Myotonic Dystrophy 1

A number sign (#) is used with this entry because myotonic dystrophy-1 (DM1) is caused by a heterozygous trinucleotide repeat expansion (CTG)n in the 3-prime untranslated region of the dystrophia myotonica protein kinase gene (DMPK; 605377) on chromosome 19q13.

A repeat length exceeding 50 CTG repeats is pathogenic (Musova et al., 2009).

Description

Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the 3-prime untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats. The disorder shows genetic anticipation, with expansion of the repeat number dependent on the sex of the transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted by males, whereas only alleles longer than 80 repeats tend to expand in maternal transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (Musova et al., 2009).

Genetic Heterogeneity of Myotonic Dystrophy

See also myotonic dystrophy-2 (DM2; 602668), which is caused by mutation in the ZNF9 gene (116955) on chromosome 3q21.

Clinical Features

ADULT-ONSET MYOTONIC DYSTROPHY

In adult-onset DM1, symptoms typically become evident in middle life, but signs can be detectable in the second decade. Bundey et al. (1970) found that the most useful method for identifying subclinical cases is slit-lamp examination for lens changes, followed by electromyography for myotonic discharges, and then by measurement of immunoglobulins.

Harper (1989) provided a monograph on myotonic dystrophy that has been updated regularly.

Unlike the other muscular dystrophies, DM initially involves the distal muscles of the extremities and only later affects the proximal musculature. In addition, there is early involvement of the muscles of the head and neck. Involvement of the extraocular muscles produces ptosis, weakness of eyelid closure, and limitation of extraocular movements. Atrophy of masseters, sternocleidomastoids, and the temporalis muscle produces a characteristic haggard appearance. Bosma and Brodie (1969) demonstrated both myotonia and weakness in patients with swallowing and speech disability. Myotonia, delayed muscular relaxation following contraction, is most frequently apparent in the tongue, forearm, and hand. Myotonia is rarely as severe as in myotonia congenita and tends to be less apparent as weakness progresses.

Many of the muscle biopsy changes are nonspecific. Most commonly there are central nuclei and ring fibers. Necrosis, regeneration, and increase of collagen are never as severe as in Duchenne muscular dystrophy. In 70% of patients there is hypotrophy of type I muscle fibers; less commonly there are markedly atrophic fibers (Casanova and Jerusalem, 1979). In many cases there are target fibers, suggesting neurogenic dysfunction, but intramuscular nerves appear histologically normal (Drachman and Fambrough, 1976). Ultrastructural studies show dilatation of T tubules or sarcoplasmic reticulum, whose contents may be unusually dense (Milhaud et al., 1964). In some cases the surface membrane may be irregular, with reduplication of basal lamina.

Neurologic Features

From a series of neurophysiologic investigations of 24 patients with myotonic dystrophy, Jamal et al. (1986) concluded that there was unequivocal evidence of widespread nervous system dysfunction. In many patients there was significant involvement of peripheral large diameter motor and sensory fibers and of small diameter sensory fibers peripherally and/or centrally. The authors stated that 'the concept of myotonic dystrophy as a pure myopathy can no longer be sustained.' This conclusion is supported by the findings in the family reported by Spaans et al. (1986). Thirteen members of a large family presented with a hereditary motor and sensory neuropathy in a dominant pedigree pattern. The mean motor conduction velocities for the median and peroneal nerves in the affected individuals were 62% and 56%, respectively, of those of the unaffected relatives. Eight of the 13 affected members also showed more or less prominent signs of myotonic dystrophy. There was no case of myotonic dystrophy alone.

Turnpenny et al. (1994) found that IQ in myotonic dystrophy declined as the age of onset of signs and symptoms decreased and as the size of the CTG expansion increased. The correlation appeared to be more linear with age of onset. Censori et al. (1994) carried out a prospective case-control study of 25 patients with myotonic dystrophy using magnetic resonance imaging (MRI) of the brain. They found that 84% of myotonic dystrophy patients showed white matter hyperintense lesions, compared with 16% of controls. Most of these lesions involved all cerebral lobes without hemispheric prevalence, but 28% of the myotonic dystrophy patients also showed particular white matter hyperintense lesions at their temporal poles. Myotonic patients also showed significantly more cortical atrophy than did controls. However, there was no relationship between atrophy or white matter hyperintense lesions and age, disease duration, or neuropsychologic impairment. Damian et al. (1994) found that amplification of the CTG repeat in leukocytes strongly correlated with cognitive test deficits when the expansion length exceeded over 1,000 trinucleotides. MRI lesions were associated with impaired psychometric performance, but the MRI findings of subcortical white matter lesions correlated only very weakly with the molecular findings.

Miaux et al. (1997) found that 9 (70%) of 13 patients with a mild form of adult myotonic dystrophy had T2-weighted signal abnormalities on brain MRI. Four patients (30%) had lesions greater than 1 cm in diameter. Lesions were symmetric, occurred in the subcortical white matter, and showed a predilection for the temporal lobe. There was some evidence of cerebral atrophy in the patients overall but no difference in IQ between patients and controls. There was no correlation between number of pathologic CTG repeats and white matter lesions, and there was no correlation between intellectual impairment and white matter lesions, except in 1 patient who had a difficult birth and temporal lobe epilepsy. Three patients had marked thickening of the skull, which was associated with ossification of the falx in 2.

