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The myotonic dystrophy gene codes for a protein kinase and contains a repeated trinucleotide motif (adenine-guanine-cytosine [AGC]) in its transcribed sequence. The repeat is polymorphic in the general population, varying in size from five to 37 AGC units in normal alleles. Myotonic dystrophy patients show expansions of the repeated sequence from over 50 elements up to several thousand units. There is a positive correlation between repeat size and clinical severity. The direct analysis of the AGC repeat size allows an easy confirmation of the clinical diagnosis of myotonic dystrophy in difficult cases and for prenatal counseling.

Background: Over the past 3 years, the genetics of the myotonic diseases have been substantially elaborated. Three genetically different groups of myotonic disease can be discerned: (1) the chloride channel myotonias, (2) the adynamiaparamyotonia complex, and (3) myotonic dystrophy. Methods and Results: Electrophysiology has suggested and molecular biology has proven that the diseases belonging to the adynamia-paramyotonia complex, ie, paramyotonia congenita, hyperkalemic and normokalemic periodic paralysis, and some rare forms of myotonic disease, are caused by point mutations in the gene encoding the α subunit of the sodium channel in adult human skeletal muscle, located on chromosome 17q23. Thirteen different mutations have been described by various groups in the United States and Germany. The various mutations causing a particular form of the complex are not located in the gene in a predictable or easily understandable regular manner. Conclusions: Further study of the genotype-phenotype correlations should not only increase our understanding of the variability of signs in this group of diseases, it could also provide us with a deeper insight in the function of the various regions of the sodium channel protein.

• Innervation of human muscle cocultured in monolayer with explants of fetal rat spinal cord plus dorsal-root ganglia produces more mature fibers, which show spontaneous, neurogenic (d-tubocurarine-blocked) contractions. On the innervated myotonic atrophy (MA) muscle fibers, 96% of acetylcholinesterase-stained patches were simple, and only 4% appeared as complicated, pretzel-like, more maturelooking structures; on control innervated fibers, 37% of the acetylcholinesterase patches had the mature appearance. The normal trend from multifocal innervation toward unifocal innervation was decreased in innervated MA muscle fibers. Microelectrode studies compared parameters of cultured aneural muscle fibers and cultured innervated-contracting muscle fibers from 7 patients with MA and 10 control patients. The mean resting membrane potentials of the two groups (aneurally cultured MA muscle fibers and innervated-contracting cultured MA muscle fibers) were 8 and 9 mV lower, respectively, than those of their counterpart controls. The mean amplitude of action potentials, the maximum rate of rise of action potentials in innervated MA muscle fibers, and the action potential amplitude in aneural MA muscle fibers were significantly smaller than in corresponding control fibers.

Background Myotonic dystrophy type 1 (DM1) is the most prevalent form of adult muscular dystrophy worldwide. Although well known for the classic manifestations of myotonia, weakness, and early cataracts, it has broad effects on multiple organ systems. Objective To analyze and compile the laboratory abnormalities of 126 adult patients with DM1. Design Laboratory data obtained before treatment were compiled and include values for 45 different laboratory tests and 2860 total studies. Setting University hospital. Patients One hundred twenty-six medically healthy, mild to moderately affected, ambulatory patients with DM1 and good venous access enrolled in one of 12 major DM1 clinical trials at a university hospital from 1975 to 2005. Results Of the 2860 laboratory studies, results for 470 (16.4%) were outside their reference ranges. Of the 45 types of laboratory tests studied, 41 demonstrated abnormal findings. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including levels of hemoglobin A 1c , follicle-stimulating hormone, luteinizing hormone in men, and γ-glutamyltransferase and creatine kinase in women. In addition, levels of lactate dehydrogenase in men and hemoglobin in women were abnormally high or low in more than 50% of the test results evaluated. Conclusion There is a high frequency of abnormal laboratory values in DM1 that may form a basis for early screening and monitoring and provide insight into the spectrum of tissues involved in this disease.

Background A family with a complicated constellation of neurologic findings, including neuropathy, myotonia, and periodic paralysis, has been described in 4 studies in the medical literature since 1934. The underlying cause of their disease has been the subject of considerable speculation and has never been identified until now. Objective To identify the molecular basis of this family’s neurologic disease. Design The coding regions of 6 genes that cause peripheral neuropathy and regions of the muscle sodium channel gene ( SCN4A ) were sequenced. Results A novel missense mutation (Arg67Pro) in the myelin protein zero gene was identified in 2 patients with Charcot-Marie-Tooth disease, and a common missense mutation (Thr704Met) was identified in the SCN4A gene in 4 family members. We discuss the difficulties of genotype-phenotype correlation in this family. Conclusions These findings indicate that 2 independent mutations segregating in this family are responsible for the puzzling clinical picture.

