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Introduction Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort. Methods We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy. Results 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient’s perceived efficacy were mexiletine and lamotrigine. Conclusion This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are the most common adult form of muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. Diagnostic delay in DM2 is due not only to the heterogeneous phenotype and the aspecific onset but also to the unfamiliarity with the disorder by most clinicians. Moreover, the DM2 diagnostic odyssey is complicated by the difficulties to develop an accurate, robust, and cost-effective method for a routine molecular assay. The aim of this review is to underline by challenging approach the diagnostic limits and pitfalls that could results in failure to recognize the presence of DM2 disease. Understanding and preventing delays in DM2 diagnosis may facilitate family planning, improve symptom management in the short term, and facilitate more specific treatment in the long term.

Myotonic dystrophy type 2 (DM2) is a common adult onset muscular dystrophy caused by a dominantly transmitted (CCTG)( n ) expansion in intron 1 of the CNBP gene. In DM2 there is no obvious evidence for an intergenerational increase of expansion size, and no congenital cases have been confirmed. We describe the clinical and histopathological features, and provide the genetic and molecular explanation for juvenile onset of myotonia in a 14-year-old female with DM2 and her affected mother presenting with a more severe phenotype despite a later onset of symptoms. Histological and immunohistochemical findings correlated with disease severity or age at onset in both patients. Southern blot on both muscle and blood samples revealed only a small increase in the CCTG repeat number through maternal transmission. Fluorescence in situ hybridization, in combination with MBNL1 immunofluorescence on muscle sections, showed the presence of mutant mRNA and MBNL1 in nuclear foci; the fluorescence intensity and its area appeared to be similar in the two patients. Splicing analysis of the INSR, CLCN1 and MBNL1 genes in muscle tissue demonstrates that the level of aberrant splicing isoforms was lower in the daughter than in the mother. However, in the CLCN1 gene, a heterozygous mutation c.501CG p.F167L was present in the daughter's DNA and found to be maternally inherited. Biomolecular findings did not explain the unusual young onset in the daughter. The co-segregation of DM2 with a recessive CLCN1 mutation provided the explanation for the unusual clinical findings.

To evaluate, by using quantitative MRI metrics, subtle cortical changes in brains of patients with the adult form of myotonic dystrophy type I (DM1) who showed no or minimal abnormalities on MRI. DM1 is an autosomal dominant multisystem disorder caused by the expansion of CTG repeats in the myotonic dystrophy-protein kinase gene. Mild to severe involvement of the CNS can be part of the clinical features of the disease. Several MRI studies have demonstrated that both focal white matter (WM) lesions and diffuse grey matter atrophy can be found in the brains of DM1 patients. However, whether these two processes are related or may occur independently is not clear. Ten genetically-proven DM1 patients who showed no or minimal abnormalities on MRI underwent a new brain MRI examination to obtain computerized measures of total and regional brain volumes normalized to head size and regional measurements of the magnetization transfer ratio (MTr). Normalized brain volumes (NBV) were significantly (p

Myotonic Dystrophy Type 1 (DM1) and 2 (DM2) present with distinct though overlapping clinical phenotypes. Comparative imaging data on skeletal muscle involvement are not at present available. We used the novel technique of whole body 3.0 Tesla (T) Magnetic Resonance Imaging (MRI) to further characterize musculoskeletal features in DM2 and compared the results with DM1.MRI findings of 15 DM1 and 14 DM2 patients were evaluated with respect to patterns of skeletal muscle affection and clinical data using the Muscular Impairment Rating Scale (MIRS) and Medical Research Council scale (MRC). All DM1 patients had pathological MRI compared with only 5 DM2 patients. In contrast to DM2, DM1 patients showed a characteristic distribution of muscle involvement with frequent and early degeneration of the medial heads of gastrocnemius muscles, and a perifemoral semilunar pattern of quadriceps muscle affection sparing the rectus femoris. The most frequently affected muscles in DM1 were the medial heads of gastrocnemius, soleus, and vastus medialis muscles. In DM2, however, the erector spinae and gluteus maximus muscles were most vulnerable to degeneration. MRI data were in line with the clinical grading in 12 DM1 and 3 DM2 patients. In 3 DM1 and 5 DM2 patients, MRI detected subclinical muscle involvement. 9 DM2 patients with mild to moderate proximal muscle weakness and/or myalgias had normal MRI. Pathological MRI changes in DM2 emerged with increasing age and were restricted to women. Whole body 3.0T MRI is a sensitive imaging technique that demonstrated a characteristic skeletal muscle affection in DM1. In contrast, MRI was no reliable indicator for skeletal muscle involvement in mildly affected DM2 patients since myalgia and mild paresis were usually not reflected by MRI signal alterations.