Donahue et al. (2009) reported a 56-year-old woman with a 10-year history of myotonic dystrophy who presented with progressive lower extremity weakness. Brain MRI showed multiple discrete and confluent areas of abnormal signal intensity throughout the subcortical white matter with predominant involvement of the frontal and anterior temporal lobes. There was also diffuse thickening of the skull with ossification of the falx. Donahue et al. (2009) noted the similarity of the white matter findings with those observed in CADASIL (125310), but noted that skull abnormalities are not seen in CADASIL.

In a study of 21 patients with myotonic dystrophy, Akiguchi et al. (1999) found that MRI results indicated progressive brain atrophy. Magnetic resonance spectroscopy demonstrated a significant reduction of the neuronal marker N-acetylaspartate, even in young patients in whom imaging studies were still equivocal.

Delaporte (1998) found that 15 DM patients with no or minimal muscle weakness demonstrated a homogeneous personality profile characterized by avoidant, obsessive-compulsive, passive-aggressive, and schizotypic traits. Fourteen healthy control individuals and 12 patients with a mild form of muscle disease did not show the same trait homogeneity. Delaporte (1998) concluded that the personality disorders were not attributable to the adjustment to a disabling condition, but rather were primary manifestations of the genetic mutation.

Modoni et al. (2004) performed detailed neuropsychologic testing of 70 patients with DM1, including 10 with congenital onset and 60 with juvenile-adult onset, who were subdivided into 4 genotypic subgroups according to number of repeat expansion. Patients with congenital onset (CTG repeats greater than 1,000) obtained the lowest scores in verbal attainment, frontal and executive functions, and general intelligence, consistent with mental retardation. Patients with 50 to 150 repeats showed age-dependent impairment in memory, frontal lobe, and temporal lobe function. Patients with 151 to 1,000 repeats showed defects only in frontal and executive tasks. Although there was a correlation between number of repeats and degree of muscle involvement for all patients, there was not a significant correlation between number of repeats and cognitive impairment, except for the congenital group.

Sergeant et al. (2001) stated that neurofibrillary tangles (NFT), as described in patients with Alzheimer disease (AD; 104300), had been described in the neocortex and subcortical regions of patients with DM1. NFTs derive from pathologic aggregation of hyperphosphorylated tau (MAPT; 157140) proteins. By neuropathologic examination, Sergeant et al. (2001) identified hippocampal NFTs in 4 of 5 patients with DM1 ranging in age from 42 to 64 years. Three patients had clinical evidence of cognitive impairment or mental retardation. In some of the patients, other brain regions also had NFTs. Biochemical characterization showed overexpression of tau protein isoforms lacking exons 2 and 3, suggesting that the DMPK mutation disrupts normal MAPT isoform expression and alters the maturation of MAPT pre-mRNA. Maurage et al. (2005) identified biochemically similar NFTs in multiple brain regions of a patient with DM2; however, the patient with DM2 was mentally normal, demonstrated no cognitive decline, and died at age 71 years from a bilateral renal thrombosis.

Cardiac Features

Hawley et al. (1983) suggested that the tendency to have heart block or arrhythmia with myotonic dystrophy is a familial characteristic. The implication was that there may be 2 forms of myotonic dystrophy. They studied 18 families and found heart block in 4.

In a single large kindred, Tokgozoglu et al. (1995) compared the cardiac findings in 25 patients with myotonic dystrophy with age-matched normal family members. They found that the patients were more likely to have conduction abnormality (52% vs 9%), mitral valve prolapse (32% vs 9%), and wall motion abnormality (25% vs 0%). Left ventricular ejection fractions and stroke volume were reduced compared with normals. Using multivariate analysis, the number of CTG repeats (range, 69 to 1367; normal, less than 38) was the strongest predictor of abnormalities in wall motion and EKG conduction. Patients with more extensive neurologic findings had a higher incidence of wall motion and/or EKG conduction abnormalities. The authors also found that the relation of mitral valve prolapse to the size of the CTG repeat was of borderline significance.

Cardiac involvement is well described in adults with myotonic dystrophy. Bu'Lock et al. (1999) undertook detailed cardiac assessment in 12 children and young adults with congenital myotonic dystrophy using control data from 137 healthy children and young adults. All patients were in sinus rhythm with a normal P wave axis. Three had first-degree heart block and 4 had a borderline P-R interval (200 ms). Four others had more complex conduction abnormalities. Three patients had mitral valve prolapse. Eleven of the 12 patients had abnormalities of 1 or more parameter of left ventricular diastolic filling. None of these patients were symptomatic. The authors commented that the prognostic implications of these findings were unclear; however, they concluded that echocardiographic assessment of left ventricular diastolic function may be a useful adjunct to electrocardiographic monitoring of patients with congenital myotonic dystrophy.

