S E M I N A R S I N NEUKOLO(;Y-VOI.UME
1I, NO. 3
SEPTEMBER 1991
Myotonic Dystrophy
Myotonia is frequently described by patients as a feeling of "stiffness."' Patients with myotonic dystrophy (MyD) are rarely disabled by this syrnptom. T h e importance of their complaint lies in the other neurologic, systemic, and hereditary manifestations of MyD.
CLINICAL FEATURES T h e presenting symptom of most patients with My11 is muscular w e a k n e s 2 Other common manifestations include complaints of stiffness o r difficulty releasing objects, mental retardation, and cataracts. Also, a number of asymptomatic patients are discovered through family investigations. T h e pattern of muscle weakness characteristic of MyD helps differentiate this disorder from other neuromuscular disease^.^," Wasting and weakness of facial muscles give a "hatchet facies" appearance that is typical of these patients (Fig. 1). Ptosis and lower facial weakness may be asymmetrical and can give the impression that patients are sleepy o r depressed. Restriction of extraocular muscle movements occurs but is not common. T h e jaw may hang open because of' masseter and temporalis weakness and severely affected patients may have difficulty with saliva d u e to palatal and pharyngeal weakness. Slurred speech and dysphagia are common. Aspiration pneumonia is a serious consequence of' palatal and pharyngeal weakness. Sternocleidomastoid atrophy and weakness are prominent and may occur early in the course of disease. This results in weakness of neck flexor muscles out of proportion to neck extensor muscle weakness. T h e marked atrophy of neck muscles produces the appearance of a long, thin, "swan neck."
MyD is unlike most myopathic processes because limb involvement is more severe distally (Fig. 2). Wrist, finger, and ankle extensors are atrophic and weak. As the disease progresses, generalized weakness occurs and may eventually affect respiration. T h e severity of symptoms is variable and rate of progression is slow. Congenitally affected se with prominent tmlinfants h a ~ ~ d i f f uhypotonia bar and respiratory dysfunction. In these children, strength develops in early years only to decline in later life. Myotonia is a delay in muscle relaxation time. This is perceived as stiffness o r difficulty in releasing objects, especially after prolonged gripping. Affected patients relate slowness initially in running o r walking but are not as symptomatic after warmup.? Grip o r percussion myotonia can be demonstrated on examination. Difficulty relaxing a forceful grip is evident and percussion of the thenar muscles, wrist extensors, and tongue reveals myotonia. Tongue percussion is best performed with a tongue blade resting on the tongue. Most MyD patients will demonstrate myotonia but it may be absent in infants, children, and patients with severe weakness. 'I'he age of onset of MyD is often difficuh to determine because of' long asymptomatic periods. 'l'he median age of onset is between 20 and 25 years." Eighty percent of patients will be affected by age 50. Some authors group patients by age because presentations for each age group are often different." Infants o r young children presenting with the congenital form are born to affected mothers. They are the most affected cognitively. Adolescents and young adults complain of progressive facial and limb weakness. Older adults may demonstrate minimal muscle weakness but cataracts may
*Associate, Division of Neurology, Department of Medicine, I h k e University Medical Center, Durham, North Carolina tAssistant Director, Electromyography Laboratol-y, Assistant Professor, Division of. Neul-ology, Department of' Medicine, Duke University Medical Center, Durham, North Carolina Reprint requests: Dr. J . Massey, Box 3403, I h k e University Medical Center, Dur-ham, NC 27710 Copyright O 1991 by 'Thienie Medical Publishers, Inc., 381 Park Avenue South, New York, N1' 100 16. All rights reserved.
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Joel C. Morgenlander, M.D.," and Janice M . Massey, M.D. i-
T h e differential diagnosis based on neuromuscular signs and symptoms includes other muscular dystrophies (for example, facioscapulohumeral dystrophy), other myotonic syndromes, nonprogressive rnyopathies (congenital myopathies), and myasthenia gravis. In adults, confusion with neuropathies is rarely a problem because the sensory examination is normal and reflexes are normal o r slightly hypoactive early. T h e medical history, hmily history, detailed physical examination, and supportive laboratory data lead to the appropriate diagnosis.
Figure 1. Characteristic facial features of a patient with myotonic dystrophy: temporal wasting, frontal balding, ptosis, and weakness of lower facial muscles producing a "fishmouth" appearance.
cause visual symptoms. Anticipation, onset of' the disease at an earlier age in subsequent generations, is a topic of dehate (see "Genetics"). T h e severity of disability incurred as a consequence of MyD relates to the degree of physical (neurologic arid systemic), cognitive, and social impairment in each patient. In one study, 20% of affected men and 50%)of women had never worked." Long-term prognosis for each individual is best determined by clinical course and evaluatiori of neurologic and systemic manifestations.
Figure 2. Thin, tapering forearm and hand demonstrating distal atrophy in a patient with myotonic dystrophy.
T h e diagnosis of' congenital MyD is often difficult to confirm. T h e condition occurs in about 1 in 3500 live births and almost exclusively in children of affected mother^.',^ Neonatal respiratory distress requiring ventilatory support may be the first symptom. Kespiratory insufficiency is due to muscular weakness and hypotonia, elevated right diaphragm, and decreased central ventilatory drive.7 Prognosis for long-term survival is poor if the neonate requires ventilatory support for more than 4 weeks." Myopathic f'acies, not specific for MyD, is frequently present in congenitally affected patients. This consists of a tent-shaped mouth with a short, anteverted philtrum. l'he jaw may hang open as in adults and feeding difficulties occur because of facial and pharyngeal weakness. Generalized hypotonia often is overlooked because other problems are so severe. Improvement usually occurs over weeks to months. Delay in motor milestones is expected. Clues to muscle weakness in utero include decreased fetal movements, polyhydramnios caused by decreased swallowing by the fetus, thin ribs from decreased respiratory movements, and pes equinovarus and arthrogryposis due to poor limb m o ~ e m e n t . ' .Cognitive ~ delay and mental retardation occur in 70% of these children.' Cerebral imaging at birth may disclose ventricular dilation, which is nonprogressive, although progressive dilation associated with intraventricular hemorrhage, subarachnoid hemorrhage, o r white matter infarcts does occur."' Differential diagnosis in affected neonates includes other causes of' neonatal hypotonia: Werdnig-Hoffmann disease, congenital myopathy, neonatal myasthenia gravis, and hypotonia d u e to central nervous system (CNS) disorders. Neonates rarely have clinical m y o t ~ n i a Furthermore, .~ electrical evidence of myotonia is frequently lacking (see "Electromyography"). Muscle biopsy may
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CONGENITAL MYOTONIC DYSTROPHY
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demonstrate hypoplasia of muscle with decreased fiber diameter.'' Muscle may not develop normally, since fibers fail to differentiate into specific fiber types.' Diagnosis is often made by recognizing the clinical presentation and examining- family members, especially the mother. Often, the parents will be asymptomatic. If examination of family members is unrevealing, electrophysiologic study o r muscle biopsy of the neonate may disclose other causes. It remains unclear why congenitally affected patients are born to mothers with M y D An environmental abnormality in utero, a circulating factor, o r both are thought to be i n v o l ~ e d . ~ , "
ELECTROMYOGRAPHY