We assessed safety and efficacy of creatine monohydrate (Cr) in myotonic dystrophy (DM1) in a double-blind, cross-over trial. Thirty-four patients with defined DM1 were randomized to receive Cr and placebo for eight weeks (10.6 g day 1–10, 5.3 g day 11–56) in one of 2 treatment sequences. There was no significant improvement using manual and quantitative muscle strength, daily-life activities, and patients' own global assessment comparing verum with placebo administration. Cr supplementation was well tolerated without clinically relevant side effects, but did not result in significant improvement of muscle strength or daily-life activities.

Myotonia is involuntarily slowed relaxation after a forceful voluntary muscle contraction. Patients experience it as muscle stiffness. Electrical hyperexcitability of the muscle fiber membrane is the basis of myotonia, which is apparent in the form of repetitive action potentials on electromyography (EMG). The stiffness recedes with repeated contractions, a phenomenon called warm-up. Patients in whom muscle stiffness worsens with repetition or with cooling suffer from paradoxical myotonia, or paramyotonia. This type of myotonia is associated with episodes of flaccid limb muscle weakness resulting in the adynamia paramyotonia complex.

We present the clinical and neuroimaging findings of five patients (four males, one female; mean age 12 years) affected by congenital myotonic dystrophy and the correlation with their molecular genetic analysis. At birth all five presented severe muscular weakness and hypotonia, associated with feeding difficulties and respiratory distress. In the same patients, congenital clubfoot or more generalized arthrogryposis was also evident. Lymphocyte DNA was characterized in each by a CTG repeat longer than 1300 in the region of the myotonic dystrophy gene in chromosome 19. The patients' neurological condition was evaluated by clinical examination, intelligence tests, electroencephalography, and brain magnetic resonance imaging. All five suffered from some impairment of intellectual function (IQ ranged from 52 to 79). In three a longitudinal evaluation of the cognitive deficit detected no deterioration. In all patients magnetic resonance imaging showed some degree of ventricular dilatation, loosely correlated to the cognitive impairment; in three there was hypoplasia of the corpus callosum and in two mild abnormalities of supratentorial white matter. The relationship between the size of the CTG repeat expansion found in lymphocyte DNA and the cerebral abnormalities appeared inconsistent in this unusual myoencephalopathy of the newborn.

We performed a double-blind placebo-controlled crossover study in 13 patients with myotonic dystrophy to address the question whether modafinil, known to improve hypersomnolence in myotonic dystrophy, may improve levels of activity as well. We used the Epworth Sleepiness Scale as a measure of hypersomnolence and a structured interview of the patient and the partner or housemate as a measure of activity. We additionally used a restricted form of the RAND-36 to relate a possible improvement of activity to perceived general health. We confirmed earlier positive findings of modafinil regarding reduced somnolence (p = 0.015), but no significant effects were seen regarding activity levels (p = 0.2 for patients’ self-reports and 0.5 for partners’ reports).

Myotonic dystrophy (DM) is associated with an expansion of an unstable (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. We studied six patients from two families who showed no expansions of the repeat, in spite of their clinical diagnosis of DM. These patients had multi-systemic manifestations that were distinguishable from those seen in other myotonic disorders, including proximal myotonic myopathy (PROMM). In one additional family, two symptomatic members showed no expanded (CTG)n repeats, while their affected relatives had the expanded repeats. DM haplotype analysis failed to exclude the DMPK locus as a possible site of mutation in each family; however, DMPK mRNA levels were normal. We conclude that a mutation(s) other than the expanded (CTG)n repeat can cause the DM phenotype. The mutation(s) in these families remain(s) to be mapped and characterized.