Antonini et al. (2000) performed a prospective study of 50 DM1 patients without known cardiac disease at the time of enrollment. Nineteen patients developed major cardiac abnormalities during the 56-month study. No correlation was found between CTG length and frequency of EKG abnormality or type of arrhythmia. CTG length was inversely correlated with age at onset of EKG abnormality.

Bassez et al. (2004) reported 11 DM1 patients under the age of 18 years who had severe cardiac involvement. Two patients died suddenly, 1 patient had cardiac arrest with successful resuscitation, and 1 asymptomatic 13-year-old girl presented with recurrent presyncope. Rhythm disturbances included atrial flutter in 4, ventricular tachycardia in 4, and atrial fibrillation in 1. Five patients had atrioventricular block necessitating pacemaker implantation. Six of 11 patients (55%) experienced arrhythmic events with vigorous exercise. Genetic analysis detected between 235 and 1,200 CTG repeats in all patients. No cardiac involvement was detected before age 10 years. Bassez et al. (2004) concluded that patients with congenital or childhood forms of DM1 may present with cardiac abnormalities and that exercise testing is a necessary evaluation in these patients.

Groh et al. (2008) found that 96 of 406 patients with genetically confirmed DM1 had severe ECG abnormalities, and that these patients were older, had more CTG repeats, and had more severe muscular impairment compared to those without ECG abnormalities. After a mean follow-up period of 5.7 years, 69 patients who did not have ECG abnormalities at the start of the study had developed ECG abnormalities and 81 patients died. There were 27 sudden deaths, 32 deaths from progressive neuromuscular respiratory failure, 5 nonsudden deaths from cardiac causes, and 17 deaths from other causes. The major cause of death in the cohort was respiratory failure associated with progressive muscular weakness. A severe ECG abnormality and a clinical diagnosis of atrial tachyarrhythmia conferred relative risks for sudden death of 3.30 and 5.18, respectively.

CONGENITAL MYOTONIC DYSTROPHY

Harper (1975) observed that in a small proportion of cases, myotonic dystrophy may be congenital with neonatal hypotonia, motor and mental retardation, and facial diplegia. With rare exception, it is the mother who transmits the disease. Diagnosis can be difficult if the family history is not known because muscle wasting may not be apparent, and cataracts and clinical myotonia are absent, although the latter is sometimes detectable by electromyography. Fried et al. (1975) observed that infants with neonatal myotonic dystrophy (almost always the mother is affected) have thin ribs. Talipes at birth, together with hydramnios and reduced fetal movements during pregnancy, is frequent. Respiratory difficulties are frequent and are often fatal. Those that survive the neonatal period initially follow a static course, eventually learning to walk but with significant mental retardation in 60 to 70% of cases. By age 10 they develop myotonia and in adulthood develop the additional complications described for the adult-onset disease. Roig et al. (1994) reported long-term follow-up of 18 patients diagnosed with congenital myotonic dystrophy. Three of the 18 had died, and 5 were lost to follow-up. The remaining 10 had IQs of less than 65. Universal findings were language delay, hypotonia, and delayed motor development. There was no difficulty with routine immunizations nor were there anesthetic complications observed in any of the 7 patients who underwent surgery.

Rudnik-Schoneborn et al. (1998) reviewed the obstetric histories of 26 women with myotonic dystrophy who had a total of 67 gestations, comparing gestations with affected and unaffected fetuses. Of the 56 infants carried to term, 29 had or most likely had inherited the gene for DM from their affected mothers; 18 of the 29 (61%) were affected by the congenital form of DM. Perinatal loss rate was 11% and associated with congenital DM. Preterm labor was a major problem in gestations with DM-fetuses (55 vs 20%), as was polyhydramnios (21% vs none). While forceps deliveries or vacuum extractions were required in 21% of deliveries with DM-fetuses and only 5% of unaffected fetuses, the frequency of cesarean sections were similar in the 2 groups. Obstetric problems were inversely correlated with age at onset of maternal DM, while no effect of age at delivery or birth order on gestational outcome was seen.

Stratton and Patterson (1993) established the molecular diagnosis of myotonic dystrophy in a fetus shown to have bilateral effusions and scalp and upper torso edema by ultrasound examination at 30 weeks' gestation. Polyhydramnios was also present. Thus, nonimmune hydrops fetalis is a manifestation of congenital myotonic dystrophy. The mother had previously unsuspected myotonic dystrophy, but she did show grasp myotonia. Her brother had a confirmed diagnosis. The DM gene showed marked expansion in her fetus. Stratton and Patterson (1993) found reports of 15 other cases of nonimmune hydrops fetalis associated with congenital myotonic dystrophy. (Robin et al. (1994) described nonimmune hydrops fetalis in association with severely impaired fetal movement, giving support to the notion that fetal hypomobility is a cause of this disorder. The hydropic infant stopped moving 8 weeks before delivery and did not move postnatally. Autopsy revealed extensive CNS destruction of unknown cause.)