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T h e electromyographic expression of clinical rnyotonia is the myotonic discharge. This characteristic rhythmic discharge is recorded with a needle electrode after voluntary contraction of a muscle o r following needle in~ertion.':~ Sustained trains of positive sharp waves probably arise from one muscle fiber. Trains of' negative spikes occur after muscle contraction. These discharges exhibit waxing and waning frequency and amplitudes, giving rise to the typical "dive-bomber" o r motor-cycle engine sound. 'The physiologic correlate fbr the myotonic discharge in MyD is still uncertain but decreased chloride conductance in the sarcolemma and abnormal N a + , K f -A7TPaseactivity have been implicated. I" I n order to differentiate myotonic discharges from endplate activity, it is suggested that: (1) duration of the discharges be over 500 msec, and (2) discharges occur in three o r more areas o f t h e muscle.lWyotonic discharges are not specific for MyD; they occur in other "myotonic" disorders. These include rnyotonia congenita, autosomal recessive generalized myotonia, paramyotonia congenita, and periodic paralysis. Examination and electrophysiologic tests permit differentiation of these syndromes.I5 In paramyotonia congenita, when the examined site is cooled, there is an increase in stiffness, with weakness and a decrernental response to repetitive nerve stimulation. In autosomal recessive generalized myotonia, large, early decrements can be found after exercise o r repetitive nerve stimulation. Weakness from periodic paralysis is particularly sensitive to prolonged exercise and potassium concentration. Myotonia congenita is best differentiated from MyD by the lack of significant weakness o r systemic manifestations. Disorders other than the rnyotonic syndromes may demonstrate rnyotonic discharges during electroniyography. 'These include polymyositis, acid
VOL.UME 11, N U M B E R 3
SEP'I'RIMH~.,'~~ 1991
maltase def'iciency, and some chronic denervating disorders. ':' Myotonic discharges are often absent in neonates and young ~ h i l d r e nalthough ,~ electrical myotoriia was reported in a 5-day-old infant with congenital MyD.'" Electrical myotonia is found when clinical myotonia is present and may be found in asymptomatic carriers." Not all muscles exanlined electrically demonstrate niyotonia with equal frequcncy. Electrical myotonia was found in all niuscles tested in only 3 of 25 patients with MyD.'' Distal extremity and facial muscles had the highest frequency of abnormalities. T h e most frequently abnormal muscles were the abductor pollicis brevis arid flexor pollicis longus (96% each) and the orbicularis oculi (95%).Proximal muscles, such as the deltoid ( 3 8 % )and vastus lateralis (48%,),were least often abnormal. T h e sensitivity of a routine electromyographic study searching for rnyotonia will thus depend on the site and number of nluscles examined. Abnormalities of motor unit potentials have also been described in Myl)." Motor unit potentials may show myopathic ftatures such as short duration, low amplitude, and increased conlplexity.'" T h e percentage of myopathic motor units may be higher in older patients and those with more severe disease."' Motor unit potential duration may also be increased in a minority of patients."' Abnormalities of nerve conduction are inconsistently found in patients with My11 and d o not correlate with severity of disease."' Slowing of conduction velocity, which is usually mild, has been tlescribed in both motor and sensory nerves."~" Prolonged F-wave latencies also occur." Decreased sensory action potential amplitudes and increased thermal and vibratory detection thresholds are fi)uncl in a minority of patients.'" IL is unclear whether these neuropathic changes are an inherent part of MyD o r related to another process. Decrement of the compound motor action potential after repetitive stimulation o r exercise is common in MyD.24.'j T h e degree of decrement is dependent on niuscular rest of at least 3 minutes prior to stimulation and does not necessarily correlate with the degree of weakness."' It may take .. several seconds of repetitive nerve stimulation for a decrement to become apparent. This is unlike the situation in primary diseases o f t h e neuromuscular junction. 1nrreasei neuromuscularjitter arid fiber density are also described in patients with Myl)." Thejitter abnormalities may include paired blocking and double discharges, suggesting a neurogenic cause. Finally, autonomic nervous system dysfunction as demonstrated by abnormal latency of the
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SEMINAKS I N NEUKOI.OGY
conduction delays."%earing acuity is abnormal in some patients because of a sensorineural defect.:'" Electroretinography may be abnormal and visual evoked potentials can show prolongation of the 1'100 latency.") Decreased maximum velocity of OTHER NEUROLOGIC MANIFESTATIONS saccades with normal smooth pursuits has also Intellectual and cognitive dysfunction are fre- been described."' T h e sum of these findings demquently present. As many as one third of patients onstrates the widespread abnormalities in the cenhave low Wechsler iQ test scores."' I n studies in tral and peripheral nervous systems. Electroencephalographic abnormalities are unwhich inheritance pattern is considered, My11 patients with maternal inheritance are more likely to common but when present consist of mild genershow cognitive deficits on standard neuropatho- alized slowing in the theta range."' Sleep disturlogic testing than those with paternal inheritan~e.:~"bance is common in patients with MyD. I n one Some authors believe that those affected at a study of eight patients, all had disrupted sleep arid younger age have more serious intellectual and six had pathologic apnedhypopnea indexes, two n.' in sex of the with progressive oxygen d e ~ a t u r a t i o n . ~T' h e apcognitive ~ l ~ s t i ~ n c t i o Differences patients d o not seen1 to play a role.") Longitudinal neas occurred at rest, and in all stages of sleep and study of the intellectual dyshnction in MyD sug- were most often central. Abnormal multiple sleep gests that deterioration over the short term (3 latency tests and obstructive sleep apnea have been years) is not significant but may occur over longer reported.:" periods.:" Personality profiles show proniirient abnorPATHOLOGY malities in 32%) of patients, most commonly those with cognitive o r physical handicaps.'" Passive-agMuscle biopsy rarely is needed to confirm the gressive traits, emotional and social immaturity, and depression were seen most often. One study diagnosis of MyD unless the clinical features o r of clepression compared normal subjects, adults family history are not typical. A muscle biopsy is with paraplegia, and patients with limb-girdle useful to exclude other diagnostic possibilities that dystl-ophy to patients with MyD.:'MyD and limb- may produce clinical o r electrical myotonia (polygirdle dystrophy patients had significantly more myositis, acid maltase deficiency). Characteristic pathologic features include indepression, suggesting that depression may be related to progressive physical disability rather than creased numbers of internal nuclei, ringed fibers, sarcoplasmic masses, type 1 fiber atrophy, type 2 an intrinsic feature of the disease. Neuropsychiatric testing and magnetic reso- fiber hypertrophy, fiber splitting of spindles, and nance imaging may bc correlated."" Twenty-bur increased terminal arborization.'.'" These changes percent of patients had severe generalized intellec- are not specific for MyD but their presence makes tual dysfunction, which was linked to maternal in- the diagnosis probable. In a study of muscle biopheritance and earlier onset rather than the degree sies from 43 patients with MyD, the first five feaof weakness. There was an increased incidence of tures just described were catalogued." All five feafhcal white matter lesions, anterior temporal lobe tures were found in f u r patients (9%). 'Iivo o r abnormalities, and increased skull thickness in fewer of these features were found in 28 patients those with severe cognitive impairment. Cortical (65%).Ragged red fiber changes due to increased and fbcal cerebral atrophy did not correlate with nunlbers of mitochondria have rarely been dethe cognitive tests. ' I h e etiology of the radio- scribed and are thought to be a secondary phegraphic abnormalities is uncertain. Other magnetic nomenon.'.' Thus, muscle biopsy has limited specresonance imaging studies showed increased ven- ificity in the diagnosis of MyD. Pathologic changes have been found in some tricular size in 7 1% of patients and increased periventric~~lar"lumpy" hyperintensity in 42% of nerve specimens from patients with MyD. Sural p~ients.:" Further studies are needed to corre- nerve biopsies from affected patients demonlate these findings with pathologic specimens. strated abnornialities, most consistent with an axC o m p ~ ~ t e dtomography demonstrates cerebral onopathy, in 1 1 of 13 biopsies."' Rare cases with atrophy o r normal pressure hydrocephalus in nerve hypertrophy have also been reported.'" Sollie caSeS.?9.'i5 T h e CNS has been the focus of more recent Somatosensory evoked potential studies in af- pathologic study. Intracytoplasmic inclusion bodies fected patients show both peripheral and central in the thalanius and substantia nigra, Marinesco conduction delays.:"',"' Brainstem auditory evoked bodies in the substantia nigra," and abnormalities Furpotentials also show both peripheral and central in cortical architecture have been de~cribed."~
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pupillary light reflex, dark adaptation, and cardiac K K interval variation has been described."
