Myotonic Dystrophy

Brief Overview of History and Epidemiology

In 1909, Hans Steinert (Leipzig, Germany) described the typical pattern of muscle weakness and myotonia in adult-onset myotonic dystrophy type 1 (DM1). Over subsequent years, clinical studies demonstrated dominant inheritance and a wide spectrum of variable multisystem manifestations (skeletal and smooth muscle, heart, brain, eyes, respiratory, gastrointestinal, immune, and endocrine systems). In 1992, researchers discovered that DM1 results from an unstable trinucleotide repeat expansion (CTG) in the dystrophia myotonica-protein kinase ( DMPK ) gene located on chromosome 19q13.3. This discovery stimulated widespread DNA testing of clinically diagnosed patients felt to have Steinert’s disease. Interestingly, in 1994, clinical researchers in the United States and Germany identified kindreds of patients with dominantly inherited myotonia, cataracts, and proximal weakness without an abnormal expansion of the CTG repeat in the DMPK gene and without linkage to hereditary myotonic disorders caused by mutations of the skeletal muscle chloride or sodium channels. They proposed two names for this newly identified disorder: myotonic dystrophy type 2 (DM2) and proximal myotonic myopathy (PROMM). In 1998, genetic mapping linked both disorders to chromosome 3q21, and in 2001, researchers discovered that DM2/PROMM resulted from an unstable CCTG repeat expansion in intron 1 of the CNBP/ZNF9 gene at locus 3q21.3.

The relatively recent discoveries of the assays to identify the mutations responsible for DM1 and DM2 create a challenge to determining the exact prevalence of DM1 and DM2. DNA confirmation of DM1 has only become widely available since the mid 1990s, and for DM2 since 2003. Prior estimates of the prevalence of myotonic dystrophy relied solely upon clinical diagnosis. Study populations primarily involved symptomatic adults and probably included a mixture of patients with DM1 and DM2. Patients with minimal or no symptoms are unlikely to have participated. Within these limitations, prior studies report a range of prevalence for myotonic dystrophy of 5 to 20 per 100,000. There are clusters of higher prevalence in the Basque region of Spain, northern Sweden, Istria region of Croatia, and the Saguenay-Lac St. Jean region of Quebec, Canada (158–189 per 100,000). Few studies of the prevalence of congenital myotonic dystrophy type 1 (CDM) and childhood DM1 are available. However, a recent nationwide study of CDM in Canada calculated the prevalence to be approximately 2.1/100,000. This estimate is lower than estimates in previous non-population-based studies in Sweden, Spain, and Britain, and probably reflects a stricter definition of CDM. The definition used for CDM in the Canadian study was: symptoms of DM1<30 days after birth (hypotonia, feeding and/or respiratory difficulty, required hospitalization>72 hours) and positive DNA testing. Other reports classifying children with positive DNA testing for DM1 have defined CDM as an infant<1 year of age with symptoms consistent with DM1; childhood DM1 (ChDM) as a child between 1–10 years of age with symptoms; and older teens and adults as the adult group. More epidemiological studies are necessary in DM1 to establish the rate of appearance and progression of disease manifestations, especially in children.

Until recently no estimates of prevalence for DM2 were available. In 2011, clinical researchers in Finland published findings indicating a higher prevalence of DM2 in Europeans than most clinicians suspected. In a large study of over 5000 anonymous blood donors, they observed a higher prevalence for DM2 than DM1. The higher prevalence of DM2 identified in this Finnish population emphasizes the wide spectrum of phenotypes and points out the diagnostic challenge that exists due to the variation in different symptoms that occur in DM2. For example, clinical findings such as myotonia on physical examination or even on electromyographic testing may be absent, limiting the ability of myotonia screening alone as a means to identify individuals with DM2. Whole blood DNA testing in individuals at known risk for DM1 or DM2 or in individuals presenting with one of the common manifestations ( Tables 37.1 and 37.2 ) is needed to determine more exactly the actual prevalence of individuals with abnormal repeat expansions of DMPK and CNBP/ZNF9 genes.