Other Features

Diabetes mellitus occurs in 5% of cases, frequently with hypersecretion of insulin (Barbosa et al., 1974). There is impaired responsiveness to follicle stimulating hormone with hypogonadism (Sagel et al., 1975), often impairment of adrenal androgens, and occasional thyroid dysfunction, but pituitary function is usually intact (Lee and Hughes, 1964). Di Chiro and Caughey (1960) reviewed radiographic findings in the skull in 18 cases. In 17, 'hyperostotic' changes in the vault were found, the sex distribution being equal. In 8 cases with hypogonadism, the hyperostosis was most advanced.

Excessive catabolism of IgG contributes to low circulating levels of IgG (Wochner et al., 1966).

Schwindt et al. (1969) claimed that 25 to 50% of patients have abdominal symptoms due to cholelithiasis. Brunner et al. (1992) described 4 DM patients with recurrent intestinal pseudoobstruction. In 1 patient it preceded significant muscle weakness by 15 years. Conservative measures usually were effective. Improved intestinal function was noted in 1 patient treated with the prokinetic agent cisapride. A partial sigmoid resection was performed in 3 patients with dolichomegacolon. Two of the patients were sibs. Brunner et al. (1992) pointed out that there are many reports of familial occurrence of specific complications of DM: cardiac conduction disturbances, focal myocarditis, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, and dilatation of the urinary tract. Familial idiopathic intestinal pseudoobstruction occurs as an intestinal myopathy (155310) or in a neuronal form (243180); it occurs also in Duchenne muscular dystrophy (310200).

Ciafaloni et al. (2008) found that 17 of 38 patients with DM1 reported excessive daytime sleepiness. Thirteen of these 17 patients underwent sleep studies, and 7 of them showed reduced sleep latency, sleep-onset REM, or both. However, CSF levels of hypocretin (HCRT; 602358), which is implicated in the pathogenesis of narcolepsy (161400), were normal in all 38 DM1 patients.

Biochemical Features

In the cytoplasm of cultured skin fibroblasts Swift and Finegold (1969) found an abnormally large amount of material with the staining properties of acid mucopolysaccharides. Because of the similarity of platelet actomyosin ('thrombosthenin') to that of muscle, Bousser et al. (1975) studied platelets in myotonic dystrophy. Although they found a normal pattern of aggregation in response to adenosine diphosphate and collagen, aggregation occurred with exceedingly low levels of adrenalin. A growing body of evidence was interpreted as indicating a generalized defect of cell membranes in myotonic dystrophy (Butterfield et al., 1974; Roses et al., 1975).

Using antisera developed against synthetic DM-PK peptide antigens for biochemical and histochemical studies, van der Ven et al. (1993) found lower levels of immunoreactive DM-kinase protein of 53 kD in skeletal and cardiac muscle extracts of DM patients than in normal controls. Immunohistochemical staining revealed that DM-PK is localized predominantly at sites of neuromuscular and myotendinous junctions of human and rodent skeletal muscles. The protein could also be demonstrated in the neuromuscular junctions of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organization.

By quantitative RT-PCR and by radioimmunoassay using antisera developed against both synthetic peptides and purified myotonin-protein kinase (Mt-PK) protein expressed in E. coli, Fu et al. (1993) demonstrated that decreased levels of the mRNA and protein expression are associated with the adult form of myotonic dystrophy. From this they suggested that the autosomal dominant nature of the disease is due to an Mt-PK dosage deficiency and that means of elevating Mt-PK level or activity should be explored for therapeutic intervention in adult patients.

Inheritance

This disorder segregates as an autosomal dominant with greatly variable penetrance. Many obligatory gene carriers are asymptomatic. With only rare exception, it is the mother who transmits the disease in cases of congenital myotonic dystrophy. Patients born of affected mothers are more severely affected than those born of affected fathers (Harper and Dyken, 1972). In Japan, Tanaka et al. (1981) also noted the maternal effect in age of onset and severity, and thought that a chemical factor, deoxycholic acid, is responsible for the effect.

Ott et al. (1990) described DNA marker-based genetic counseling in a family with an affected mother and 3 children, each by a different partner. Two of the children were affected. In the third child, myotonic dystrophy could be excluded in the presymptomatic period. In genetic counseling, the recommended risk estimate that any heterozygous woman with myotonic dystrophy will have a congenitally affected child is 3 to 9%. However, after having such an offspring, a DM mother's risk increases to 20 to 37% (Koch et al., 1991). Koch et al. (1991) concluded that the clinical status of the mother at the time of pregnancy and delivery had an important influence on the outcome in the infant. Only women with multisystem effects of the disorder had a congenitally affected child. No heterozygous woman with polychromatic lens changes as the only finding had a congenitally affected child. For classically affected women with systemic manifestations, risk figures that approach the occurrence risk given to mothers with previously born congenitally affected children seemed appropriate. The findings of this study supported the earlier proposal that maternal metabolites acting on a heterozygous offspring account for the congenital involvement. Neither genomic imprinting nor mitochondrial inheritance could explain the correlation between the clinical status of heterozygous mothers and that of their children.