Background Myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM) is an autosomal dominant multisystem disorder. Musculoskeletal pain is one of its frequent symptoms but also occurs in other chronic noninflammatory muscle disorders (OMD). Objectives To characterize the phenotype of DM2/PROMM-associated musculoskeletal pain and to test whether it shows features distinct from OMD. Setting Outpatient clinic for patients with neuromuscular disorders, university hospital. Patients Twenty-four patients with DM2/PROMM (12 women and 12 men; median age, 57 years) and 24 age- and sex-matched patients with OMD consecutively recruited during a 3-year period were examined for musculoskeletal pain. Methods Standardized pain assessment; McGill Pain Questionnaire; depression score; and quantification of pain thresholds to blunt pressure on limb muscles with analgometer. Results Unlike patients with OMD who have musculoskeletal pain, patients with DM2/PROMM distinguished a wide spectrum of coexisting pain types. The major pain type in patients with DM2/PROMM was exercise-related, temperature-modulated, and palpation-induced, whereas, cramps were rare. In 8 of the patients with DM2/PROMM and in 3 of the patients with OMD, musculoskeletal pain was the most disabling symptom. Conclusion Besides many similarities, DM2/PROMM-associated musculoskeletal pain shows features distinct from OMD.

Background Paramyotonia congenita (PMC) of von Eulenburg is an autosomal dominant muscular disease characterized by exercise- and cold-induced myotonia and weakness. To date, 18 missense mutations in the adult skeletal muscle sodium channel α-subunit ( SCN4A ) gene have been identified to cause a spectrum of muscular diseases, including PMC of von Eulenburg, PMC without cold paralysis, potassium-aggravating myotonia, and hyperkalemic periodic paralysis. However, no obvious correlations can be made between the location or nature of amino acid substitutions in SCN4A and its clinical phenotypes. Objective To describe clinical and genetic features of a family with PMC of von Eulenburg. Results A Japanese family with cold-induced myotonia and weakness was diagnosed as having PMC of von Eulenburg. This phenotype was identified to be caused by a novel mutation that substituted a glutamic acid residue for a highly conserved glycine residue in the fourth transmembrane segment (S4) of domain IV. This predicted a decrease in positive charge specific for the S4. Conclusion In addition to the G1456E identified in this study, 4 mutations that cause a decrease in positive charge in the S4/D4 are associated with the phenotype of PMC of von Eulenburg. This provides an important genotype-phenotype correlation in sodium channelopathies.

To evaluate by magnetic resonance spectroscopy the age-related cerebral alterations present in myotonic dystrophy (MD) and to compare these results with those obtained by magnetic resonance imaging.Twenty-one patients (aged 16-63 years) with MD were compared with 16 age-matched healthy control subjects.In magnetic resonance spectroscopy, the mean (+/- SD) ratio of N-acetylaspartate to creatine and phosphocreatine in the patients with MD (1.09 +/- 0.32) was significantly lower than that in the control subjects (1.93 +/- 0.43) (P.001). The mean ratio of N-acetylaspartate to choline-containing compounds in the patients with MD (1.70 +/- 0.44) was also significantly lower than that in the control subjects (2.75 +/- 0.53) (P.001). These changes could be observed already in the younger patients. In magnetic resonance imaging, the mean brain area was significantly decreased and the mean ventricular space was significantly increased in patients with MD compared with the control subjects. Although we have confirmed brain atrophy in patients with MD in previous reports, a regression analysis indicated that the brain shrinks progressively with age in patients with this disorder and in control subjects, resulting in overlapping values for younger subjects.Magnetic resonance spectroscopy indicates that the cerebral abnormalities in patients with MD may be present at an early stage, when the results of magnetic resonance imaging studies are still equivocal.

Objectives To seek cerebral metabolite abnormalities in patients with myotonic dystrophy and to determine whether the degree of cerebral abnormalities (measured by proton magnetic resonance spectroscopy) correlates with severity of the genetic defect (measured by trinucleotide repeats). Design Fourteen patients with myotonic dystrophy were compared with 24 healthy control subjects. Setting A university-affiliated medical center. Results Compared with healthy subjects, patients with myotonic dystrophy had elevated levels of myoinositol (+19% in the occipital region and +12.9% in the temporoparietal region), total creatine (+7.6% and +6.8%), and choline-containing compounds (+21% and +7.7%). Furthermore, the creatine and myoinositol peak areas correlated with the number of trinucleotide cytosine-thymine-guanine n (CTG) n repeats from leukocytes, especially in the temporoparietal brain region ( r =0.76; P =.004). Conclusions Neurochemical alterations observed with proton magnetic resonance spectroscopy are proportional to the cytosine-thymine-guanine repeat size. Increases in myoinositol and creatine concentrations may be caused by increased glial content, while elevated levels of choline-containing compounds are most likely caused by increased glial content and cell membrane abnormalities. Proton magnetic resonance spectroscopy is a powerful noninvasive tool to study brain biochemistry, which may reflect the extent of neuropathological involvement in patients with myotonic dystrophy.