Mode of Inheritance and Prevalence

DM1 and DM2 are autosomal dominant. Anticipation (earlier onset of more severe symptoms in successive generations) occurs primarily in DM1 (see Figure 37.1 ). Congenital myotonic dystrophy (CDM) occurs almost exclusively through maternal transmission (see Figures 37.2 and 37.3 ). In contrast, both mothers and fathers with DM1 can have children with childhood onset of DM1. However, only 5–10% of DM1 patients have onset before their mid-teens. DM2 occurs neither in infancy nor childhood, although teenage onset of myotonic symptoms can occur in some DM2 patients carrying concomitant mutations in the gene for the skeletal muscle chloride channel.

Clinical Presentation and Phenotypes

Tables 37.1 and 37.2 summarize the genetics, core clinical features, and multisystem manifestations typically observed in the initial evaluation of adults with either mild or moderate signs and symptoms of DM1 and DM2. Figure 37.4 outlines the workup and Table 37.3 presents general guidelines for patient care. Childhood and infant onset symptoms occur only in DM1. Figures 37.5 and 37.6 outline the evaluation and workup of DM1 patients who present in infancy and childhood. Table 37.4 summarizes the clinical problems they often have as well as their management.

Myotonic Dystrophy Type 1 (Steinert’s Disease): Age of Onset and Clinical Presentation

DM1 can present from birth to late adult life. Teenage or later onset is typical for 90% of individuals with DM1, and in this phenotype one of the core features ( Table 37.1 ), such as myotonia, is often the initial sign or symptom. However, one of the multisystem manifestations ( Table 37.2 ) can be the first complaint. In the absence of an established family history of DM1, care providers must have a high degree of suspicion in order to avoid overlooking the diagnosis of DM1. Because of the variable nature of these multisystem features, such as cataracts, gastrointestinal complaints, and sleep disturbances, care providers often do not consider DM1 as the cause and a delay in diagnosis occurs. Early onset in infants or children often shortens the time for diagnostic testing for DM1. Symptoms of CDM appear in the newborn period, can be life threatening, and manifestations include generalized weakness and hypotonia, respiratory failure/insufficiency, feeding difficulty, clubfoot deformity, increased risk of germinal matrix/intracerebral hemorrhage, and eventration of the diaphragm ( Table 37.4 , Figure 37.5 ). Childhood myotonic dystrophy (ChDM) may be more difficult to diagnose if there is no diagnosis of an affected parent or no positive family history of DM1 ( Table 37.4 , Figure 37.6 ). ChDM is often defined as having onset of DM symptoms<10 years, an uneventful prenatal and neonatal history, normal development within the first year of life, and increasing manifestations in the toddler years. ChDM typically causes intellectual deficiency, difficulty with speech or hearing, delayed bowel-bladder training, clumsiness, or rarely cardiac dysrhythmia or postoperative apnea.