Contrary to the findings and conclusions of Koch et al. (1991), Goodship et al. (1992) described a family in which a 53-year-old woman had no symptoms of myotonic dystrophy, a normal electromyogram, and only dot polychromatic lens opacities on slit-lamp examination. She had, however, given birth 30 years before to a child with congenital myotonic dystrophy. Furthermore, she had a son and daughter with adult onset of symptoms of myotonic dystrophy and another daughter who after normal developmental milestones had early adult onset of symptoms and who gave birth to an offspring with congenital myotonic dystrophy.

Ives et al. (1989) described possible homozygosity for the DM gene. The possible homozygotes were more severely affected than heterozygotes. For a variety of reasons the authors had found it difficult to obtain molecular proof of homozygosity. On the other hand, Cobo et al. (1993) studied a consanguineous French Canadian family in which 2 sisters were homozygous for the 'at risk' haplotype but were asymptomatic and showed no evidence of DM on extensive clinical examination. Both sisters possessed 2 alleles with repeat sizes normally seen in minimally affected patients. Both parents were affected. Martorell et al. (1996) described 3 unrelated homozygous myotonic dystrophy patients. One patient had the classic form of myotonic dystrophy and the other 2 were mildly affected. A remarkable feature was the mildness of the phenotype in the homozygous patients; one, for example, had late-onset cataract as the only manifestation. With the observations of Cobo et al. (1993), this led Zlotogora (1997) to conclude that in myotonic dystrophy, homozygotes do not differ from heterozygotes and that, like Huntington disease (HD; 143100), DM is a 'true dominant.'

Zuhlke et al. (2007) reported 2 additional unrelated cases of homozygous myotonic dystrophy, both products of incestuous unions. Both patients had a severe, congenital phenotype and expanded alleles (330/770 repeats in one patient and 200/1,200 repeats in the other).

On the possibility that mitochondrial genetic modifying factors might be responsible for DM, Thyagarajan et al. (1991) completely sequenced the mitochondrial genome in 2 patients with congenital DM. Comparison of the 2 sequences with control data failed to reveal any specific nucleotide or length variant. After isolation of the gene mutant in myotonic dystrophy and identification of its gene product as a serine-threonine kinase, Jansen et al. (1993) tested for evidence of imprinting of either the paternal or the maternal alleles in both human and mouse tissues. No evidence of imprinting was found involving the expression of the DM kinase gene.

Jansen et al. (1994) used the term gonosomal mosaicism to refer to combined somatic and germline mosaicism which they demonstrated in DM. Studies of variation in the (CTG)n repeat in sperm and body cells of the same individual were demonstrated. The rather frequent observation of offspring with triplet repeat length larger than that found in sperm suggested that intergenerational length changes in the unstable (CTG)n repeat occur during early embryonic mitotic divisions. The initial size of the (CTG)n repeat, the overall number of cell divisions involved in tissue formation, and a specific selection process in spermatogenesis may all influence variation in repeat size.

Carey et al. (1994) examined meiotic drive and segregation distortion at the DM locus. The study was undertaken because the haplotype analysis of DM chromosomes had detected a very limited pool of founder chromosomes (Harley et al., 1992; Mahadevan et al., 1992), raising the question of how a disease that usually decreases reproductive fitness within a few generations has been maintained in the population over hundreds of generations. Carey et al. (1994) found that healthy individuals heterozygous for DM alleles in the normal size range preferentially passed on alleles of more than 19 CTG repeats to their offspring. They suggested that this phenomenon may act to replenish a reservoir of potential DM mutations and that this distortion of the transmission ratio may offer an example of meiotic drive in humans. This segregation distortion may act as a mechanism to maintain alleles in the population that lie at the larger end of the normal range in the trinucleotide repeat disorders. It was unclear whether the segregation distortion was a direct consequence of the CTG repeat number or whether the preferential transmission of the larger allele was due to linkage to segregation distorting loci on the same chromosome.

Martorell et al. (2001) studied the frequency and germline stability of DMPK (605377) alleles in an effort to understand the constant population incidence of the disease despite its low reproductive fitness. The authors analyzed the DMPK CTG repeat length in more than 3,500 individuals from 700 Spanish families. A trimodal distribution of CTG repeat lengths in the normal population was observed: 5 repeats, 9-18 repeats, and 19-37 repeats. Five-repeat alleles and 9- to 18-repeat alleles were stably inherited. The third mode, 19-37 repeats, was skewed toward increasing allele length with frequent de novo expansions. The authors also analyzed alleles with repeat lengths of 38-54 repeats, or 'premutation' alleles. Individuals with premutation alleles were asymptomatic. Premutation alleles were found to be very unstable and liable to frequent large expansions in the male germline, with expansion observed in 25 of 25 transmissions. Sperm from a premutation carrier demonstrated a range of diverse alleles positively skewed toward expansion. Martorell et al. (2001) concluded that the incidence of DM1 is likely maintained in the population by expansion of alleles within the normal range to the premutation range and subsequently into the disease-manifesting range in successive generations.