Twenty patients with myotonic dystrophy underwent neuropsychological evaluation. Performances were analysed with respect to general cognitive profile, family patterns of cognitive impairment, relation with sex, age, extent of muscular involvement, and sex of affected parent. Results showed severe intellectual deficit in 50% of patients and selective impairment of visuospatial and constructional functions. Female patients showed significantly worse global intellectual status than males. No difference in intellectual level was observed in patients with respect to age, extent of muscular involvement and sex of affected parent. No family pattern of cognitive impairment could be identified. Our results show that an extensive neuropsychological battery can reveal the existence of selective mental impairment. It may provide further data on cognitive impairment onset, progression and relation to muscular involvement.

Cranial magnetic resonance imaging (MRI) in 19 German patients with genetically proven myotonic dystrophy Type 1 (DM1, n = 10) or Type 2 (DM2, n = 9) showed pathological findings consisting of white matter lesions (WML) and/or brain atrophy in 9/10 DM1 and 8/9 DM2 patients. Anterior temporal WML (ATWML) were exclusively seen in DM1 patients. Our findings indicate a high frequency of central nervous system (CNS) involvement in both disorders. However, temporopolar pathology, previously associated with intellectual dysfunction, seems to be restricted to DM1.

The myotonic dystrophies are a group of dominantly inherited disorders characterized by muscle wasting, myotonia, cataracts, hypogonadism and other system manifestations. Myotonic dystrophy type 1 (DM1) results from an unstable expansion of a CTG repeat in 3' UTR of the DM protein kinase (DMPK) gene on chromosome 19q 13.3. Myotonic dystrophy type 2 (DM2) is caused by an unstable expansion of a CCTG tetraplet repeat in intron 1 of the zinc finger 9 (ZFN9 gene) on chromosome 3q 21.3. However, the clinical diagnosis of DM2 is more complex than that of DM1, and conventional molecular genetic methods used for diagnosis of DM1 are not helpful for DM2. We here describe the detailed clinical, laboratory and biomolecular tests to identify DM2 and related myotonic disorders. At present, foci of accumulated noncoding CCTG repeat RNA (ribonuclear inclusions) in the cell nuclei are thought to interfere with the regulation and expression of several genes at the basis of multisystemic aspects of myotonic dystrophy type 2.

We have performed genetic screening on the skeletal muscle chloride channel gene (CLCN1) in Taiwanese population. A total of four patients with myotonia congenita (MC) together with 106 normal individuals were examined. All 23 exons of the CLCN1 gene were analysed by direct sequencing of PCR products to detect the nucleotide changes. Five mutations and three polymorphisms were identified in this study. Among these, three missense mutations (S471F, P575S, D644G) and one polymorphism (T736I) are novel and could be unique to the Taiwanese. In addition, a previously documented recessive G482R mutation was identified in a heterozygous patient and his nonsymptomatic father, indicating that this mutation might indeed function recessively or dominantly with incomplete penetrance. In conclusion, this is the first report of MC in Taiwan with proven CLCN1 gene mutations and showing high molecular heterogeneity in Taiwanese MC patients.

The severity of clinical symptoms of myotonic dystrophy type 1 (DM1) has been shown to be closely related to the size of a CTG triplet repeat in the gene encoding myotonin protein kinase. Neuro-otological examinations that include eye movement and stapedial reflex (SR) tests can contribute to the quantitative evaluation of muscular involvement in DM1. We previously found that saccadic eye movement velocity in DM1 patients was significantly lower than that in control subjects and that the saccadic velocity and size of the CTG triplet repeat in DM1 patients had a strong inverse correlation. We now report a case-control study that compared the SR wave form (latency: L, contraction time: C50, and relaxation time: D50) measured by the acoustic impedance method in 13 patients with DM1 and in 14 control subjects matched for age and sex. The correlation between the SR wave form and CTG repeat length in DM1 patients obtained by Southern blot analysis with EcoRI was also examined. We found (1) no significant difference between the pure tone audiometric threshold at 500 Hz in the DM1 patients and that in the control subjects; (2) or between the SR thresholds in the patients and controls (500 Hz stimuli); (3) C50 and D50 in DM1 patients to be significantly prolonged, whereas L was not; (4) C50 and D50 in DM1 patients to be significantly correlated with CTG repeat length, whereas L was not. Measurement of SR by the acoustic impedance method is completely non-invasive, causes no discomfort to the subject, and does not depend on the person's effort or cooperation. Our findings show that SR measurement can be used for a quantitative evaluation of muscle involvement in DM1. We believe that the prolongation of D50 in DM1 is caused by myotonia, which has to be confirmed by further clinical and pathological studies.

Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen's disease, one (Q658X) in a family with Becker's disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease.

Myotonic dystrophy (DM) is a well-known multisystem disorder with dominant inheritance. Proximal myotonic myopathy (PROMM) has been defined only recently, it is rather similar to but distinct from DM. Molecular genetic testing of the CTG trinucleotide repeat expansion is a reliable diagnostic method in DM. In PROMM these CTG repeats are normal, and no genetic test is so far available. Comparing the phenotypes of DM and PROMM, an important point seems to be that PROMM is a more benign disorder. There are almost no obvious mental changes in PROMM patients; premature death is extremely rare; anticipation appears to be present but to a milder degree; a severe congenital type of PROMM apparently is very rare if it occurs at all. On the other hand, at least in the German population, the frequency of PROMM may be almost equal to that of DM.

Sirs: Myotonia is a clinical phenomenon consisting of uncontrolled temporary muscle stiffness after voluntary or evoked muscle contractions [1]. It is a cardinal symptom in non-dystrophic myotonias, including chloride and sodium channelopathies. Myotonia typically occurs after a period of rest and decreases with continuing exercise, commonly referred to as the warm-up phenomenon. This is in contrast with what occurs in paradoxical myotonia, where muscle stiffness increases as a result of continuing exercise. The warm-up phenomenon is an established clinical feature in chloride channelopathies, both in recessive myotonia congenita (Becker’s disease) as well as in dominant myotonia congenita (Thomsen’s disease). It has also been shown to occur in limb muscles of patients with a sodium channelopathy [1, 4]. By contrast, paradoxical myotonia has been established by others as the characteristic feature of sodium channel myotonias [3]. Thus, unlike the phenotypic homogeneity of chloride channelopathies, sodium channel mutations are associated with a broad spectrum of clinical phenotypes [5]. Here we report three patients with a predominant and generalised warm-up phenomenon associated with the V445M missense mutation of the SCN4A gene encoding the alpha-subunit of the voltage gated sodium channel. Three patients, from two families, with an autosomal dominant non-dystrophic myotonia and a predominant warm-up phenomenon were referred to our clinic. All patients had complaints of generalised muscle stiffness since birth and had earlier been diagnosed as Thomsen’s disease, but recent chloride channel gene (CLCN1) mutation screening was negative. Clinical myotonia was generalised, severe and painful. All patients noticed aggravation of myotonia at cold temperatures and only one patient reported aggravation after eating potassium rich food. They all used sodium channel blockers (mexiletine 200 mg three times a day, procainamide 1000 mg three times a day and quinine 200 mg three times a day respectively) with a good subjective effect. Needle EMG of all patients revealed myotonic discharges in all muscles investigated (left biceps muscle, right first interosseus muscle, right rectus femoris muscle, left tibialis anterior muscle and left orbicularis oculi muscle). We measured the warm-up phenomenon in three different muscle groups during a drug free period. The warm-up phenomenon of eyelid muscles and right hand flexor muscles was quantified by measuring the difference between two relaxation times - timed with a stopwatch - , i.e. after maximum voluntary contraction of three seconds following ten minutes of rest and after ten successive contractions. For leg muscles we compared the first and tenth trial on a ‘chair test’ in which the time required to rise from a standardised chair, to move around it and to sit down again was measured. DNA extracted from 20 ml of blood was screened for mutations in SCN4A by direct nucleotide sequence analysis. All patients showed a marked generalised warm-up phenomenon (Table 1). Direct nucleotide sequence analysis of all three patients showed the same missense mutation (c.1333G>A; p.V445M) in SCN4A. Table 1 Clinical relaxation times (in seconds) of three patients after the first (1st) and tenth (10th) maximum voluntary contraction of eyelid muscles (eyes), right hand flexor muscles (hand) and leg muscles (legs) The V445M sodium channel mutation was first reported by Rosenfeld et al. causing a painful myotonia congenita [4]. The warm-up phenomenon was mentioned in one patient. Here we report three patients with a predominant and generalised (eyelid muscles, right hand flexor muscles and leg muscles) warm-up phenomenon in association with the same V445M sodium channel mutation. Although quantitative computer analysis for the warm-up phenomenon of a single muscle group has already been developed, we used clinical tests in order to be able to measure this phenomenon in three various muscle groups [2]. For a definite molecular diagnosis clinicians should be aware that a predominant and generalised warm-up phenomenon may be found in chloride channelopathies but also in sodium channelopathies. A definite diagnosis is important for informing patients about their disease, orienting therapy and genetic counselling [5]. Thus, in patients with severe, painful myotonia in combination with a clear warm-up phenomenon, we recommend screening of SCN4A with particular attention for the V445M mutation.