239
ther pathologic study with clinical correlation may lead to explanations for cognitive and other central dysfunction in these patients.
SYSTEMIC MANIFESTATIONS
240
V0I.UME 1 I, NUMBER 3
SEPTI:'IWHEK I991
in muscle but f'u~ictional benefit has riot been in whole-body insulin sens h o ~ n . " ' . "A~ decrease ~ sitivity may also contribute to muscle wasting."' 1%dr'lthyroid .. function can be increased in some patients and an association with primary hyperparathyroidism and multiple endocrine neoplasia, type 2A has been reported.""-hx Amenorrhea and menstrual disturbances are common."!' Pregnancies are high risk anti may result in fetal l o ~ s . ~ ~ "Muscle ! ' ~ ~ " weakness and symptomatic myotonia may worsen during pregnancy, often in the third trimester. Karely, symptoms appear first during pregnancy. Impro\ernent may occur early after delivery."" Mothers have a high incidence of spontaneous abortion, premature delivery, and neonatal death. Second trin~esterabortions are attributable to uterine involve~nent.~' I'reiiiature labor and abnormalities in all stages of labor are caused in part by uterine dysfunction."!' Ketained placenta and postpartum hemorrhage
Cardiac dysfunction is prominent. U p to 90% of patients have an electrocardiographic (ECG) abnormality, although most are asymptomatic."" An abnormal ECG is more common in severely affected patients." I n mildly affected patients, firstdegree atrioventricular block and left anterior hemiblock are common, whereas atrial fibrillation o r flutter, Q waves, and repolarization abnormalities are seen in more disabled patients."' T h e most common electrophysiologic abnormality is a prolongation of'the interval from the bundle of His t o ventricular conduction, but other conduction defects are found.52 Mitral valve prolapse is more common in My11 0ccLlr~li!l,72 Granulocyte dysfunction may be severe." Impatients; this finding may relate to body habitus."" Sudden death, the most feared cardiac cornpli- munoglobulin abriornlalities related to abnormal cation, occurs in 4%.'" This may be due to brady- distribution of immunoglobulin G cause lower levarrhythmias o r to tachyarrhyth~nias such as re- els in some patients.74 current ventricular tachy~ardia."~""l'here is Ocular manifestations of MyD are frequent. replacement of myocardiuni by fibrous o r fatty tis- lypical nlulticolored, subcapsular cataracts are losue in some patients." Close clinical arid ECG fol- cated in anterior o r posterior zones in 90% of aflow-up to detect changes such as progressive heart fected p a t i e n t ~ . ~ W t h eless r characteristic lens block can lead to treatment before a cardiac corn- changes, such as cortical spokes and snowball forplication occurs. mations, are common but are not diagn~stic.'~' CatRespiratory coniplications include aspiration aracts are not seen in patients under 10 years of pneumonia, susceptibility to respiratory depres- age. I n older individuals, nondiagnostic cataracts sants, and central hypoventilation.""" Chest wall o r prior cataract removal makes diagnosis more mechanics may be affected by muscular myotonia diff'icult. Pigmentary retinopathy and macular changes are rather frequent.',7" and cause diff'iculty with artificial ventilation."' Complications from general anesthesia inGastrointestinal symptoms from upper o r lower tract dysfunction are common.' Smooth muscle clude increased sensitivity to CNS depressants, dysfunction causes delayed esophageal and gastric which may prolong -- length of artificial ventilation emptying times."!' Degeneration of' the myenteric postoperatively." 1)epolarizing agents such as sucplexus occurs in some patients.") Fecal impaction and cinylcholine can cause increased rnyotonia, making megacolon may result horn colonic dysfunction. intubation and ventilation difficult, but this is more Smooth muscle abnorinalities lead to gallbladder, common in other rnyotonic syndromes.ix Maligureteral, uterine, and ciliary body dysfunction.' Mild nant hyperthermia is an uncommon complication.' elevation of serum gamma-glutarnyltransferase may Cardiac monitoring is required because -- of frequent underlying rhythm disturbances." reflect liver in~olvement."~ Endocrine abnormalities are common. Early balding in males is typical although n o n s p e ~ i f i c . ~ GENETICS Testicular atrophy, degeneration of tubule cells, and hyperplasia of Leydig cells are common in MyL) is an autosomal dominant disease with ma1es.l.' Low testosterone and elevated gonadotropin levels are found consistently in males, whereas variable penetrance and expressivity." Incidence is females usually have normal gonadotropin lev- estimated at 5 per 100,000.7' Since the abnormal els.'."' T h e decreased testosterone levels may con- gene product is unknown, current gene linkage tribute to decreased muscle mass through an ana- studies utilizing probes near the affected gene will bolic d e f e ~ t . " ' Exogenous ~ testosterone given to locate and ultimately characterize the gene and its patients with MyD increases protein synthesis protein p r o d u ~ t . ~If" linkage of the MyD locus is
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S E M I N A R S I N NF,UROI.O(;Y
M Y O T O N I C DYSTROPHY-MORCENLANDER, MASSEY
PATHOPHYSIOLOGY T h e exact pathophysiologic mechanisms for the expression of MyD are uncertain. 'They have been reviewed in depth elsewhere.' Previously mentioned abnormalities may contribute to muscle membrane instability. Defects in membranes from muscle and red blood cells due to decreased protein phosphorylation support the concept of membrane d y s f u n ~ t i o n . ~Decreased ~,~" muscle protein synthesis as a consequence of endocrine dysfunction may in part explain muscle wasting.""