Leeflang et al. (1996) directly analyzed meiotic segregation and the question of meiotic drive at the DM locus using single-sperm typing. They studied samples of single sperm from 3 individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than the 19 CTG repeats. To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size of the DM locus: D19S207 in 2 donors and D19S112 in the third. Using statistical models specifically designed to study single-sperm segregation data, they found no evidence of meiotic segregation distortion. This suggested to Leeflang et al. (1996) that any greater amount of segregation distortion at the DM locus must result from events following sperm ejaculation.

Magee and Hughes (1998) studied 44 sibships with myotonic dystrophy. When the transmitting parent was male, 58.3% of the offspring were affected, and when the transmitting parent was female, 68.7% were affected. Overall, the DM expansion was transmitted in 63% of cases. Magee and Hughes (1998) concluded that DM expansion tends to be transmitted preferentially.

Nakagawa et al. (1994) described 2 sisters with congenital myotonic dystrophy born to a normal mother and an affected father. The sisters had symptoms from birth. The age of onset of DM in the father was 39 years. Analysis of the CTG trinucleotide expansion in this family showed increase in the repeat length with increasing severity, with the smallest expansion in the grandfather and the largest expansion in the younger of the 2 affected sisters. The observation refutes the hypothesis that congenital DM is exclusively of maternal origin.

Bergoffen et al. (1994) observed inheritance from a mildly affected father. This family illustrated that the congenital form can occur without intrauterine or other maternal factors operating. Nakagawa et al. (1993) also reported a case of congenital myotonic dystrophy inherited from the father. De Die-Smulders et al. (1997) reported a further case of congenital myotonic dystrophy inherited from the father. The patient was a 23-year-old, mentally retarded male suffering from severe muscular weakness who presented with respiratory and feeding difficulties at birth. His 2 sibs suffered from childhood-onset DM, whereas their father had adult onset of DM at around 30 years of age. De Die-Smulders et al. (1997) reviewed 6 other cases of paternal transmission of congenital DM and found that the fathers of these children showed, on average, shorter CTG repeats and hence less severe clinical symptoms than the mothers of children with congenital DM. The authors concluded that paternal transmission of congenital DM preferentially occurs with onset of DM past 30 years of age in the father.

Zunz et al. (2004) examined whether myotonic dystrophy exhibits the phenomenon of preferential transmission of the larger mutated alleles that had been described in other trinucleotide repeat disorders. They cited several reports (e.g., Carey et al., 1994; Leeflang et al., 1996; Magee and Hughes, 1998) indicating that the frequency of transmission of the mutated alleles is higher than 50%, a finding contrary to mendelian laws of segregation. However, these studies were based on data from the analysis of pedigrees with ascertainment bias. Zunz et al. (2004) determined the frequency of transmission of mutated alleles using data from prenatal molecular studies, which were not subject to ascertainment bias. Eighty-three fetuses were examined. Thirty of 62 mothers (48.38%) and 8 of 21 fathers (38.09%) transmitted the mutated allele, giving an overall transmission rate of 45.78%. Zunz et al. (2004) found no evidence of statistically significant deviation of the frequency of transmission of the mutated alleles from the 50% expected in autosomal dominant disorders. Unlike previous studies, the study of Zunz et al. (2004) excluded preferential transmission in myotonic dystrophy, a finding they concluded might be attributable to the lack of correction for ascertainment bias in previous studies and to the use of prenatal data in their study.

Zeesman et al. (2002) reported a child with congenital DM and 1,800 CTG repeats born to an asymptomatic father with 65 repeats and compared the case to 4 previously reported cases. They noted that polyhydramnios was present in most cases and that all fathers whose status was known had small repeat sizes and/or were asymptomatic at the time of their child's birth.

In a study of mitochondrial DNA from 35 patients with congenital myotonic dystrophy, Poulton et al. (1995) could find no evidence that mutations in mtDNA are involved in the pathogenesis of congenital myotonic dystrophy. Associated mitochondrial mutations might help account for the maternal inheritance pattern and the early onset of the congenital form.

Mapping

The linkage of secretor (Se; 182100) and myotonic dystrophy was suspected by Mohr (1954) when he was doing the studies that demonstrated the first autosomal linkage in humans, that between secretor and Lutheran blood group (Lu; 111200). Mohr (1954) failed to establish fully the DM linkage because of the relative insensitivity of the sib-pair method of linkage analysis he was using (Smith, 1986). Renwick et al. (1971) confirmed the linkage. The Lu-Se-DM linkage group and the Km (Inv)-Jk-Co linkage group were tentatively tied together by a family with myotonic dystrophy reported by Larsen et al. (1979, 1980). From study of a single large kindred, Larsen et al. (1979) suggested that Km and Jk are linked to myotonic dystrophy. An order of Km, Jk, Lu, Se, and DM was suggested. No recombination in 7 informative meioses occurred between Km and Jk, none in 5 between Se and DM, 3 out of 10 between Jk and Se, and 3 in 12 between Jk and DM.