Background: Previous investigations in three families have shown that proximal myotonic myopathy (PROMM) is not linked to the gene loci for myotonic dystrophy (DM) or to the loci of the genes of the muscle sodium and chloride channels associated with other myotonic disorders. It is important to extend our clinical knowledge of this interesting new disorder by studying other families. Patients: Thirty-five patients in 14 new families; 27 patients were examined. Methods: Clinical examination, electromyography, muscle biopsy, DNA analysis. Results: The following findings were noted: proximal without distal weakness of the legs (n=21); myotonia on electromyograms (n=23); intermittent clinical myotonia (n=17); cataracts (n=24) and a number of the cataracts were identical to the type in DM (n=11); and peculiar muscle pain (n=14). A few patients had cardiac arrhythmias, and others had elevations in the concentrations of serum γ-glutamyltransferase. None of the patients had significant muscle atrophy. Muscle biopsy specimens showed mild myopathic changes. All patients had normal trinucleotide (cytosine, thymine, and guanine) repeat size of the DM gene in leukocyte DNA. Muscle DNA probes from three patients showed findings identical to those of their leukocyte DNA probes. Conclusions: Proximal myotonic myopathy is a new genetic disorder similar to, but distinct from, DM. Patients suspected of having DM but with negative DNA studies may have PROMM. The gene defect for PROMM awaits discovery. Because of the similarities between PROMM and DM, this discovery will not only shed light on the pathomechanism of PROMM, but it may also increase our understanding of DM.

Recessively inherited disorders can most often be condidered loss of function : the patient has only defective copies of the defective gene (homozygous or hemizygous), with little or no functional protein products produced. Dominantly inherited disorders can most often be considered change of function : the patient has both mutant and normal copies of the gene (heterozygous); however, the mutant gene produces an abnormal protein product that causes dysfunction of the cell. Categorization of inherited disorders simply by their inheritence pattern thus affords some predictions concerning the underlying biochemical defect. To illustrate these generalizations, the molecular data on two important human inherited neurologic disorders will be described. X-linked recessive Duchenne/Becker muscular dystrophy has been shown to caused by loss of function of the dystrophin product. Dominantly inherited hyperkalemic periodic paralysis and paramyotonia congenita have been shown to be the result of single amino acid changes of the skeletal muscle voltage-sensitive sodium channel that alter the channel's function in response to environmental or physiologic stimuli (change of function).

Autosomal-dominantly inherited nondystrophic myotonic disorders are an interesting group of muscle diseases that provide considerable opportunity for future molecular genetic studies to identify the genes responsible for specific membrane functions. A family with such a myotonic disorder is described with features that are distinctly different from myotonia congenita and paramyotonia congenita. Five members were affected in three generations. The myotonia fluctuated to an unusual degree. It did not worsen with cold but increased markedly with potassium loading. Muscle weakness never occurred. Analysis of the contraction force of the flexor digitorum muscle showed a unique type of myotonia, namely, exercise-induced delayed-onset myotonia. Microelectrode studies done on one muscle biopsy specimen revealed a normal chloride conductance of the muscle fiber membrane.

Background Myotonic dystrophy is caused by unstable (CTG) n repeat expansion. On normal chromosomes, this repeat is highly polymorphic, with a copy number ranging from 4 to 38. Myotonic dystrophy is considered more prevalent in Western European and Japanese populations but less prevalent, rare, or even absent in others. It has been proposed that the expanded (CTG)n alleles originated from the group of the large normal alleles. Objective To determine whether there is a lower prevalence of the large alleles in the Kuwaiti population. Design and Participants We determined the size distribution of the CTG repeats by means of polymerase chain reaction in blood DNA derived from 185 healthy Kuwaiti individuals representing the 5 Kuwaiti provinces. Results We found a total of 17 (CTG)n alleles, with a range of 5 to 37 repeats. The (CTG)5 allele was the most frequent single allele (100/370 [27.0%]), whereas the (CTG) 10-13 was the most frequent class of alleles (161/370 [43.5%]). Using 18 repeats as the cutoff point, χ 2 analysis showed a statistically significant lower frequency of greater than 18 alleles in the Kuwaiti population compared with the European population (χ 2 = 12.7; P Conclusions These data may explain the rare occurrence of myotonic dystrophy in the Kuwaiti population. Further study of healthy families within the high-normal repeat range is in progress to investigate the possible instability of the (CTG)>18 alleles in our area.