We have analysed the [AGC] expansion in leucocytes, muscle and sperm from 17 individuals affected by myotonic dystrophy (DM). Skeletal muscle showed a larger repeat number than leucocytes in the same patient. A similar degree of expansion was detected in differently affected muscles of a single patient. The germline mutation (or = 350 repeats) was expanded in somatic cells of the progeny in all patients examined. Our results provide evidence of an early postzygotic instability of the [AGC] repeat in DM.

An unstable DNA sequence of a gene encoding a protein kinase has been identified as the molecular basis of myotonic dystrophy. The correlation between different symptoms of myotonic dystrophy and the size of this unstable base triplet (CTG)n repeat was investigated in 14 patients. DNA was prepared from whole blood by standard procedures. Detailed clinical, psychological, electrophysiological (quantified measurement of myotonia, electrocardiography) and other laboratory examinations (muscle biopsy in 4 patients, slit lamp examination) were performed. Triplet size correlated significantly with muscular disability and inversely with age at onset of the disease. A greater frequency of mental and gonadal dysfunction could be observed in patients with a larger repeat size. Other symptoms, however, such as cataract, myotonia, gastrointestinal dysfunction and cardiac abnormalities were not correlated with repeat size. Somatic mosaicism with different amplification rates in various tissues might be one possible explanation for the variable phenotypes. Furthermore, other factors such as different expression of the myotonic dystrophy gene might contribute to the clinical variability of the disease at a given triplet size.

Sirs: Myotonic dystrophy type 1 (DM1) is a well known genetic muscle disorder characterized by distal muscle wasting, predominantly distal weakness and myotonia that is associated with a number of systemic abnormalities, including some in the central nervous system. In more than 50 % of patients, especially in those with intellectual impairment, cerebral white matter abnormalities, mainly anterior temporal white matter or periventricular hyperintensities have been noted on cranial magnetic resonance imaging (MRI) [4, 7]. However, diffuse white matter abnormalities involving extratemporal areas have not been reported. A 60-year-old female patient admitted with complaints of slowly progressive difficulty in walking, climbing stairs and easy fatigability that started five years previously. Mild weakness of the upper extremities, dysarthria, difficulty in swallowing and forgetfulness were added to the clinical picture over the past year. On neurological examination dysarthria, bilateral ptosis, facial diparesis and decreased elevation of palatal arcs were detected. Muscle strength testing revealed mild symmetrical weakness (MRC grade 4) of neck flexors, shoulder abductors, hip flexors, ankle plantar-flexors and dorsi-flexors. Elbow extensors and distal upper extremity muscles which are characteristically involved early in the course of DM1 were normal in strength. Muscle stretch reflexes were hypoactive and plantar responses were flexor. No increase in muscle tone was detected. Corneal opacities, frontal baldness and bilateral temporal muscle atrophy were detected on physical examination. She had grip, percussion and tongue myotonia. She reported similar facial features and mild symptoms of weakness in her father. Routine laboratory investigations, including serum electrolytes, electrocardiography and thyroid function tests were within normal limits, except for mild elevation in gammaglutamyltransferase (110 IU/L) and serum creatine kinase (282 IU/L). No insulin resistance was detected. In her Mini-Mental State examination, mild impairment was detected in short-term memory and calculation. Sensory and motor nerve conduction studies were within normal limits; needle electromyography demonstrated myotonic discharges. Cranial MRI was performed because of the presence of mild cognitive impairment. Cerebral and cerebellar atrophy, diffuse periventricular hyperintense white matter lesions were detected on T2-weighted images, suggestive of a demyelinating process, especially leukodystrophy (Figs. 1, 2). No contrast enhancement was found. These unusual MRI findings posed a diagnostic difficulty. Lysosomal enzyme screening was performed in serum and cerebrospinal fluid samples and the possibility of lysosomal enzyme deficiency was ruled out. Muscle biopsy from the biceps brachii muscle revealed increased fiber size variability with many scattered angular fibers in addition to small rounded ones. Twenty-five percent of the fibers had internal nuclei. The endomysial connective tissue was normal. ATPase stains showed no preferential atrophy or fiber type predominance. No suggestive findings of a lysosomal storage disease was detected. Cytosine-thymine-guanine (CTG) triLETTER TO THE EDITORS