The challenge in reaching a rapid diagnosis of DM1 often comes in thinking of this disease. DM1, especially in adults and mild cases in childhood, has a wide spectrum of clinical manifestations (gastrointestinal, brain, heart, eyes), many not clearly related to skeletal muscle. They can present in isolation, staggered in time of onset and severity, and separate from the subsequent onset of skeletal muscle signs and symptoms. DM1 can present in late life with only cataracts, baldness, or occasionally with heart block. Weakness and myotonia may be absent or very mild. In the second and third decades, DM1 can present with variable grip myotonia, trouble holding items, ankle weakness, or intermittent slurring of speech. Mild weakness of the face, long finger flexors, intrinsic hand, and foot dorsiflexor muscles is usually present, as is myotonia. The myotonia typically occurs following a strong grip or after percussion of the thenar and forearm wrist extensor muscles. An affected parent of an infant or child with DM1 may have only mild disease manifestations. These clinical findings may be subtle, for example in an undiagnosed pregnant mother with DM1; they may only be detected on a focused clinical evaluation to detect myotonia after she gives birth to a baby with severe CDM. Not uncommonly the mother has a history of decreased fetal movements and polyhydramnios followed by failed labor and an urgent cesarean section. Placenta previa and a history of miscarriage are common. Because of the marked variation in severity and spectrum of manifestations of DM1, birth of an infant with CDM often comes with a sudden impact. Abruptly, three generations of a family become aware that they are affected by a dominantly inherited, progressive disease that at present has no curative treatment. Family counseling and emotional support to the mother and father as well as emergent medical treatment for the infant become essential responsibilities for care. Grip and percussion myotonia are not present in infancy and early childhood in DM1, and are sometimes difficult to detect on clinical examination in adults with marked wasting of forearm and intrinsic hand muscles. Dysarthria, difficulty swallowing, gastrointestinal dysmotility (frequent bowel movements, intermittent constipation), hypersomnia, cognitive-behavioral problems, sleep apnea, decreased vital capacity, and cardiac conduction disturbances develop over subsequent years. Further longitudinal studies of the rate of progression of the wide spectrum of the clinical manifestations of the different phenotypes in DM1, especially in children, are needed to supplement the limited number of prior studies. Such studies will help extend and enhance current standards of care for DM1. Our present estimates of mortality and end of life events are also limited.

In CDM, estimated mortality ranges between 16% and 41% in the neonatal period. Contributors to reduced survival include respiratory failure and elective withdrawal of care. In a study of 838 adults with DM1 in Quebec from 1985 to 2010, there were 321 deaths with a median age of death of 56 years. This study showed a significant difference between median age of death between childhood onset (median=48.5 years), adult onset (median=54 years), and mild phenotypes (median=73 years). Another study of 406 DM1 patients in the United States reported 118 deaths with a median age of 54 years, the majority caused by respiratory and cardiac complications, similar to previous reports. Going forward, it will be important to document how mortality rates for DM1 change over the next decade as care providers implement improvements in the treatment of respiratory and cardiac manifestations.

Myotonic Dystrophy Type 2 (Proximal Myotonic Myopathy): Age of Onset and Clinical Presentation

DM2 presents in adult life, usually with myotonic stiffness or weakness (proximal legs or long finger flexors). Tables 37.1 and 37.2 summarize the core features and multisystem manifestations of DM2, while Table 37.3 provides guidelines for care. Frequently, the myotonia fluctuates, being prominent only on “bad days.” Muscle pain similarly varies in severity over days to weeks, the cause for which is unknown. It typically appears to be independent of exercise and unrelated to the severity of myotonia on clinical examination. In the initial stages of DM2, there is often mild weakness of long finger flexors, thigh flexors, neck flexors, and hip extensors along with grip myotonia. The myotonia is most apparent following percussion of forearm extensor and thenar muscles. The myotonia that occurs after a powerful grip often has a jerky, tremulous quality that differs from the grip myotonia observed in DM1. Patients with this jerky myotonia frequently have brisk tendon reflexes and often have mild sustention tremor.

The prominent facial weakness and the wasting of facial, forearm, and distal leg muscles that are typically seen in DM1 are not observed in DM2. Even in the late stages, typical DM2 patients have relatively mild muscle wasting with the occasional exception of the gluteal and proximal thigh muscles. Occasionally, patients with DM2 have calf muscle hypertrophy. Early onset of cataracts that require surgery is common. Later in life, patients may present with complaints of difficulty climbing stairs or arising from a squat, often attributed to “arthritis” or “old age.” Myotonia and muscle pain are less prominent when onset is late. In contrast to DM1, respiratory failure and cardiac conduction disturbances are less common in DM2. Difficulty swallowing, gastrointestinal dysfunction, and cognitive disturbances do occur in DM2, but their frequency seems less than in DM1. Additional investigation of the natural history of DM2 is necessary to establish the actual frequency of these complaints and their relationship, if any, to the severity of muscle weakness and/or myotonia. There are no large-scale studies evaluating the disease manifestations that contribute to mortality in DM2. Future research is necessary to determine if the causes of death in DM2 differ significantly from those of the general population.