Background Many inherited progressive encephalopathies have a poor outcome, and some are caused by repeat expansion mutations. How would the presence of 2 different expansion mutations affect the phenotype? Objective To describe a patient who has 2 distinct, rare genetic disorders: myotonic dystrophy (DM, OMIM 160900) and progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1, OMIM 254800). Both conditions are caused by repeat expansion mutations. They affect the central nervous system causing mental retardation, but also produce a wide spectrum of disabilities in daily living. Setting Referral center. Methods Clinical description with accompanying photographs, electroencephalography and magnetic resonance imaging; DNA analysis of both of the mutations and chromosomal analysis with prometaphase spreads. Results The patient had clinical characteristics and findings of both myotonic dystrophy and progressive myoclonus epilepsy of the Unverricht-Lundborg type. Electroencephalographic recordings over a 3-year period showed typical findings for myoclonus epilepsy. The patient had no gross anomalies in brain magnetic resonance imaging. She had a normal karyotype, and both of the diagnoses were confirmed at the molecular level with the direct detection of the mutations. Conclusions Despite having 2 different progressive inherited disorders affecting the central nervous system, the patient, at age 28 years, showed only mild mental retardation with very slow progression. However, clear deterioration in activities of daily living has taken place during last 3 years.

Objectives: To define a new type of dominant myotonic muscle disorder and to identify the gene lesion. Design: Case series, clinical examination and electromyography, measurements of grip force and relaxation time, and DNA analysis to probe for mutation in the gene for the skeletal muscle sodium channel. Setting: Outpatient clinic and home. Patients: Three families studied; all together, 17 affected and nine unaffected individuals. Results: The findings in these three families confirm the existence of myotonia fluctuans as we described it previously in another family. Myotonia (prolongation of relaxation time) developed 20 to 40 minutes after exercise. Potassium caused generalized myotonia. Cooling had no major effect on muscle function. Three families had a common mutation in exon 22 and one family had a mutation in exon 14 of the gene for the sodium channel α subunit. Conclusions: Myotonia fluctuans is a disorder of the muscle sodium channel. There are at present two other distinct clinical muscle disorders associated with mutations in the sodium channel: hyperkalemic periodic paralysis and paramyotonia congenita. The findings in the present report indicate that myotonia fluctuans belongs to a third type of sodium channel disorder. Further work is needed to understand the complex genotype-phenotype correlations in sodium channel disorders.

• Although intellectual impairment is common in patients with myotonic dystrophy, this aspect of the disease has received relatively little research attention. We examined 41 patients with myotonic dystrophy using objective neuropsychological procedures and magnetic resonance imaging. Ten patients (24%) had severe and generalized intellectual dysfunction, while lesser or no cognitive impairment characterized the remaining patients. Degree of intellectual impairment was not related to neuromuscular status or sex. Patients with severe intellectual disturbance had significantly earlier onset of both myotonia and weakness and were more likely to inherit the disease from their mother. Magnetic resonance imaging findings indicated that while degree of cerebral atrophy was not related to severity of intellectual impairment, skull thickness, focal white matter lesions, and anterior temporal lobe abnormalities were significantly more common in patients with severely disturbed intellect. This study reports a number of previously unreported cerebral magnetic resonance imaging findings associated with intellectual impairment in myotonic dystrophy, but the etiology of these changes awaits neuropathologic examination.

• Acetazolamide is effective treatment for myotonia in certain patients with myotonia congenita. Since potassium metabolism may be abnormal in myotonia congenita, we studied the effect of acetazolamide administration on potassium regulation and glucose disposal, using the euglycemic insulin clamp technique in patients with myotonic disorders and in normal subjects. Glucose disposal was normal in patients with myotonia congenita; administration of acetazolamide increased glucose disposal in normal subjects and in patients with myotonia congenita. By contrast, patients with myotonic dystrophy showed insulin resistance and decreased glucose disposal that was not improved by acetazolamide administration. Patients with myotonia congenita had elevated potassium levels in the basal state and a greater fall in potassium level during the insulin clamp procedure than controls. Patients with myotonic dystrophy had normal or low basal potassium levels and a subnormal decrease in potassium level during the insulin clamp procedure. Administration of acetazolamide did not alter these abnormalities in potassium metabolism in patients with either myotonia congenita or myotonic dystrophy.

PROCAINE amide hydrochloride has been used widely to treat cardiac arrhythmia during the past 15 years,1and it is also useful in the treatment of myotonia.2,3There have been reports of minor side effects (fever, rash, arthralgia, chills, headache, myalgia, lymphadenopathy, leukopenia, and eosinophilia4-9) which subside after medication is withdrawn, and there has been one case of fatal agranulocytosis.10 During the past few years there have been several observations of a syndrome resembling systemic lupus erythematosus (SLE) in patients receiving procaine amide (Table 1). The present report describes this syndrome in a patient with myotonic muscular dystrophy. By way of contrast, we also describe a patient with chronic SLE who received the drug with no deleterious effect in the treatment of an unusual intercurrent myotonic disorder. Report of Cases CASE 1.—This case involves a transient syndrome resembling SLE in a patient treated with procaine amide