DIAGNOSIS AND TREATMENT In adults, history and physical examination along with routine electromyographic studies and
Excerpta Medica, 1977:705-12 5. Dyken PR, Hat-per PS. Congenital dystrophia myotonica. Neurology 1973;23:465-73 6. Perron M, Vcillette S, Mathieu J . La dystrophie myotonique: I . caracteristiques socioeconomiques et residentielles des malades. Carl .J Neurol Sci 1989; 16: 109-13 7. Wesstrom G, Bensch J , Schollin J . Congenital myotonic dystrophy. Acta Paetliatr Scand 1986;75:849-54 8. Harper PS. Col~geriitalmyotonic dystrophy in Britain. 1. Clinical aspects. Arch Llis Child 1975;50:505-13 9 , Rutherford MA, Heckmatt JZ, Dubowitz V. Congenital myotonic dystrophy: respiratory function at birth determines survival. Arch Dis Child 1989;64: 191-5 10. Kegev R, Vries LS, Heckmatt JZ, Dubowitz V. Cerebral ventricular dilation in congenital myotonic dystrophy. J Pediatr 1987; 11 1:372-6 I I. Sarnat HB, Silbert SW. Maturational arrest of fetal muscle in neonatal myotonic dystrophy. Arch Neurol 1976;33:466-74 12. Harper PS. Congenital myotonic dystrophy in Britain. 11. Genetic basis. Arch Dis Child 1975;50:514-21 13. Kirnura J . Elcctrodiagnosis in diseases of nerve and muscle: Principles arid practice, 2nd ed. Philadelphia: FA Davis, I989 14. Barchi RL. Myotonia. Neurol Clin 1988;6:473-84 15. Streib EW. Differential diagnosis of myotonic syndromes. Muscle Nerve 1987; 10:603-15
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sufficiently close to the probe, it will segregate with slit-lamp examination of the eye provide the diagthe MyD gene during meiosis without recombina- nosis in most patients and suspected carriers. Oction. This localizes the gene. Ultimately, character- casionally, genetic studies are needed to detect the ization of the MyD gene and product may lead to condition in asymptomatic people. Treatment of most patients includes supportan effective treatment for patients. Early linkage of MyD to the Lutheran blood ive therapy for weakness such as bracing, wheelgroup, secretor locus, and complement component chair use, and physical therapy to prevent contracC3 localized the gene to chromosome 19.81,82 tures. Systemic complications are managed as they Tighter linkage has been found to apolipoprotein arise, but ECG should be performed at regular inC2 and the gene for muscle-specific creatine ki- tervals to monitor rhythm. Many treatment opn a ~ e . ~ " , ~ " ~MyD h e gene is now known to be on the tions exist for symptomatic myotonia.'.' The first long arm of chromosome 19.2 Special techniques choice is phenytoin because of its benefit in reduchave been used to produce other probes linked by ing myotonia without significant cardiac t~xicity.~' Procainamide and quinine lessen myotonia but MyD.$" With use of the probes, diagnosis now can be may prolong the PK i n t e r ~ a l . ~Other ' antiarperformed with an accuracy of over 99% and ge- rhythmic medications such as tocainamide reduce netic counseling can be gi~en.~"renatal diagnosis myotonia and are safe at low doses." Reports that can be made at around 10 weeks using chorionic imipramine and nifedipine cause reduced myvillus tissue obtained by biopsy. Carrier detection otonia without severe side effects are encouragfor diagnosis and hmily planning may be indi- ing,94,95 MyD should be considered as a diagnostic poscated. These procedures should be performed at medical centers where experience with the disor- sibility in any patient complaining of stiffness. When the diagnosis is confirmed, other family der is extensive. As mentioned previously, anticipation may oc- members should be evaluated. there may be a selection cur in MyD.'"owever, bias caused by recognition of severe cases in the young and mild cases in the older patients." Further bias may be introduced by reduced reproducREFERENCES tion in young, severely affected patients. One study of' 14 families examined 6 1 parent-child pairs (ex1. Harper PS. Myotonic dystrophy. In: Engel AG, Banker BQ, eds: Myology. New York: McGraw-Hill, 1986; cluding the index patient) in an attempt to clarify 1267-96 the debate. Onset of symptoms was recorded by 2. Harper PS. Myotoriic dystrophy, 2nd ed. London: WR Saundcrs, 1989 decade. Among 60 pairs, symptom onset was ear3. Jozefowicz KF, Griggs KC. Myotonic dystrophy. Neurol lier in the child.'%reater mean difference in age Clin 1988;6:455-72 of onset was found in paternal pairs than maternal 4. Harper PS. Phenotypic- variation in rnyotonic dystrophy: causes and consequences. I n : Rowland LP, ed. Pathopairs. This study supports the concept of anticipageriesis of human muscular dystrophies. Amsterdam: tion.
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16. Swift T R , Ignacio OJ, Dykeri PK. Neor~ataldystrophia ntyotonica: electrophysiologic studies. An1 J Dis Child 1975; l2!):734-7 17. Sun SF, Streih EW. Myotonic dystrophy: limited elcctron~yogr-apliicabnormalities in two definite cases. Clin Genet l983;23: 1 1 1-4 18. Streib EW, Sun SF. Distribution ofelertricd myotor~iain niyotonic muscular dystrophy. Ann Neurol 1'383; 14:80-2 19. Buchthal F. Diagnostic significance of' the tnyopathic EMG. I n : Kowland 1.P. e d : Pathogenesis of' human muscular dystrophies. Amstertlani: Excerpta Metlica, 1977;205-18 20. Martinez A(:, Ferrer MT, Perez Concle MC. Electrophysiologic studies in niyotonic dystrophy. 1: Potential nlotor unit parameters and conduction velocity o f the motor and sensory peripheral ner-ve fibers. Elcctromyogr Clin Neurophysiol 1984;24:52:1-35 2 1. Morigia SK, Lundervold A. Elcctrophysiological almortnalities in cases of' dystrophia rnyotonica. Eur Neurol 1975;13:360-76 22. Panayiotopoulos GP. F-wave conduction velocity in the d e e p perorleal nerve: (:harcot-Mat-ie-Tooth disease and dystrophia niyotonica. Muscle Nerve 1978; 1: 37-44 23. ,lama1 (;A, Weir A l , Hansen S, Ballantyne JP. Myotonic dystrophy: a reassessment by conventional and more recently introduced neurophysiologiral techniques. Brain 1986; 109: 1279-96 24. Aniinoff MJ, Layzer RB, Satya-Murti S, Faden .4l. 'L'he declining electrical response of muscle to repetitive nerve s~riiulation in n~yotonia. Neurology 1{177;27: 8 12-6 25. Strcib EW, Sun SF, Yar-kowsky T. 'I'ransient paresis in rnyotonic syndronies: a sitnplified electr-ophysiolc)gic a p p r o a c h Muscle Nerve 1'382;5:7 19-23 26. Rrown JC:. Muscle weakness after rest in niyotonic disorders: a n electrophysiological study. J Neurol Neurosurg Psychiatry 1974;37: 1336-42 27. Stalberg E, Trontelj JV. Single fibre elertrornyography. Old Woking: Mirvalle Press, 1979 28. Bird 'I'D, Keenan AM, Pfeifet- M . Autonomic nervous systcrn function in genetic neuroniuscular disorders. Arch Neut-ol 1984;4 1 :43-6 29. Bird T D , Follett C, Griep E. (hgriitive and pet-sonality fur~ctionin rnyotonic tr~uscular-dystrophy. ,I Ncurol Neurosurg Psychiatry 1983;46:07 1-80 3 0 . I'ortwood MM, Wicks 1.1, Lieberman JS, Duveneck h1J. Intellectual a t ~ dcognitive function in adults with myotonic ~nusc-ulardystrophy. Arch Phys Metl Kehal~il 1986;67:299-303 31. POI-twood M, Wicks J , 1.ieI~er11ianJ , et at. Longitudinal study of intellectual f'unctiorl in myotonic muscular dystrophy. Muscle Ncrve 1986;9(suppl):199 32. Duvcrieck b!J, Portwooti MM. Wicks JJ, Liebet-tnati JS. Ikpression in myotonic muscular dystrophy. Arch Phys Metl Rehabil IWi;67:875-7 33. Huber SJ, Kissel,l'f, Shuttleworth EC, et al. Magnetic resonance imaging and clinical correlates of' intellectual impairment in tnyotoriic dystrophy. Arch Neurol 1989; 46:5Yti-40 34. (;laritz RH, Wright KR, Huckman MS, et al. ( k r ~ t r a lnervous system magnetic resonance imaging findings it1 rnyotonic dystrophy. Arch Neurol 1988;45:36-7 35. Christensen I'B. Normal pressure hydrocephalus in ntyotonic dystrophy. Eul. Neurol 1988;28:285-7 36. Bartel I', Lotz B, Robinson E, Van d e r Meyderi C. Posterior tibia1 and s u r d nerve somatosensory evoked potenrials in dystrophia rnyotonica. J Neurol Sci 1985; 70:55-65 37. Gaties .1', Kerty E. Multitnodal evoked potentials, EEG and electroretinography in patients with dystrophia rnyotonica. Acta Neurol Scand l988;78:436-42 38. Thompson DS, Wootiward .JB, Kingel SP, Nelson LM. Evoked potential abnormalities in myotonic dystrophy.