Myotonic dystrophy (MD) is characterized by myotonia, weakness and extramuscular symptoms, including intellectual impairment. We performed magnetic resonance imaging (MRI) of brain and muscle in 25 MD patients: 81% had cerebral atrophy (severe in 36%); 68% had focal white matter lesions, which were large and multiple in 27%. Brain MRI findings correlated with mental impairment; the severity of both correlated with disease duration. Changes in brain and muscle MRI were progressive with time, but independent of each other. Muscle MRI findings were fatty degeneration and loss of bulk. In the calves, the medial gastrocnemius muscles were involved earliest and the posterior tibial muscles relatively spared. In the thighs the vastus muscles were damaged most often and the rectus femoris least. Focal muscle damage was efficiently visualized, sometimes preceding clinical detection. Muscle MRI was less sensitive than conventional methods for early diagnosis, but ideal for follow-up, owing to its non-invasiveness and examiner-independence.

The antimyotonic effect of the antiarrhythmic drug tocainide was tested in 14 patients. With 1200 to 1600 mg/d all patients reported good improvement. This was substantiated by objective tests. Only four patients noticed minor side effects.

Myotonia was induced in rats with clofibrate given in daily subcutaneous injections of 0.4 g/kg. The first myotonic discharges were recorded electromyographically from the extensor digitorum longus, tibialis anterior, and gastrocnemius muscles after 4 days on clofibrate, but from the soleus not until after 11 days. Clofibrate induced myotonic activity in chronically denervated muscle also. During repetitive nerve stimulation the electrical response of the muscle was declining in all myotonic rats. It did so also when repetitive stimulation was applied directly to the muscle, which would seem to suggest a myotonic defect as the cause. Several drugs were tested and diphenylhydantoin proved to inhibit myotonia most effectively. Animals on an extended clofibrate schedule (12 weeks) had ECG abnormalities resembling those seen in patients with myotonic dystrophy.

Myotonic reaction and paresis accompanied by painful muscle contractions limited to the upper limbs, which decrease remarkably in the cold, were observed in a 29 year old man. The histological investigation revealed minimal non-specific signs of myopathy. The biochemical studies of muscular tissue contained a normal amount of myophosphorylase, acid maltase and glycogen. Ischemic work induced normal elevation of venous lactate. The activities of CPK, LDH and SGOT in the blood serum were occasionally increased. The EMG showed typical myotonic bursts and electrical silence during painful muscle contractions. Repetitive high frequency stimulation demonstrated a clear initial increase of the amplitude of action potentials followed by a decrease in the contracted muscle. The father of the patient suffered from dystrophia myotonica. This coincidnece suggests that this myotonic myopathy is a variant of dystrophia myotonica.

Determinations of protein and phospholipid composition, as well as enzymatic activity, were carried out in plasma membranes isolated from the muscle of rats, after different periods of 20,25-diazacholesterol administration. A decrease in the level of phospholipids, and in the total amount of plasma membrane proteins, connected with a relative reduction in the amount of protein of a molecular weight of 100000 daltons, was found. The activity of (Na+ + K+)-ATP-ase gradually decreased while a reverse tendency was observed in the case of 5'-nucleotidase. Changes in ATP-ase and phospholipids appeared even prior to electrophysiologically recorded signs of the myotonia. The mechanism of these changes and their possible role in myotonia are discussed.

This report describes a patient with myotonic dystrophy who had severe action and percussion myotonia. The patient was unresponsive to diphenylhydantoin therapy. Treatment with acetazolamide, 250 mg daily, decreased the myotonia markedly. A possible mechanism of the favorable effect of acetazolamide in myotonia is discussed.