IN 1886 Eulenberg 1 described "paramyotonia congenita," an inherited syndrome in which episodes of myotonia and weakness were induced by exposure to cold. A similar condition was reported independently by Rich. 2 During the ensuing years additional cases were published, emphasizing the myotonia rather than the episodic weakness which was also part of Eulenberg's original description. A link with periodic paralysis was not considered until 1957, when French and Kilpatrick 3 studied a patient with paramyotonia who was subject to attacks of generalized weakness. An oral dose of potassium chloride induced an attack of weakness lasting several days, without a fall in the serum potassium level. Just prior to the report of French and Kilpatrick, Helweg-Larsen et al 4 in Denmark and Gamstorp 5 in Sweden described a hyperkalemic form of periodic paralysis, "adynamia episodica hereditaria." Myotonia was not mentioned in these Scandinavian cases, but paralysis could be induced by

RECENT investigations have shown that actomyosin can be isolated from human muscle biopsy samples; it has a magnesium (Mg ++ ) moderated adenosine triphosphatase (ATPase) activity and at low ionic strength it undergoes superprecipitation, an in vitro analogue of contraction, in the presence of adenosine triphosphate (ATP), magnesium chloride and calcium chloride. 1 Both ATPase activity and superprecipitation are inhibited by removal of calcium with either a chelating agent or human fragmented sarcoplasmic reticulum. Fragmented sarcoplasmic reticulum can also be obtained from human biopsy samples 2 and, as in the case of rabbit muscle, 3-6 it manifests an ATP dependent calcium uptake by which it can lower the concentration of ionized calcium below the 10- 6 M threshold required for actomyosin superprecipitation. 4 In extension of the above studies, the present work on purified myosin from normal and myotonic dystrophic human muscle was undertaken. The procedure described is geared to the

An in vivo gracilis anticus preparation for microelectrode intracellular study of neuromuscular transmission was developed. The mean resting muscle fiber membrane potential was —73 mV. Resting miniature endplate potential (mepp) frequency was 2 to 4/sec in most fibers. Depolarization induced by external application of 20 millimolar K+ was slow in increasing mepp frequency. Frequency reached 100 to 150/sec rapidly with 35 millimolar K+. The potassium depolarization augmented mepp frequency was reduced up to 60% by increasing intravenous doses of diphenylhydantoin (DPH) up to 40 mg/kg with a median effective dose of 15 mg/kg. Depolarized muscle membrane potential was increased 15% after intravenously administered DPH. The DPH appears to stabilize the motor nerve terminal and muscle membrane. These actions may account for its effect in generalized myokymia and myotonia.

Adenyl cyclase activity in normal human muscle is stimulated four to seven times by epinephrine and about 18 times by sodium fluoride. The enzyme is present in all particulate fractions of muscle (myofibrils, mitochondria, sarcoplasmic reticulum) but not in the soluble phase. The highest specific activity is found in isolated plasma membrane. Basal enzyme activity was normal in muscle from patients with Duchenne or facioscapulohumeral dystrophy but the response to epinephrine was about 30% of normal and the response to sodium fluoride about half normal. In polymyositis, responses were normal, and intermediate values were found in myotonic dystrophy. In denervated muscle, responses were enhanced. In fetal muscle there was no response to epinephrine but sodium fluoride stimulated, suggesting that the mechanisms of these agents differ.

This report discusses the status of the paramyotonia congenita described by Eulenberg 1 with relation to other types of myotonia. The classification of myotonic disorders has caused controversy for decades. The dispute has arisen primarily over whether myotonic dystrophy and myotonia congenita should be identified as separate diseases or merely variants of the same disorder. A discussion of paramyotonia frequently has been added but usually given secondary importance. Most investigators have concluded that paramyotonia is only a variant of the other forms in which symptoms are aggravated by cold. This clinical analysis of a family with paramyotonia indicates that it is an independent entity. To avoid confusion in this paper, the term "paramyotonia" will be used to describe the disease reported by Eulenberg consisting of myotonia worsened by cold, weakness, and dominant inheritance. The term "myotonia" will be used to describe inability to relax a muscle group promptly after contraction.

FAMILIAL myotonic dystrophy usually has its onset in adult life and shows myotonia and muscle wasting as its principal characteristics. A high incidence of cataracts, frontal baldness, hypothyroidism, testicular or ovarian atrophy, and diabetes mellitus support the multisystem nature of the disease. The skeletal muscle manifestations have been of principal interest to neurologists. MacDermot 1 and Coers 2 describe abnormalities of the neuromuscular junction similar to those seen in denervation of muscle. Daniel and Strich 3 report proliferation of intrafusal fibers in muscle spindles. However, the main histopathology lies in the skeletal muscle fibers themselves. Variation in individual fiber size, loss of fibers with rare Fig 1.—Left, A portion of hypertrophic fiber with usual cross striations fills the upper field. In the lower portion of the figure, a large area of degeneration has replaced fibrils with alternating zones of dense and light material. To the right of the