S E P T i M U E R I991
Electt-oe~tceplii~lc~gr Clin Neul-ophysiol 1983;56:453-6 39. Wright KB, Glantz KH, Butcher J . Hearing loss in Inyotonic dystrophy. Ann Neurol 1988;23:202-3 40. I'itito F, Arnantini A, d e Scisciolo G,et al. Electt-ophysiological studies of the visual systrm in rnyotonic dystrophy. Acta Neurol Scand 1987;76:351-8 (X, Gielen
1I, NO. 3
SEPTEMBER 1991
Myotonic Dystrophy
Myotonia is frequently described by patients as a feeling of "stiffness."' Patients with myotonic dystrophy (MyD) are rarely disabled by this syrnptom. T h e importance of their complaint lies in the other neurologic, systemic, and hereditary manifestations of MyD.
CLINICAL FEATURES T h e presenting symptom of most patients with My11 is muscular w e a k n e s 2 Other common manifestations include complaints of stiffness o r difficulty releasing objects, mental retardation, and cataracts. Also, a number of asymptomatic patients are discovered through family investigations. T h e pattern of muscle weakness characteristic of MyD helps differentiate this disorder from other neuromuscular disease^.^," Wasting and weakness of facial muscles give a "hatchet facies" appearance that is typical of these patients (Fig. 1). Ptosis and lower facial weakness may be asymmetrical and can give the impression that patients are sleepy o r depressed. Restriction of extraocular muscle movements occurs but is not common. T h e jaw may hang open because of' masseter and temporalis weakness and severely affected patients may have difficulty with saliva d u e to palatal and pharyngeal weakness. Slurred speech and dysphagia are common. Aspiration pneumonia is a serious consequence of' palatal and pharyngeal weakness. Sternocleidomastoid atrophy and weakness are prominent and may occur early in the course of disease. This results in weakness of neck flexor muscles out of proportion to neck extensor muscle weakness. T h e marked atrophy of neck muscles produces the appearance of a long, thin, "swan neck."
MyD is unlike most myopathic processes because limb involvement is more severe distally (Fig. 2). Wrist, finger, and ankle extensors are atrophic and weak. As the disease progresses, generalized weakness occurs and may eventually affect respiration. T h e severity of symptoms is variable and rate of progression is slow. Congenitally affected se with prominent tmlinfants h a ~ ~ d i f f uhypotonia bar and respiratory dysfunction. In these children, strength develops in early years only to decline in later life. Myotonia is a delay in muscle relaxation time. This is perceived as stiffness o r difficulty in releasing objects, especially after prolonged gripping. Affected patients relate slowness initially in running o r walking but are not as symptomatic after warmup.? Grip o r percussion myotonia can be demonstrated on examination. Difficulty relaxing a forceful grip is evident and percussion of the thenar muscles, wrist extensors, and tongue reveals myotonia. Tongue percussion is best performed with a tongue blade resting on the tongue. Most MyD patients will demonstrate myotonia but it may be absent in infants, children, and patients with severe weakness. 'I'he age of onset of MyD is often difficuh to determine because of' long asymptomatic periods. 'l'he median age of onset is between 20 and 25 years." Eighty percent of patients will be affected by age 50. Some authors group patients by age because presentations for each age group are often different." Infants o r young children presenting with the congenital form are born to affected mothers. They are the most affected cognitively. Adolescents and young adults complain of progressive facial and limb weakness. Older adults may demonstrate minimal muscle weakness but cataracts may
*Associate, Division of Neurology, Department of Medicine, I h k e University Medical Center, Durham, North Carolina tAssistant Director, Electromyography Laboratol-y, Assistant Professor, Division of. Neul-ology, Department of' Medicine, Duke University Medical Center, Durham, North Carolina Reprint requests: Dr. J . Massey, Box 3403, I h k e University Medical Center, Dur-ham, NC 27710 Copyright O 1991 by 'Thienie Medical Publishers, Inc., 381 Park Avenue South, New York, N1' 100 16. All rights reserved.
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Joel C. Morgenlander, M.D.," and Janice M . Massey, M.D. i-
T h e differential diagnosis based on neuromuscular signs and symptoms includes other muscular dystrophies (for example, facioscapulohumeral dystrophy), other myotonic syndromes, nonprogressive rnyopathies (congenital myopathies), and myasthenia gravis. In adults, confusion with neuropathies is rarely a problem because the sensory examination is normal and reflexes are normal o r slightly hypoactive early. T h e medical history, hmily history, detailed physical examination, and supportive laboratory data lead to the appropriate diagnosis.
Figure 1. Characteristic facial features of a patient with myotonic dystrophy: temporal wasting, frontal balding, ptosis, and weakness of lower facial muscles producing a "fishmouth" appearance.
cause visual symptoms. Anticipation, onset of' the disease at an earlier age in subsequent generations, is a topic of dehate (see "Genetics"). T h e severity of disability incurred as a consequence of MyD relates to the degree of physical (neurologic arid systemic), cognitive, and social impairment in each patient. In one study, 20% of affected men and 50%)of women had never worked." Long-term prognosis for each individual is best determined by clinical course and evaluatiori of neurologic and systemic manifestations.
Figure 2. Thin, tapering forearm and hand demonstrating distal atrophy in a patient with myotonic dystrophy.
T h e diagnosis of' congenital MyD is often difficult to confirm. T h e condition occurs in about 1 in 3500 live births and almost exclusively in children of affected mother^.',^ Neonatal respiratory distress requiring ventilatory support may be the first symptom. Kespiratory insufficiency is due to muscular weakness and hypotonia, elevated right diaphragm, and decreased central ventilatory drive.7 Prognosis for long-term survival is poor if the neonate requires ventilatory support for more than 4 weeks." Myopathic f'acies, not specific for MyD, is frequently present in congenitally affected patients. This consists of a tent-shaped mouth with a short, anteverted philtrum. l'he jaw may hang open as in adults and feeding difficulties occur because of facial and pharyngeal weakness. Generalized hypotonia often is overlooked because other problems are so severe. Improvement usually occurs over weeks to months. Delay in motor milestones is expected. Clues to muscle weakness in utero include decreased fetal movements, polyhydramnios caused by decreased swallowing by the fetus, thin ribs from decreased respiratory movements, and pes equinovarus and arthrogryposis due to poor limb m o ~ e m e n t . ' .Cognitive ~ delay and mental retardation occur in 70% of these children.' Cerebral imaging at birth may disclose ventricular dilation, which is nonprogressive, although progressive dilation associated with intraventricular hemorrhage, subarachnoid hemorrhage, o r white matter infarcts does occur."' Differential diagnosis in affected neonates includes other causes of' neonatal hypotonia: Werdnig-Hoffmann disease, congenital myopathy, neonatal myasthenia gravis, and hypotonia d u e to central nervous system (CNS) disorders. Neonates rarely have clinical m y o t ~ n i a Furthermore, .~ electrical evidence of myotonia is frequently lacking (see "Electromyography"). Muscle biopsy may
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CONGENITAL MYOTONIC DYSTROPHY
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demonstrate hypoplasia of muscle with decreased fiber diameter.'' Muscle may not develop normally, since fibers fail to differentiate into specific fiber types.' Diagnosis is often made by recognizing the clinical presentation and examining- family members, especially the mother. Often, the parents will be asymptomatic. If examination of family members is unrevealing, electrophysiologic study o r muscle biopsy of the neonate may disclose other causes. It remains unclear why congenitally affected patients are born to mothers with M y D An environmental abnormality in utero, a circulating factor, o r both are thought to be i n v o l ~ e d . ~ , "