Eiberg et al. (1981, 1983) concluded that C3 (120700), Le (111100), myotonic dystrophy, secretor, and Lutheran are linked. Since fibroblast C3 had been assigned to chromosome 19, the finding indicated that myotonic dystrophy is on chromosome 19, providing serum C3 (polymorphism of which was used in the above linkage studies) is under the same genetic control (or at least syntenic genetic control) as fibroblast C3.

Cook (1981) had found positive lod scores for serum C3 and peptidase D (613230), a chromosome 19 locus. Linkage of peptidase D to myotonic dystrophy (O'Brien et al., 1983) proved the assignment of the Lutheran-secretor linkage group to chromosome 19 and provided regional assignment. Using an RFLP related to a C3 probe, Davies et al. (1983) found evidence of linkage with myotonic dystrophy. Laberge et al. (1985) found a lod score of 4.574 at a recombination fraction of 0.12 for linkage of DM and APOE (107741) in French Canadians (males and females combined). Meredith et al. (1985) found close linkage (maximum lod = 7.8 at 4% recombination) of DM to APOC2 (608083). APOE and APOC2 are known to be closely linked.

Brook et al. (1985) concluded that the DM locus is probably in the 19p13.2-19cen segment. Friedrich et al. (1987) quoted studies of somatic cell hybrids carrying various fragments of chromosome 19 that provide unambiguous proof for location of the PEPD gene on 19q, thus corroborating the assignment of DM to that region. The hereditary motor and sensory neuropathy in the family described by Jamal et al. (1986) showed segregation with genetic markers known to be linked to myotonic dystrophy on chromosome 19. Spaans et al. (1986) raised the question of whether the disorder might be caused by an allele of the 'common' DM gene or alternatively by 2 closely linked genes on chromosome 19.

Shaw et al. (1986) reviewed gene mapping of chromosome 19 with particular reference to myotonic dystrophy. Suppression of recombination near the centromere and the large male-female differences in recombination are 'complications' of linkage mapping of the DM locus and use of linkage markers in genetic counseling. Shaw et al. (1986) concluded from linkage studies that myotonic dystrophy is located in the region of the centromere of chromosome 19.

Roses et al. (1986) described RFLPs at the D19S19 locus, which is linked to DM (maximum lod = 11.04 at theta = 0.0). Bartlett et al. (1987) reported that the genomic clone called LDR152 (D19S19) is tightly linked to DM; the maximum lod score was 15.4 at a recombination fraction = 0.0 (95% confidence limits 0.0-0.03). Using 2 RFLPs of the APOC2 gene, Pericak-Vance et al. (1986) demonstrated tight linkage to myotonic dystrophy; the maximum lod score was 16.29 at a recombination fraction of 0.02.

In 3 large kindreds, Friedrich et al. (1987) did linkage studies using RFLPs related to the C3 gene and the chromosome 19 centromeric heteromorphism as genetic markers. Three-point linkage analysis excluded DM from the 19cen-C3 segment and strongly supported its assignment to the proximal long arm of chromosome 19.

Harper (1986) demonstrated 2 to 5% recombination between myotonic dystrophy and APOC2, leading him to the conclusion that myotonic dystrophy may be just onto 19q or very close to the centromere on 19p. Bird et al. (1987) concluded that the APOC2 gene is very closely linked to the DM locus and proposed that APOC2 markers may be used for prenatal diagnosis of myotonic dystrophy because the loci are closely linked. Smeets et al. (1988) used synthetic oligonucleotides to discriminate between E3 and E4 alleles of APOE. The relevant segment of the APOE gene was enzymatically amplified and linkage with DM tested. A maximum lod score of 7.47 at a recombination frequency of 0.047 was found (male theta = female theta). No recombination (maximum lod score = 5.61 at theta = 0.0) was found between APOE and APOC2. Further analysis of the relationship of the human APOC2 gene to myotonic dystrophy was provided by MacKenzie et al. (1989), who reported a linkage study utilizing 6 RFLPs in 50 families with myotonic dystrophy. They observed significant linkage disequilibrium between the DM locus and APOC2 alleles. The maximum lod score was 17.869 at a theta of 0.04.

Bender et al. (1989) found no evidence of linkage with any of 35 serologic and biochemical markers. Brunner et al. (1989) concluded that the DM and CKMM loci are distal to the APOC2-APOE gene cluster; the orientation of DM and muscle-type creatine kinase (CKMM; 123310) was undetermined.

Johnson et al. (1989) presented evidence that DM is distal to the apolipoprotein cluster. Yamaoka et al. (1990) found a maximum lod score of 28.41 at theta = 0.01 for the linkage between CKMM and DM. They concluded, furthermore, that CKMM is on the same side and closer to DM than APOC2. Walsh et al. (1990) found a peak lod score of 9.29 at 2 cM for linkage of DM to APOC1 (107710) and a lod score of 8.55 at 4 cM for linkage of DM to CYP2A (122720). A maximum lod score of 9.09 at theta = 0.05 was observed for the linkage of APOC1 to CYP2A. CYP2A appeared to be proximal to DM, CKMM, and APOC2.