Myotonia, the continued active contraction of a muscle accompanied by electrical after-discharge activity in the electromyogram (EMG), is a characteristic inherited disorder. Acquired instances of myotonia rarely have been reported—most recently as a complication of diazacholesterol therapy. 1 Most other instances of acquired clinical myotonia lack typical electrical discharges. This report describes a man with typical clinical and electrical myotonia associated with a small cell carcinoma of the lung. Report of a Case.— A 59-year-old man had a six-week history of muscle stiffness. No family member had a history of myotonia, and the patient had no prior history of stiffness of the limbs. For two weeks prior to admission he had received prednisone and phenylbutazone but had otherwise taken no drugs. He had noted increasing fatigue and weight loss for two months. Examination showed no weakness, wasting, or hypertrophy of skeletal muscle. A severe stiffness of his gait improved when

• In five families we have confirmed the close linkage between the genes for myotonic dystrophy and apolipoprotein Cll. The total maximum lod (log of the odds) score was 3.32 at 0 recombination. We demonstrate that the use of a Ban I restriction site polymorphism for apolipoprotein Cll adds additional useful information when combined with the more commonly used Taq I polymorphism. The potential practical clinical use of these markers for the prenatal diagnosis of myotonic dystrophy is demonstrated.

A patient with myotonic periodic paralysis improved when he had a negative sodium balance. Potassium balance and serum potassium level did not correlate with his clinical condition. This raises the possibility that sodium distribution across the muscle membrane is of importance in the pathogenesis of this condition.

• We evaluated findings in 14 patients with myotonic dystrophy (MD) using magnetic resonance imaging of the brain and compared them with those in age-matched controls with headache. There was an increased incidence of ventriculomegaly and a lumpy and/or thick pattern of periventricular hyperintensity in patients with MD as compared with the age-matched controls. These white matter abnormalities do not appear to be etiologically specific, but some possible explanations for these frequent findings in MD are discussed.

We studied two patients with abnormal spontaneous muscular activity. The first had widespread fasciculations, painful spasms, delayed muscular relaxation, and hyperhidrosis. Improvement occurred after several years. The second case had generalized paresthesia, mild stiffness, a positive result from Trousseau's test, and was relieved by administration of carbamazepine. Both patients had abnormal conduction velocity. Examination of muscle biopsy specimens disclosed fiber type grouping and increased collateral ramification of motor axons. These observations exemplify symptoms and signs that resemble those of myotonia and tetany and occasionally occur in partial denervation. They provide additional evidence of the neurogenic nature of Isaacs-Mertens syndrome. © 1981, American Medical Association. All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

• In a patient with congenital hypertrophy of the right leg, there developed progressive enlargement of the extremity and inflammatory pseudotumor and electrical myotonia within the enlarged muscle. In three other reported cases, progressive muscle enlargement was associated with abnormal spontaneous electrical and mechanical activity of muscle. In all four cases, the muscle enlargement was probably due to a combination of work hypertrophy secondary to the abnormal mechanical activity and stretchinduced hypertrophy of denervated muscle.

Myotonic discharges in rats given 20, 25-diazacholesterol hydrochloride and fibrillation discharges in denervated rat muscle both were silenced by procaine hydrochloride, tetrodotoxin or ischemia, or potassium chloride (after initial activation). They both were activated by succinylcholine, but only the fibrillations were silenced by alpha-bungarotoxin or atropine sulfate. It is hypothesized that fibrillations and diazacholesterol-induced myotonia are mediated through mechanisms involving ionic channels, that both can be produced by activation of the junctional/nonjunctional acetylcholine receptors (or some mechanism coupled to the receptors), but that an unfettered alpha-bungarotoxin-binding portion of the acetylcholine-receptor molecule and an unblocked atropine-binding site are obligatory only for production of fibrillations.

Introduction Because of their hereditary nature, human muscular dystrophies are assumed to be inborn errors of metabolism. The ultimate classification of these diseases will depend upon recognition of the specific metabolic fault in each. At the present time, however, McArdle's disease (deficiency of muscle phosphorylase) is the only inherited myopathy in which the enzymatic abnormality has been identified. Classification, therefore, depends upon clinical grounds, and these are sometimes imprecise. The myopathy of myotonic dystrophy is different from most other dystrophies for three reasons: (1) Limb weakness is primarily distal; (2) cranial muscles (especially facial, masticatory, and oropharyngeal) are frequently affected; and (3) myotonia is present. If myotonia were not present, the syndrome would resemble "distal myopathy." Furthermore, the ocular muscles are said to be involved in some cases of myotonic dystrophy, and in some cases of "ocular myopathy," other cranial muscles and limb muscles may be involved. Transitional forms of