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T h e electromyographic expression of clinical rnyotonia is the myotonic discharge. This characteristic rhythmic discharge is recorded with a needle electrode after voluntary contraction of a muscle o r following needle in~ertion.':~ Sustained trains of positive sharp waves probably arise from one muscle fiber. Trains of' negative spikes occur after muscle contraction. These discharges exhibit waxing and waning frequency and amplitudes, giving rise to the typical "dive-bomber" o r motor-cycle engine sound. 'The physiologic correlate fbr the myotonic discharge in MyD is still uncertain but decreased chloride conductance in the sarcolemma and abnormal N a + , K f -A7TPaseactivity have been implicated. I" I n order to differentiate myotonic discharges from endplate activity, it is suggested that: (1) duration of the discharges be over 500 msec, and (2) discharges occur in three o r more areas o f t h e muscle.lWyotonic discharges are not specific for MyD; they occur in other "myotonic" disorders. These include rnyotonia congenita, autosomal recessive generalized myotonia, paramyotonia congenita, and periodic paralysis. Examination and electrophysiologic tests permit differentiation of these syndromes.I5 In paramyotonia congenita, when the examined site is cooled, there is an increase in stiffness, with weakness and a decrernental response to repetitive nerve stimulation. In autosomal recessive generalized myotonia, large, early decrements can be found after exercise o r repetitive nerve stimulation. Weakness from periodic paralysis is particularly sensitive to prolonged exercise and potassium concentration. Myotonia congenita is best differentiated from MyD by the lack of significant weakness o r systemic manifestations. Disorders other than the rnyotonic syndromes may demonstrate rnyotonic discharges during electroniyography. 'These include polymyositis, acid
VOL.UME 11, N U M B E R 3
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maltase def'iciency, and some chronic denervating disorders. ':' Myotonic discharges are often absent in neonates and young ~ h i l d r e nalthough ,~ electrical myotoriia was reported in a 5-day-old infant with congenital MyD.'" Electrical myotonia is found when clinical myotonia is present and may be found in asymptomatic carriers." Not all muscles exanlined electrically demonstrate niyotonia with equal frequcncy. Electrical myotonia was found in all niuscles tested in only 3 of 25 patients with MyD.'' Distal extremity and facial muscles had the highest frequency of abnormalities. T h e most frequently abnormal muscles were the abductor pollicis brevis arid flexor pollicis longus (96% each) and the orbicularis oculi (95%).Proximal muscles, such as the deltoid ( 3 8 % )and vastus lateralis (48%,),were least often abnormal. T h e sensitivity of a routine electromyographic study searching for rnyotonia will thus depend on the site and number of nluscles examined. Abnormalities of motor unit potentials have also been described in Myl)." Motor unit potentials may show myopathic ftatures such as short duration, low amplitude, and increased conlplexity.'" T h e percentage of myopathic motor units may be higher in older patients and those with more severe disease."' Motor unit potential duration may also be increased in a minority of patients."' Abnormalities of nerve conduction are inconsistently found in patients with My11 and d o not correlate with severity of disease."' Slowing of conduction velocity, which is usually mild, has been tlescribed in both motor and sensory nerves."~" Prolonged F-wave latencies also occur." Decreased sensory action potential amplitudes and increased thermal and vibratory detection thresholds are fi)uncl in a minority of patients.'" IL is unclear whether these neuropathic changes are an inherent part of MyD o r related to another process. Decrement of the compound motor action potential after repetitive stimulation o r exercise is common in MyD.24.'j T h e degree of decrement is dependent on niuscular rest of at least 3 minutes prior to stimulation and does not necessarily correlate with the degree of weakness."' It may take .. several seconds of repetitive nerve stimulation for a decrement to become apparent. This is unlike the situation in primary diseases o f t h e neuromuscular junction. 1nrreasei neuromuscularjitter arid fiber density are also described in patients with Myl)." Thejitter abnormalities may include paired blocking and double discharges, suggesting a neurogenic cause. Finally, autonomic nervous system dysfunction as demonstrated by abnormal latency of the
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SEMINAKS I N NEUKOI.OGY
conduction delays."%earing acuity is abnormal in some patients because of a sensorineural defect.:'" Electroretinography may be abnormal and visual evoked potentials can show prolongation of the 1'100 latency.") Decreased maximum velocity of OTHER NEUROLOGIC MANIFESTATIONS saccades with normal smooth pursuits has also Intellectual and cognitive dysfunction are fre- been described."' T h e sum of these findings demquently present. As many as one third of patients onstrates the widespread abnormalities in the cenhave low Wechsler iQ test scores."' I n studies in tral and peripheral nervous systems. Electroencephalographic abnormalities are unwhich inheritance pattern is considered, My11 patients with maternal inheritance are more likely to common but when present consist of mild genershow cognitive deficits on standard neuropatho- alized slowing in the theta range."' Sleep disturlogic testing than those with paternal inheritan~e.:~"bance is common in patients with MyD. I n one Some authors believe that those affected at a study of eight patients, all had disrupted sleep arid younger age have more serious intellectual and six had pathologic apnedhypopnea indexes, two n.' in sex of the with progressive oxygen d e ~ a t u r a t i o n . ~T' h e apcognitive ~ l ~ s t i ~ n c t i o Differences patients d o not seen1 to play a role.") Longitudinal neas occurred at rest, and in all stages of sleep and study of the intellectual dyshnction in MyD sug- were most often central. Abnormal multiple sleep gests that deterioration over the short term (3 latency tests and obstructive sleep apnea have been years) is not significant but may occur over longer reported.:" periods.:" Personality profiles show proniirient abnorPATHOLOGY malities in 32%) of patients, most commonly those with cognitive o r physical handicaps.'" Passive-agMuscle biopsy rarely is needed to confirm the gressive traits, emotional and social immaturity, and depression were seen most often. One study diagnosis of MyD unless the clinical features o r of clepression compared normal subjects, adults family history are not typical. A muscle biopsy is with paraplegia, and patients with limb-girdle useful to exclude other diagnostic possibilities that dystl-ophy to patients with MyD.:'MyD and limb- may produce clinical o r electrical myotonia (polygirdle dystrophy patients had significantly more myositis, acid maltase deficiency). Characteristic pathologic features include indepression, suggesting that depression may be related to progressive physical disability rather than creased numbers of internal nuclei, ringed fibers, sarcoplasmic masses, type 1 fiber atrophy, type 2 an intrinsic feature of the disease. Neuropsychiatric testing and magnetic reso- fiber hypertrophy, fiber splitting of spindles, and nance imaging may bc correlated."" Twenty-bur increased terminal arborization.'.'" These changes percent of patients had severe generalized intellec- are not specific for MyD but their presence makes tual dysfunction, which was linked to maternal in- the diagnosis probable. In a study of muscle biopheritance and earlier onset rather than the degree sies from 43 patients with MyD, the first five feaof weakness. There was an increased incidence of tures just described were catalogued." All five feafhcal white matter lesions, anterior temporal lobe tures were found in f u r patients (9%). 'Iivo o r abnormalities, and increased skull thickness in fewer of these features were found in 28 patients those with severe cognitive impairment. Cortical (65%).Ragged red fiber changes due to increased and fbcal cerebral atrophy did not correlate with nunlbers of mitochondria have rarely been dethe cognitive tests. ' I h e etiology of the radio- scribed and are thought to be a secondary phegraphic abnormalities is uncertain. Other magnetic nomenon.'.' Thus, muscle biopsy has limited specresonance imaging studies showed increased ven- ificity in the diagnosis of MyD. Pathologic changes have been found in some tricular size in 7 1% of patients and increased periventric~~lar"lumpy" hyperintensity in 42% of nerve specimens from patients with MyD. Sural p~ients.:" Further studies are needed to corre- nerve biopsies from affected patients demonlate these findings with pathologic specimens. strated abnornialities, most consistent with an axC o m p ~ ~ t e dtomography demonstrates cerebral onopathy, in 1 1 of 13 biopsies."' Rare cases with atrophy o r normal pressure hydrocephalus in nerve hypertrophy have also been reported.'" Sollie caSeS.?9.'i5 T h e CNS has been the focus of more recent Somatosensory evoked potential studies in af- pathologic study. Intracytoplasmic inclusion bodies fected patients show both peripheral and central in the thalanius and substantia nigra, Marinesco conduction delays.:"',"' Brainstem auditory evoked bodies in the substantia nigra," and abnormalities Furpotentials also show both peripheral and central in cortical architecture have been de~cribed."~
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pupillary light reflex, dark adaptation, and cardiac K K interval variation has been described."