DM1: Normal Gene Product

Table 37.1 summarizes information on the dystrophia myotonica protein kinase (DMPK) gene and the associated mutation that leads to DM1. The protein encoded by this gene is a serine-threonine kinase closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. The serine-threonine kinase appears to function normally in patients with DM1. The 3′ untranslated region of the DMPK gene in normal leukocyte DNA contains 5 to 37 copies of a CTG trinucleotide. This CTG repeat is unstable in DM1 and may range in length from 50 to 4000 repeats in the circulating blood of different patients. In asymptomatic or “premutation carriers” of the unstable CTG repeat in the DMPK gene, the expansion size is 30 to 50 repeats. The repeat size becomes unstable once it exceeds 50 CTG repeats.

DM2: Normal Gene Product

Table 37.1 summarizes information on the CNBP gene (often termed the zinc finger 9 protein gene, ZNF9 gene) that is responsible for DM2. CNBP encodes cellular nucleic acid-binding protein. Its role in humans is not clearly understood, but it influences embryonic development. It appears to function normally in DM2, in which there is an unstable expansion of the CCTG repeat in intron 1 of the CNBP gene. The normal CCTG repeat structure is approximately 10 to 20 repeats. In carriers of the premutation, there are 22 to 33 uninterrupted CCTG repeats. These premutation carriers are asymptomatic and are unlikely ever to show symptoms. Symptomatic DM2 patients have CCTG repeat lengths ranging from 75 to 11,000 repeats (mean 5000 CCTG repeats)

DM1 and DM2: Genotype-Phenotype Correlations

In DM1, there is a rough correlation between the length of the abnormal CTG expansion in circulating leukocyte DNA and the severity of disease, with exceptions occurring frequently in clinical practice. Age of onset of DM1 shows a correlation. Individuals having 50 to 100 CTG repeats in leukocyte DNA typically develop mild symptoms later in life. Patients with 150 to 1000 CTG repeats often have manifestations typical of adult onset DM1 as summarized in Tables 37.1 and 37.2 . Individuals with over 1000 repeats are likely to have congenital or childhood forms of DM1, although a number of these patients have CTG expansions that range between 150 and 1000 repeats.

Published reports of genotype-phenotype correlations have made the assumption that most DM1 patients have continuous uninterrupted abnormally expanded tracts of CTG repeats in the 3′ untranslated region of the DMPK gene; however, recent reports point out the limitations in this assumption. The most recent report estimates that approximately 4.8% of DM1 patients have CCG interruptions within the 3′-end of the CTG motif at the DMPK gene locus . This study used bidirectional triplet primed PCR (TP-PCR) and sequencing to identify the variant expansions. Of the 5 patients identified, 3 tested negative for an abnormal CTG expansion using a standard DNA analysis of the DMPK gene by routine long-range PCR. More investigations of variant mutations affecting the CTG repeat motif of the DMPK gene locus are necessary before making firm conclusions about their contribution to phenotypic variation in DM1. However, these findings support the use of bidirectional TP-PCR in the detection of “variant” DM1 CTG repeat expansions and its inclusion in the routine diagnostic DNA testing to screen for DM1.

In DM2 the abnormal length of the CCTG repeat in circulating blood spans a wider range of size than in DM1 and does not correlate with the clinical severity.

Both DM2 and DM1 show somatic instability of the mutant alleles. The size of the repeat expansion increases over time, across generations, and shows somatic mosaicism, even in post-mitotic tissue. For example, CTG repeat lengths in skeletal muscle, heart, and brain of DM1 patients often are 5- to 10-fold longer than in their circulating leukocyte DNA. Intergenerational repeat variations and somatic mosaicism result from contractions and expansions due to defects in DNA replication, DNA repair, and recombination. Studies from population-based mathematical modeling of DM1 mutant alleles from leukocyte DNA demonstrate a bias toward expansion. This bias appears to be due to expansion and contractions that are coupled to DNA repair or transcription rather than dependent on DNA replication.