal translocation from the Insulin resistance and diabetes mellitus, a key nucleus to the cell cytoplasm. Mutant RNA accumulates DM1 manifestation, can occur after the third decade in the nucleus where it forms aggregates termed nuclear and is exceptionally diagnosed during childhood foci. These intranuclear RNA foci trap specific RNA(Guiraud-Dogan et al., 2007). However, other endobinding proteins that mainly act as splicing regulatory crine dysfunctions may appear sooner during the factors. As a consequence, deregulation of the normal second decade of life, such as growth hormone defisplicing of several other transcripts leads to aberrant isociency or hypothyroidism. forms that cause some of the multisystemic features of the disease (Mankodi and Thornton, 2002; Day and Ranum, 2005). LABORATORY INVESTIGATIONS For instance, the aberrant splicing of chloride channel Serum creatine kinase (CK) and routine biological anaCLC1 transcripts has been demonstrated to cause myolyses are usually normal. Besides rare hormonal disturtonia, whereas the insulin receptor splicing defect is bances, a low IgG level, similar to adult patients, can thought to lead to insulin insensitivity and predisposition be observed, but its role in predisposition to infection to diabetes (Guiraud-Dogan et al., 2007). Similarly, has not been documented. Electromyography is of little altered splicing of the cardiac troponin T may play a part in cardiac disorders. Moreover, splicing alterations interest in children. It is useful in showing myotonic disof the microtubule-associated tau mRNA have been charges in the parent who transmitted the disease (and observed in CNS tissue of adult DM1 patients, as well keep in mind the importance of the search for a clinical ●

CONGENITAL AND INFANTILE MYOTONIC DYSTROPHY as in a murine model. Adult DM1 brains show neurofibrillary degeneration resulting in the intraneuronal aggregation of hyperphosphorylated tau proteins (Sergeant et al., 2001). Tau splicing is tissue- and cellspecific and is highly regulated during development and cell differentiation. Whether childhood DM1 would be a variant of tauopathies is an attractive but undemonstrated hypothesis. Besides splicing deregulation of several pre-mRNAs, some studies evidenced other disturbances such as alteration of transcription. This overloading mechanism of mutant RNA, accumulating as nuclear foci, varies from one cell to another, and among various tissues. This could explain the polymorphism of the disease and the absence of clear genotype/phenotype correlation in a given patient.

MOLECULAR BIOLOGYAND PHENOTYPE/GENOTYPE CORRELATIONS Diagnosis of DM1 is made by molecular biological techniques that can evidence the CTG expansion in DMPK: PCR, triplet repeat primed-PCR (TP-PCR), and Southern blot to evaluate the size of longer repeat tracts. Classically, a correlation exists between the expansion length and the severity of the disease leading to a dosage gene effect. Similarly a negative correlation has been observed between the expansion size and age at onset of the disease. These results have been demonstrated by statistical analyses in several studies but remain poorly applicable to single cases. The extreme polymorphism of the clinical forms and progressive aspects of childhood-onset DM1, the variable prognosis and severity of the disease are probably a consequence of the somatic mosaicism which takes places in the brain as well as in many other organs. This mosaicism has been demonstrated in adult patients but not in childhood DM1 up to now. Nevertheless, there is a marked heterogeneity in CTG expansion size in the different tissues of affected individuals. Then, an evaluation of genotype/phenotype correlation is complicated by this tissue-specific, expansion-biased, somatic instability of the mutant alleles over a patient’s lifespan. The phenomenon of an unstable mutation, which is best exemplified in DM1, explains the great limitation of attempts aiming at predicting disease severity and prognosis in children with DM1. The same reasons account for limitation in genetic counseling, in particular for prenatal diagnosis based on trophoblast cells or amniotic cells (Tsiflidis et al., 1992; Ashizawa et al., 1993; Lavedan et al., 1993; Di Costanzo et al., 2008).

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TREATMENT Treatment is symptomatic only. Physiotherapy and/or orthopedic treatments may be indicated depending on the clinical evolution; if there are orthopedic complications, correction and improved function are likely after surgery (Canavese and Sussman, 2009). Some pharmacological treatments may be useful, such as procainamide in case of gastrointestinal symptoms, dopaminergic therapy for patients with periodic limb movements, or modafinil where there is documented daytime somnolence. As far as cardiac conduction disorders are concerned, no consensus has been reached regarding the best approach for follow-up and prevention of sudden death (Groh et al., 2008; Breton and Mathieu, 2009). Pacemaker implantation has to be discussed in case of heart block, and the use of antiarrhythmic drugs for atrial or ventricular arrhythmia, a very rare situation in childhood, is indicated. Finally, the most important part of treatment consists in the evaluation of neuropsychological and psychiatric dysfunction, with special education and training depending on the psychopathology presented by the patient. Interestingly, several very recent studies have reported on preclinical efficacy of different molecular therapeutic approaches which target the mutant expanded RNA, including antisense oligonucleotides, siRNA, and morpholinos. Screening of drugs can identify candidates, such as pentamidine, which have the potential to reduce the interaction between foci and splicing protein.

CONCLUSIONS DM1 in childhood is a relatively rare disease, with an incidence worldwide of about 1/20 000, except for some parts of the world where a gene founder effect exists (up to 1/500 live-born in the Saguenay–Lac-Saint-Jean area, in Quebec, Canada) (Mathieu et al., 1990). Due to the nonspecificity of the first clinical signs, diagnosis is often delayed infantile/juvenile forms. Genetic counseling is very difficult given the extreme polymorphism and unpredictability of the disease. Although a prognosis is impossible, some characteristics share a poor prognosis: early onset of the disease, in particular antenatal signs leading to the congenital form CDM1, respiratory distress, severity of intellectual disability, and coexistence of psychiatric symptoms.

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