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ther pathologic study with clinical correlation may lead to explanations for cognitive and other central dysfunction in these patients.
SYSTEMIC MANIFESTATIONS
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in muscle but f'u~ictional benefit has riot been in whole-body insulin sens h o ~ n . " ' . "A~ decrease ~ sitivity may also contribute to muscle wasting."' 1%dr'lthyroid .. function can be increased in some patients and an association with primary hyperparathyroidism and multiple endocrine neoplasia, type 2A has been reported.""-hx Amenorrhea and menstrual disturbances are common."!' Pregnancies are high risk anti may result in fetal l o ~ s . ~ ~ "Muscle ! ' ~ ~ " weakness and symptomatic myotonia may worsen during pregnancy, often in the third trimester. Karely, symptoms appear first during pregnancy. Impro\ernent may occur early after delivery."" Mothers have a high incidence of spontaneous abortion, premature delivery, and neonatal death. Second trin~esterabortions are attributable to uterine involve~nent.~' I'reiiiature labor and abnormalities in all stages of labor are caused in part by uterine dysfunction."!' Ketained placenta and postpartum hemorrhage
Cardiac dysfunction is prominent. U p to 90% of patients have an electrocardiographic (ECG) abnormality, although most are asymptomatic."" An abnormal ECG is more common in severely affected patients." I n mildly affected patients, firstdegree atrioventricular block and left anterior hemiblock are common, whereas atrial fibrillation o r flutter, Q waves, and repolarization abnormalities are seen in more disabled patients."' T h e most common electrophysiologic abnormality is a prolongation of'the interval from the bundle of His t o ventricular conduction, but other conduction defects are found.52 Mitral valve prolapse is more common in My11 0ccLlr~li!l,72 Granulocyte dysfunction may be severe." Impatients; this finding may relate to body habitus."" Sudden death, the most feared cardiac cornpli- munoglobulin abriornlalities related to abnormal cation, occurs in 4%.'" This may be due to brady- distribution of immunoglobulin G cause lower levarrhythmias o r to tachyarrhyth~nias such as re- els in some patients.74 current ventricular tachy~ardia."~""l'here is Ocular manifestations of MyD are frequent. replacement of myocardiuni by fibrous o r fatty tis- lypical nlulticolored, subcapsular cataracts are losue in some patients." Close clinical arid ECG fol- cated in anterior o r posterior zones in 90% of aflow-up to detect changes such as progressive heart fected p a t i e n t ~ . ~ W t h eless r characteristic lens block can lead to treatment before a cardiac corn- changes, such as cortical spokes and snowball forplication occurs. mations, are common but are not diagn~stic.'~' CatRespiratory coniplications include aspiration aracts are not seen in patients under 10 years of pneumonia, susceptibility to respiratory depres- age. I n older individuals, nondiagnostic cataracts sants, and central hypoventilation.""" Chest wall o r prior cataract removal makes diagnosis more mechanics may be affected by muscular myotonia diff'icult. Pigmentary retinopathy and macular changes are rather frequent.',7" and cause diff'iculty with artificial ventilation."' Complications from general anesthesia inGastrointestinal symptoms from upper o r lower tract dysfunction are common.' Smooth muscle clude increased sensitivity to CNS depressants, dysfunction causes delayed esophageal and gastric which may prolong -- length of artificial ventilation emptying times."!' Degeneration of' the myenteric postoperatively." 1)epolarizing agents such as sucplexus occurs in some patients.") Fecal impaction and cinylcholine can cause increased rnyotonia, making megacolon may result horn colonic dysfunction. intubation and ventilation difficult, but this is more Smooth muscle abnorinalities lead to gallbladder, common in other rnyotonic syndromes.ix Maligureteral, uterine, and ciliary body dysfunction.' Mild nant hyperthermia is an uncommon complication.' elevation of serum gamma-glutarnyltransferase may Cardiac monitoring is required because -- of frequent underlying rhythm disturbances." reflect liver in~olvement."~ Endocrine abnormalities are common. Early balding in males is typical although n o n s p e ~ i f i c . ~ GENETICS Testicular atrophy, degeneration of tubule cells, and hyperplasia of Leydig cells are common in MyL) is an autosomal dominant disease with ma1es.l.' Low testosterone and elevated gonadotropin levels are found consistently in males, whereas variable penetrance and expressivity." Incidence is females usually have normal gonadotropin lev- estimated at 5 per 100,000.7' Since the abnormal els.'."' T h e decreased testosterone levels may con- gene product is unknown, current gene linkage tribute to decreased muscle mass through an ana- studies utilizing probes near the affected gene will bolic d e f e ~ t . " ' Exogenous ~ testosterone given to locate and ultimately characterize the gene and its patients with MyD increases protein synthesis protein p r o d u ~ t . ~If" linkage of the MyD locus is
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S E M I N A R S I N NF,UROI.O(;Y
M Y O T O N I C DYSTROPHY-MORCENLANDER, MASSEY
PATHOPHYSIOLOGY T h e exact pathophysiologic mechanisms for the expression of MyD are uncertain. 'They have been reviewed in depth elsewhere.' Previously mentioned abnormalities may contribute to muscle membrane instability. Defects in membranes from muscle and red blood cells due to decreased protein phosphorylation support the concept of membrane d y s f u n ~ t i o n . ~Decreased ~,~" muscle protein synthesis as a consequence of endocrine dysfunction may in part explain muscle wasting.""