Smeets et al. (1989), Davies et al. (1989), Roses et al. (1989), Brunner et al. (1989), Harley et al. (1989), Brook et al. (1989), and Miki et al. (1989) presented linkage data for markers surrounding the myotonic dystrophy locus on human chromosome 19. Smeets et al. (1989) and Davies et al. (1989) also presented physical maps of the region derived from pulsed field gel electrophoresis analysis.

In a study of 65 myotonic dystrophy families from Canada and the Netherlands, Brunner et al. (1989) obtained a maximum lod score of 22.8 at a recombination frequency of 0.03 for linkage to CKMM. MacKenzie et al. (1990) ruled out a defect of the RYR1 gene (180901) as the cause of myotonic dystrophy; the 2 loci showed an interval of about 10 cM (maximum lod = 4.8). The order of loci was found to be 19cen--RYR1--APOC2--CKMM--DM--qter.

Bailly et al. (1991) excluded mutation of the CKMM gene as the cause of this disorder. CKMM cDNA was isolated from the skeletal muscle of an individual with DM. Sequencing of the CKMM cDNA from the chromosome 19 carrying the DM gene showed 2 novel polymorphisms but no translationally significant mutation.

Harley et al. (1991) concluded that the DM gene lies in region 19q13.2-q13.3 and that the closest proximal markers are APOC2 and CKM, approximately 3 cM and 2 cM from DM, respectively, in the order cen--APOC2--CKMM--DM. Ten of 12 polymorphic markers on 19q were shown to be proximal to the DM gene; the 2 that were distal to DM, PRKCG (176980) and D19S22, were approximately 25 cM and 15 cM, respectively, removed from DM.

Brunner et al. (1991) restudied the family reported by Spaans et al. (1986), ruled out linkage to chromosome 17 markers, thus excluding the gene (601097) associated with Charcot-Marie-Tooth disease, type Ia (118220), and demonstrated linkage to DNA markers from the APOC2 locus on chromosome 19. All affected individuals had inherited a unique APOC2 haplotype that was not found in their clinically and electrophysiologically normal sibs. In this family, a moderately severe neuropathy appeared to be the only clinical sign of myotonic dystrophy for many years. The results were consistent with either an unusual neuropathic mutation in the DM gene or involvement of 2 closely linked genes.

Linkage studies by Cobo et al. (1992) established the D19S63 marker as useful for prenatal and presymptomatic diagnosis and, as the closest marker to DM, in isolating the gene.

Molecular Genetics

Identification of an Expanded Triplet Repeat

Harley et al. (1992) isolated a human genomic clone that detected novel restriction fragments specific to persons with myotonic dystrophy. A 2-allele EcoRI polymorphism was seen in normal persons, but in most affected individuals one of the normal alleles was replaced by a larger fragment, which varied in length both between unrelated affected individuals and within families. The unstable nature of this region was thought to explain the characteristic variation in severity and age at onset of the disease.

From a region of chromosome 19 flanked by 2 tightly linked markers, ERCC1 (126380) proximally and D19S51 distally, Buxton et al. (1992) isolated an expressed sequence that detected a DNA fragment that was larger in affected persons than in normal sibs or unaffected controls.

Aslanidis et al. (1992) cloned the essential region between the above mentioned markers in a 700-kb contig formed by overlapping cosmids and yeast artificial chromosomes (YACs). The central part of the contig bridged an area of about 350 kb between 2 flanking crossover borders. This segment, which presumably contained the DM gene, was extensively characterized. Two genomic probes and 2 homologous cDNA probes were situated within approximately 10 kb of genomic DNA and detected an unstable genomic segment in myotonic dystrophy patients. The length variation in this segment showed similarities to the instability seen in the fragile X locus (300624). The authors proposed that the length variation was compatible with a direct role in the pathogenesis of myotonic dystrophy.

Using positional cloning strategies, Brook et al. (1992) identified a CTG triplet repeat that is larger in myotonic dystrophy patients than in unaffected individuals. This sequence is highly variable in the normal population. Unaffected individuals have between 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat-containing segment up to several kilobase pairs.

Tsilfidis et al. (1992) found a correlation between the length of the CTG trinucleotide repeat and the occurrence of severe congenital myotonic dystrophy. Furthermore, mothers of congenital DM individuals had higher than average CTG repeat lengths.

Shelbourne et al. (1993) described a probe that allowed direct identification of the myotonic dystrophy mutation in 108 of 112 unrelated patients. In 3 families for whom the clinical and genetic data obtained with linked probes were ambiguous, the specific probe identified persons at risk and demonstrated that a possible sporadic case of myotonic dystrophy was, in fact, familial. In 1 family, the size of the unstable myotonic dystrophy-specific fragment decreased on transmission to offspring who remained asymptomatic, which was an example of the reverse of anticipation.

Thornton et al. (1994) reported the clinical findings, muscle pathology, and genetic data on 3 individuals from 2 families with myotonic dystrophy in whom no trinucleotide repeat expansion