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Background: Slow-channel congenital myasthenic syndromes (SCCMS) typically show dominant inheritance. They are caused by missense mutations within the subunits of muscle nicotinic acetylcholine receptors (AChR) that result in prolonged ion channel activations. SCCMS mutations within the AChR α subunit are located in various functional domains, whereas fully described mutations in AChR non-α subunits have, thus far, been located only in the M2 channel-lining domain. The authors identified and characterized two ε-subunit mutations, located outside M2, that underlie SCCMS in three kinships. In two of the three kinships, the syndrome showed an atypical inheritance pattern.Methods: These methods included clinical diagnosis, mutation detection, haplotype analysis, and functional expression studies using single-channel recordings of mutant AChR transiently transfected into HEK293 cells.Results: The authors identified two SCCMS mutations in the AChR ε subunit, εL78P and εL221F. Both mutations prolonged ACh-induced ion channel activations. εL78P is present in a consanguineous family and appears to be pathogenic only when present on both alleles, and εL221F shows variable penetrance in one of the two families that were identified harboring this mutation.Conclusion: SCCMS mutations may show a recessive inheritance pattern and variable penetrance. A diagnosis of SCCMS should not be ruled out in cases of CMS with an apparent recessive inheritance pattern.

One hundred consecutive patients with myasthenia gravis (MG) referred between 1985 and 1989 were analysed for epidemiological characteristics, evolution of early signs, delay in diagnosis, yield of diagnostic tests and effects of treatment. The female to male ratio was 1.6:1.0. Sixteen patients had a thymoma. Ocular MG occurred in 14. Associated autoimmune diseases were found in 15 patients. In 34% of the women and 10% of the men the diagnosis was delayed for more than 2 years. In the first 3 months progression was more rapid in men than in women. Anti-acetylcholine receptor antibodies were found in 94% of the patients with generalized MG and in 29% of the ocular patients. The neostigmine or the edrophonium test was positive in 84% of the generalized and in 60% of the ocular patients. Electromyography was diagnostic in 71% of the generalized and in 42% of the ocular patients tested. Thymectomy was performed in 56 patients (12 with thymomas). Fifty-one per cent were treated with one or more immunosuppressive drugs, at any time. After a mean follow-up of 9.6 years after onset remissions had occurred in 43%, considerable improvement in 25%, moderate improvement in 20% and 12% remained unchanged. There were no deaths due to MG. Thirty-six per cent remained dependent on immunosuppressive drugs. Medication-free remission was most frequent (35%) in the early-onset (

We carried out an epidemiological study on thr prevalence and annual incidence of myasthenia gravis on tropical islands Curacao and Aruba in the period 1980 1995. Twenty-one patients (seven men and 14 women) were identified. The point prevalence increased from 29 per million in 1980 to about 70 per million in 1990-1995; the annual incidence over the total period was 4.7 per million. The female:male ratio was 2:1; purely ocular cases (2/21) comprised 9.5% and thymomas (4/21), 19%. These data are in accordance with most other epidemiological studies in non-tropical areas. No other studies on myasthenia gravis in tropical areas have been reported. (C) 2000 Elsevier Science B.V. All rights reserved.

A review is given of the aetiology and possible treatment of acquired (non-congenital), blepharoptosis, which is a common but not specific sign of neurological disease. The diagnostic categories of upper eyelid drooping are scheduled as (a) pseudo-ptosis due to a local process or overactivity of eye closure, including blepharospasm, and (b) true ptosis due to a paresis of the eyelid levators (m. tarsalis superior or m. levator palpebrae) or to a disinsertion of the m. levator palpebrae (aponeurotic ptosis). A paresis of the m. tarsalis is due to a lesion in the central, intermediate or peripheral neuron of the sympathetic chain and constitutes one of the components of Horner's syndrome. A paresis of the m. levator palpebrae may be due to a failure in central innervation, in oculomotor (n.III) function, in neuromuscular transmission or to a lesion in the muscle itself.

A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.

The frequency of HLA types in a selected group of 40 patients with myasthenia gravis in relation to the effect of thymectomy and also to gender, and thymus histology was studied. As generally described we found a significant increase in the frequency of HLA-A1, HLA-B8, HLA-DR3 and HLA-DQ2 in the total group. There were no further differences between subgroups of patients, which demonstrates that HLA type is not indicative for the effect of thymectomy in myasthenia gravis.