MOST investigators now agree that paramyotonia congenita is an hereditary syndrome transmitted as a dominant trait, that it is a specific disorder, unrelated to myotonia congenita or dystrophia myotonnica, and that cold temperatures increase the intensity of the paramyotonic symptoms. In a previous study 1 the clinical features of a family with paramyotonia congenita were presented as well as experiments performed in cooperation with an intelligent paramyotonic patient and her father. The conclusions of that study were that the symptoms and signs of paramyotonia congenita resulted from repeated contraction of a muscle rather than from simple exposure of the body to cold (paradoxical myotonia). Although exposure to cold markedly decreased the amount of exertion necessary to produce symptoms, paramyotonic signs could be produced with vigorous exercise after an hour-long exposure in a room at the patient's body temperature, 98.6 F (37.0 C). Moreover, myotonia and weakness did not occur after

IN 1886, Eulenberg 1 described a disease characterized by periodic attacks of myotonia and paralysis, occurring in 26 members (six generations) of one family. 1 The disease was called paramyotonia. The following criteria for its diagnosis were proposed by Drager et al 2 : (1) single autosomal dominant inheritance, (2) stationary (nonprogressive) character, (3) presentation of normal muscle bulk (no atrophy, no hypertrophy), (4) presence of myotonia, particularly in the cold, (5) episodes of flaccid weakness. Since Eulenberg's original account, there have been approximately 38 published communications of similar cases (Table 1). 1-22 This disease was distinguished from familial periodic paralysis (later found to be associated with hypokalemia) and from congenital myotonia (Thomsen's disease). In 1956, Gamstorp 5 presented 139 cases of an unusual variety of periodic paralysis in which the potassium levels in the serum during paresis were elevated, rather than depressed; and in fact, muscular weakness was precipitated

MYOTONIA, the denominating characteristic of three genetically determined diseases of muscle (myotonia congenita, myotonia dystrophica, and paramyotonia), and dystrophy of muscle fibers, a feature of one of these diseases (myotonia dystrophica), remain obscure. Concerning the localization of myotonia, a number of investigators believe it might reside in the muscle cell. Grund 1 and later Schaffer 2 noted the persistence of this phenomenon after complete block of the nerve fibers supplying the muscle; and Gregor and Schilder 3 and later Lindsley and Curnen 4 observed it during the relaxation phase of contraction, when few nerve impulses were reaching the muscle. Brown and Harvey 5 in a myotonic disease of goats also demonstrated that complete denervation of muscle failed to abolish the myotonia. Landau 6 and Floyd et al 7 have shown that curare has no effect on human myotonia. Denny-Brown and Nevin 8 confirmed this localization but also obtained evidence

In Reply.— I have belatedly reviewed Dr Bretag's article and find that we essentially agree in our independent assessments of the theoretical relationship between reduced chloride conductance of the sarcolemma and the repetitive action potentials observed in myotonia. I cannot agree, however, with several of Dr Bretag's comments. As was indicated in my article, the initial sequence of simulations presented therein did not include terms for contributions from the T-tubular system. The computational complexity required to accurately include these terms would have restricted the flexibility of the model in these initial studies requiring multiple simulations. Dr Bretag refers to the pronounced effects on simulated myotonia that he observes from inclusion of a passive resistivecapacitative representation of the T-system. However, it is clear from recent work 1.2 that the T-tubular system is not passive, but rather actively conducts action potentials down its length. Thus, it is incorrect to consider the T-system as a

The muscle membrane in myotonia congenita is characterized by a normal resting potential with a greatly increased resting resistance usually attributed to a decrease in membrane chloride permeability (P cl ). In this report, the hypothesis that decreased P cl alone can account for the repetitive action potentials of myotonia is tested with a mathematical model of the muscle membrane and is shown to be valid. Reduction of P cl to 20% of control values will produce myotonic activity in response to a single stimulus. Membrane resistance and potential approximate those found experimentally. The model predicts that increasing external K + will aggravate myotonia due to a reduction of P cl , while decreasing K out will prevent repetitive spiking. Further, myotonia can be prevented by reducing peak membrane sodium permeability or by shifting the voltage dependency of the membrane rate constants for sodium in a depolarizing direction. These results are shown to correlate well with clinical observation and provide explanations for the action of drugs effective in the treatment of myotonia.

\s=b\Three quantitative measures of autonomic nervous system (ANS) function were evaluated in 12 patients with two types of autosomal dominant neuromuscular disorder, type 1 hereditary motor-$ sensory neuropathy and myotonic dystrophy. The three measures were latency of the pupillary light reflex, dark-adapted pupil size during parasympathetic block-$ ade, and ECG RR interval variation. The results showed deficits in sympathetic and/or parasympathetic nervous system function in several patients, with a variability of expression expected in autosomal dominant genetic diseases. The ANS function may commonly be deficient in both of these disorders. Further investigation is required to determine the potential clinical importance of these findings. (Arch Neurol 1984;41:43-46)