DIAGNOSIS AND TREATMENT In adults, history and physical examination along with routine electromyographic studies and
Excerpta Medica, 1977:705-12 5. Dyken PR, Hat-per PS. Congenital dystrophia myotonica. Neurology 1973;23:465-73 6. Perron M, Vcillette S, Mathieu J . La dystrophie myotonique: I . caracteristiques socioeconomiques et residentielles des malades. Carl .J Neurol Sci 1989; 16: 109-13 7. Wesstrom G, Bensch J , Schollin J . Congenital myotonic dystrophy. Acta Paetliatr Scand 1986;75:849-54 8. Harper PS. Col~geriitalmyotonic dystrophy in Britain. 1. Clinical aspects. Arch Llis Child 1975;50:505-13 9 , Rutherford MA, Heckmatt JZ, Dubowitz V. Congenital myotonic dystrophy: respiratory function at birth determines survival. Arch Dis Child 1989;64: 191-5 10. Kegev R, Vries LS, Heckmatt JZ, Dubowitz V. Cerebral ventricular dilation in congenital myotonic dystrophy. J Pediatr 1987; 11 1:372-6 I I. Sarnat HB, Silbert SW. Maturational arrest of fetal muscle in neonatal myotonic dystrophy. Arch Neurol 1976;33:466-74 12. Harper PS. Congenital myotonic dystrophy in Britain. 11. Genetic basis. Arch Dis Child 1975;50:514-21 13. Kirnura J . Elcctrodiagnosis in diseases of nerve and muscle: Principles arid practice, 2nd ed. Philadelphia: FA Davis, I989 14. Barchi RL. Myotonia. Neurol Clin 1988;6:473-84 15. Streib EW. Differential diagnosis of myotonic syndromes. Muscle Nerve 1987; 10:603-15
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sufficiently close to the probe, it will segregate with slit-lamp examination of the eye provide the diagthe MyD gene during meiosis without recombina- nosis in most patients and suspected carriers. Oction. This localizes the gene. Ultimately, character- casionally, genetic studies are needed to detect the ization of the MyD gene and product may lead to condition in asymptomatic people. Treatment of most patients includes supportan effective treatment for patients. Early linkage of MyD to the Lutheran blood ive therapy for weakness such as bracing, wheelgroup, secretor locus, and complement component chair use, and physical therapy to prevent contracC3 localized the gene to chromosome 19.81,82 tures. Systemic complications are managed as they Tighter linkage has been found to apolipoprotein arise, but ECG should be performed at regular inC2 and the gene for muscle-specific creatine ki- tervals to monitor rhythm. Many treatment opn a ~ e . ~ " , ~ " ~MyD h e gene is now known to be on the tions exist for symptomatic myotonia.'.' The first long arm of chromosome 19.2 Special techniques choice is phenytoin because of its benefit in reduchave been used to produce other probes linked by ing myotonia without significant cardiac t~xicity.~' Procainamide and quinine lessen myotonia but MyD.$" With use of the probes, diagnosis now can be may prolong the PK i n t e r ~ a l . ~Other ' antiarperformed with an accuracy of over 99% and ge- rhythmic medications such as tocainamide reduce netic counseling can be gi~en.~"renatal diagnosis myotonia and are safe at low doses." Reports that can be made at around 10 weeks using chorionic imipramine and nifedipine cause reduced myvillus tissue obtained by biopsy. Carrier detection otonia without severe side effects are encouragfor diagnosis and hmily planning may be indi- ing,94,95 MyD should be considered as a diagnostic poscated. These procedures should be performed at medical centers where experience with the disor- sibility in any patient complaining of stiffness. When the diagnosis is confirmed, other family der is extensive. As mentioned previously, anticipation may oc- members should be evaluated. there may be a selection cur in MyD.'"owever, bias caused by recognition of severe cases in the young and mild cases in the older patients." Further bias may be introduced by reduced reproducREFERENCES tion in young, severely affected patients. One study of' 14 families examined 6 1 parent-child pairs (ex1. Harper PS. Myotonic dystrophy. In: Engel AG, Banker BQ, eds: Myology. New York: McGraw-Hill, 1986; cluding the index patient) in an attempt to clarify 1267-96 the debate. Onset of symptoms was recorded by 2. Harper PS. Myotoriic dystrophy, 2nd ed. London: WR Saundcrs, 1989 decade. Among 60 pairs, symptom onset was ear3. Jozefowicz KF, Griggs KC. Myotonic dystrophy. Neurol lier in the child.'%reater mean difference in age Clin 1988;6:455-72 of onset was found in paternal pairs than maternal 4. Harper PS. Phenotypic- variation in rnyotonic dystrophy: causes and consequences. I n : Rowland LP, ed. Pathopairs. This study supports the concept of anticipageriesis of human muscular dystrophies. Amsterdam: tion.
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16. Swift T R , Ignacio OJ, Dykeri PK. Neor~ataldystrophia ntyotonica: electrophysiologic studies. An1 J Dis Child 1975; l2!):734-7 17. Sun SF, Streih EW. Myotonic dystrophy: limited elcctron~yogr-apliicabnormalities in two definite cases. Clin Genet l983;23: 1 1 1-4 18. Streib EW, Sun SF. Distribution ofelertricd myotor~iain niyotonic muscular dystrophy. Ann Neurol 1'383; 14:80-2 19. Buchthal F. Diagnostic significance of' the tnyopathic EMG. I n : Kowland 1.P. e d : Pathogenesis of' human muscular dystrophies. Amstertlani: Excerpta Metlica, 1977;205-18 20. Martinez A(:, Ferrer MT, Perez Concle MC. Electrophysiologic studies in niyotonic dystrophy. 1: Potential nlotor unit parameters and conduction velocity o f the motor and sensory peripheral ner-ve fibers. Elcctromyogr Clin Neurophysiol 1984;24:52:1-35 2 1. Morigia SK, Lundervold A. Elcctrophysiological almortnalities in cases of' dystrophia rnyotonica. Eur Neurol 1975;13:360-76 22. Panayiotopoulos GP. F-wave conduction velocity in the d e e p perorleal nerve: (:harcot-Mat-ie-Tooth disease and dystrophia niyotonica. Muscle Nerve 1978; 1: 37-44 23. ,lama1 (;A, Weir A l , Hansen S, Ballantyne JP. Myotonic dystrophy: a reassessment by conventional and more recently introduced neurophysiologiral techniques. Brain 1986; 109: 1279-96 24. Aniinoff MJ, Layzer RB, Satya-Murti S, Faden .4l. 'L'he declining electrical response of muscle to repetitive nerve s~riiulation in n~yotonia. Neurology 1{177;27: 8 12-6 25. Strcib EW, Sun SF, Yar-kowsky T. 'I'ransient paresis in rnyotonic syndronies: a sitnplified electr-ophysiolc)gic a p p r o a c h Muscle Nerve 1'382;5:7 19-23 26. Rrown JC:. Muscle weakness after rest in niyotonic disorders: a n electrophysiological study. J Neurol Neurosurg Psychiatry 1974;37: 1336-42 27. Stalberg E, Trontelj JV. Single fibre elertrornyography. Old Woking: Mirvalle Press, 1979 28. Bird 'I'D, Keenan AM, Pfeifet- M . Autonomic nervous systcrn function in genetic neuroniuscular disorders. Arch Neut-ol 1984;4 1 :43-6 29. Bird T D , Follett C, Griep E. (hgriitive and pet-sonality fur~ctionin rnyotonic tr~uscular-dystrophy. ,I Ncurol Neurosurg Psychiatry 1983;46:07 1-80 3 0 . I'ortwood MM, Wicks 1.1, Lieberman JS, Duveneck h1J. Intellectual a t ~ dcognitive function in adults with myotonic ~nusc-ulardystrophy. Arch Phys Metl Kehal~il 1986;67:299-303 31. POI-twood M, Wicks J , 1.ieI~er11ianJ , et at. Longitudinal study of intellectual f'unctiorl in myotonic muscular dystrophy. Muscle Ncrve 1986;9(suppl):199 32. Duvcrieck b!J, Portwooti MM. Wicks JJ, Liebet-tnati JS. Ikpression in myotonic muscular dystrophy. Arch Phys Metl Rehabil IWi;67:875-7 33. Huber SJ, Kissel,l'f, Shuttleworth EC, et al. Magnetic resonance imaging and clinical correlates of' intellectual impairment in tnyotoriic dystrophy. Arch Neurol 1989; 46:5Yti-40 34. (;laritz RH, Wright KR, Huckman MS, et al. ( k r ~ t r a lnervous system magnetic resonance imaging findings it1 rnyotonic dystrophy. Arch Neurol 1988;45:36-7 35. Christensen I'B. Normal pressure hydrocephalus in ntyotonic dystrophy. Eul. Neurol 1988;28:285-7 36. Bartel I', Lotz B, Robinson E, Van d e r Meyderi C. Posterior tibia1 and s u r d nerve somatosensory evoked potenrials in dystrophia rnyotonica. J Neurol Sci 1985; 70:55-65 37. Gaties .1', Kerty E. Multitnodal evoked potentials, EEG and electroretinography in patients with dystrophia rnyotonica. Acta Neurol Scand l988;78:436-42 38. Thompson DS, Wootiward .JB, Kingel SP, Nelson LM. Evoked potential abnormalities in myotonic dystrophy.
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Electt-oe~tceplii~lc~gr Clin Neul-ophysiol 1983;56:453-6 39. Wright KB, Glantz KH, Butcher J . Hearing loss in Inyotonic dystrophy. Ann Neurol 1988;23:202-3 40. I'itito F, Arnantini A, d e Scisciolo G,et al. Electt-ophysiological studies of the visual systrm in rnyotonic dystrophy. Acta Neurol Scand 1987;76:351-8 (X, Gielen