The authors state that they inadvertently published incorrect data in the analysis of one of the mutations in this manuscript. The data presented for the analysis of mutation AChR eL78P (c.233C>T) was for the …

Circulating antibodies to acetylcholine receptor protein (anti-AChR) were measured in the sera collected from 75 patients (53 women, 22 men, ages 9-83 year, 20 with a thymoma) with myasthenia gravis (MG) during 5-44 (mean 25) months. The clinical state of each patient was graded on a 6-point scale. Anti-AChR concentrations were measured by a radioimmunoassay with human antigen. We analysed the relation between the change in clinical state and the change in anti-AChR concentration in 155 periods (1-7, mean 2.1 per patient). The change in clinical state is given as the difference in score at the onset and at the end of this period. The change in anti-AChR concentration is expressed as the percentage of the original concentration at the onset of the period. The results were analysed in relation to the therapy and to the severity of the MG at the onset of each period. A strong correlation between a change in anti-AChR concentration and a change in clinical condition existed during treatment with prednisone or immunosuppression and in the period after thymectomy, while a weaker correlation was present in periods without immunosuppression. In only 3 patients did the changes in anti-AChR concentration precede the clinical change. No changes in anti-AChR concentrations were found if improvement was due to the effect of anticholinesterases or if deterioration was caused by infection or emotion. The serial measurement of anti-AChR may be a valuable method of following the basic trend of the MG in severely affected patients.

A 48-year-old man presented with a malignant thymoma in combination with myositis, myasthenia gravis, a giant cell myocarditis and recurrent intractable ventricular tachycardias. Despite various therapies (chemical, electrical and surgical), arrhythmias supervened in the presence of a normal coronary arteriogram. Active myocarditis was believed to be the mechanism of the ventricular tachycardias.

Myasthenia gravis is a chronic disease characterized by a fluctuating weakness of voluntary muscle, with a preference for the muscles innervated by cranial nerves. The pathophysiological mechanism is a loss of postsynaptic acetylcholine receptors to less than 20-30% so that the safety margin of neuromuscular transmission is lost. It is probable that the function of the remaining acetylcholine receptors is impaired by antibodies against receptor protein, which can be demonstrated in the serum in 80-90% of the patients, and which are highly specific for the disease. An experimental autoimmune myasthenia can be induced in many animal species by immunization with purified receptor protein and this disease is remarkably similar to the human myasthenia with exception of the fluctuating course. The human disease has to be considered as an autoimmune disease, although the initiating mechanism is unknown. The occurrence of tumors of the thymus in 10-15% and the presence of germinal centres in about 70% of the thymus glands removed by operation are highly suggestive of the importance of the thymus in the pathogenesis, but the definite mechanism (harbouring of an abnormal antigen in myoid cells, or/and false instruction of thymocytes with lack of suppressor cells) is essentially unknown. In most patients the disease tends ot have a favourable course from 5-10 years after onset and complete remission occur in about 20% after 10-20 years. Therapy with anticholinesterases, providing an increase in acetylcholine, is of partial benefit in most patients. Thymectomy has an excellent effect in about 30% of the patients without thymoma under the age of 40 during the first three years of the disease, and is of benefit in still another 30-40%. The use of prednisone and immuno-suppressive drugs has improved the prognosis of the 20% of the patients with severe life threatening symptoms, half of whom have a thymoma.

Urine samples and serum samples of a patient with cerebrotendinous xanthomatosis (CTX) were investigated by means of capillary gas chromatography, both before and during oral treatment with ursodeoxycholic acid (UDCA), and the results compared with those obtained during chenodeoxycholic acid (CDCA) therapy. The predominantly excreted bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and two abnormal bile acids, i.e. 23-norcholic acid and 23-hydroxycholic acid were determined. In addition, the serum cholestanol/cholesterol ratio was determined. Whereas previous experiments demonstrated that the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and the abnormal bile acids decreased within a few weeks during CDCA therapy, the present study shows that their urinary excretions remain essentially the same during UDCA treatment. In contrast to the decrease in the serum cholestanol/cholesterol ratio during CDCA therapy, this ratio remains essentially the same during UDCA therapy. It is therefore concluded that, in contrast to CDCA therapy, UDCA treatment is not effective in the treatment of CTX.

The clinical condition and the serum levels of antibodies to acetylcholine receptor protein were followed in 30 patients with myasthenia gravis before and in a period varying from 2 to 4 (mean 3) yr after thymectomy. Twenty-five patients improved in the 2 yr following thymectomy. A highly significant correlation was found between the change in clinical condition and the change in antibody levels. Only 3 patients improved without a fall of antibody level. Prethymectomy antibody levels were positively correlated with the severity of the clinical condition and with the degree of thymus hypertrophy.

In a selected group of 69 patients with myasthenia gravis treated with prednisone, the factors were studied that might have influenced the reoccurrence or exacerbation of clinical signs after initial improvement in two-thirds of the patients. It was not evident that the speed of dose reduction was responsible for the relapse in most patients. Azathioprine added to the prednisone regimen was found to reduce the relapse rate at steroid reduction. Pure ocular cases and patients who underwent thymectomy without thymoma had a higher chance to remain in remission after prednisone was stopped. Maintenance dose could be determined in 18 patients and was 0.42 mg/kg/2 d., but the difference between patients with or without azathioprine was not significant.