To the Editor.— Dr Barchi's article, "Myotonia: An Evaluation of the Chloride Hypothesis" ( Arch Neurol 32:175, 1975), confirms many of the conclusions regarding low membrane chloride conductance that I have previously arrived at, using a similar mathematical model of myotonia. 1.2 However, I am in disagreement with Dr Barchi regarding the following points. 1. He has apparently neglected the important resistive-capacitive pathway of the sarcotubular system in order to simplify his computations. By contrast, my work has illustrated the pronounced effect of small changes in the electrical properties of this system on the pattern of repetitive electrical activity in myotonia. 2. Several of Dr Barchi's "suggestions" are difficult to justify. For example, his suggested explanation for the "warm-up" phenomenon must be considered with regard to other workers' opposing views, especially for the effects of altered external potassium ion concentration. 3.4 3. Although Dr Barchi has presented convincing evidence of the

The book is divided into 13 chapters covering fundamental techniques of electromyography (EMG) and nerve conduction studies. Specific disease entities described include spinal muscular atrophy, peripheral neuropathy, myopathy, polymyositis and dermatomyositis, myotonia, disorders of neuromuscular transmission, facial nerve dysfunction, and motor disturbances of cerebral origin. Each chapter is well organized and contains useful electrophysiological information. In addition to the data on electrodiagnosis, succinct clinical descriptions of many neurological entities are provided. There are a few shortcomings. The descriptions of peripheral neuropathies appear before the sections on technique and interpretation of nerve conduction studies. Chapters 6 and 7, which deal with myopathies and myositis, are abbreviated to ten pages, of which at least five are used for illustrations; this discussion is much too brief for an EMG book of 163 pages. References in this book are extensive but nondiscriminative, and viewpoints that are not generally accepted are sometimes quoted. Only a

MUSCLE disorders are commonly generalized and usually symmetrical. However, this is a report of a patient with a congenital hypertrophy of muscle and bone confined to one lower extremity. This child has developed impressive myotonia and later weakness confined to the same extremity and now, at age 15, shows no sign of involvement of the other limbs or muscular groups. The muscular abnormality has been proven to be myopathic in nature. There is no clinical nor electromyographic evidence of myopathy in other parts of the body. A search of the literature has not revealed any case similar to the patient to be presented. Report of a Case A 15-year-old French Canadian girl was admitted to The Montreal Children's Hospital for evaluation of hypertrophy of the right lower extremity (Fig 1). She was born after a normal pregnancy and delivery. At birth it was noted that the right lower limb

FAMILIAL myotonia is usually a manifestation of myotonia congenita, paramyotonia, myotonic dystrophy, or hyperkalemic periodic paralysis. These diseases affect the muscles, and, in patients with myotonic dystrophy, the lens, gonads, hair follicles, and, occasionally, the skeleton and central nervous system. Recently, familial myotonia and nonprogressive myopathy were described in association with a bone disease causing dwarfism, skeletal deformities, and anomalies of the face and orbital region. 1 The skeletal deformities differed from those which occasionally occur in patients with myotonic dystrophy. Similar abnormalities have not been reported to occur as atypical manifestations of one of the known hereditary diseases associated with myotonia. 2 Because of the familial incidence, they are also very unlikely to result from the accidental association of two rare diseases, one affecting the muscles and the other the skeleton. These abnormalities probably are manifestations of a previously unrecognized hereditary disease. The results of the investigations of

THE FIRST report of muscular changes in hypothyroidism was Kocher's 1 account of muscular enlargement, weakness, and slow movements in a young cretin. Many authors, however, credit Debre and Semelaigne, 2 who renewed interest in this childhood syndrome and cured one of their cases with thyroid. In the meantime, Hoffmann 3 described an adult with enlarged muscles, weakness, slow movements, and delayed relaxation. He differentiated the abnormal relaxation from myotonia by its failure to improve after several contractions, as occurs in myotonia, a distinction not confirmed until after clinical application of electro-myography 39 years later. 4 Hoffmann 3 also reported a cure with thyroid. Later authors described numerous cases in myxedematous adults who also had painful muscle spasms and muscle percussion reactions similar to myotonia. Electromyography, however, demonstrated electrical silence in most cases during the myotonic-like manifestations, hence the descriptive terms pseudomyotonia and myotonoid reaction. 5,6 The major points

Three cases of chronic cervical intervertebral disk protrusion with associated myelopathy at C5-6 level presented the so-called pseudomyotonic reaction on relaxation of grip. They were studied clinically and electromyographically. This phenomenon of slow extension of fingers, resembling grip myotonia, was associated with neurogenic atrophy; it was exaggerated by repeated movements: it occurred either unilaterally or bilaterally; there was no mechanical or percussion myotonia. In all these characteristics it differed from the true myotonic reaction. This phenomenon occurs as a result of simultaneous contraction of the antagonistic muscles of the extensor and flexor muscles of the forearm. It probably results from misdirection of the regenerated radial nerve in relation to the median nerve at the level of nerve root.