Radioactive Iodinated Serum Albumin (RISA) was given intrathecally to 83 neurological and neurosurgical patients. In order to evaluate the distribution of RISA in the subarachnoid space and its disappearance from it, AP and lateral brain scans were performed after 4, 24 and 48 h, and in some cases after 5 days. This method was called RISA cisternography by Di Chiro et al. (1964). This paper reports on 100 consecutive examinations by this method. The results of the investigation contributed significantly to diagnosis in patients with communicating hydrocephalus and with some other kinds of presenile dementia, in post-traumatic conditions and in other patients suffering from local obstruction or dilatation of the subarachnoid space. Eighteen patients without definite intracranial pathology or obstruction of the spinal subarachnoid space, showed pictures considered to be normal. Sterile meningitis developed in 3 patients, and 3 other patients showed brief transient pyrexia without subjective complaints. There are reasons to suppose that these complications can be avoided if the RISA is used within 6 days of delivery.

A survey is given of the personal findings and para-clinical investigations in a group of 180 patients suffering from myasthenia gravis. The clinical picture is described in detail; emphasis is laid upon some less well-known features of the disease. The procedures which may contribute to the occasional difficulty in diagnosis are described; these include the Jolly reaction, the provoked electromyogram and the curare test. The associated pathology in this series includes a thymoma in 10%, thyroidal lesions in 10%, rheumatoid arthritis in at least 5 women, aplastic anaemia in 2 patients, allergies and some rare diseases in many patients. Laboratory investigations include the muscle-histology in 30 patients, data of 18 autopsies and the microscopy of the thymomas. Hyper γ-globulinaemia was found in 3 patients. The therapeutic measures used in our series include anti-cholinesterases, thymectomy, rest and supporting psychotherapy.

An isotope dilution technique was used to establish whether the use of aldactone-A had an effect on the potassium, sodium and water metabolism in 11 patients with generalized myasthenia gravis. In agreement with the findings of Delwaide et al. (1972), these patients were found to show a decrease in exchangeable potassium. The use of aldactone-A had no demonstrable effect on this finding. It is possible that the decrease observed was caused by medication with cholinesterase inhibitors.

Myasthenia gravis is a chronic disease characterized by a fluctuating weakness of voluntary muscles, with a preference for the muscles innervated by the cranial nerves. Ocular symptoms (ptosis, diplopia) were present at onset in 65% of 432 own patients and in 10% of these patients the disease remained confined to the extrinsic eye muscles. A complete remission occurred in 30% of the purely ocular cases within 10 years of onset. The diagnosis depends upon the pattern of weakness, the spontaneous or provoked fluctuation of the symptoms and the favourable response to anticholinesterases. The presence of antibodies against acetylcholine receptor protein is the most recent tool to confirm the diagnosis, but they are absent in 10-20% of the patients with generalized MG and in 20-50% of the purely ocular cases. As the reaction to anticholinesterases in ocular MG is sometimes equivocal or even absent auxillary investigations (electromyography, tonography, nystagmography, curaretest) may be necessary. Oral anticholinesterases (Pyridostigmin, Prostigmin, Ambenomium) usually have a moderate effect on the ptosis and a poor effect on the diplopia so that other measures (ptosishooks, covering one eye) are necessary. In selected patients alternate-day Prednisone is the therapy of choice.

The clinical features and additional investigations of 20 Dutch patients suffering from cerebrotendinous xanthomatosis (CTX), an inborn error of metabolism in bile acid synthesis, are described. The onset was in the second or third decade. The clinical picture at the time of examination consisted of a combination of two or more of the following signs: cataract, xanthoma of a tendon, mental deterioration, pyramidal tract signs, cerebellar signs and epilepsy. Mental retardation was reported in patients. CT-scanning showed cerebellar hypodensity in 8 out of 16 patients but this feature did not correlate well with cerebellar signs. The EEG was abnormal in all but one patient. Treatment with chenodeoxycholic acid resulted in a normalization of EEG and biochemical abnormalities but not of the clinical signs. Cholic acid was equally effective but had much less side effects. The importance of a diagnosis in early life is stressed as well as the examination of clinically unaffected heterozygous relatives.

Two patients are described with a myasthenic syndrome that presented in early adult life. One patient had 2 asymptomatic first degree relatives with similar electrophysiological findings. Both patients had abnormal fatiguability, arm weakness being prominent; neither of them responded to anti-cholinesterase medication. An abnormal decrement at 3 Hz stimulation was present, and a single stimulus evoked a repetitive response. Electrophysiological studies on biopsied intercostal muscle showed miniature endplate potentials of normal amplitudes but with prolonged rise and decay times. Anticholinesterase staining (Case 1) was not reduced, and showed elongation of some endplates. Ultrastructural studies (Case 2) showed degeneration of junctional folds and diffusely thickened endplate basal lamina. Calcium deposits were not observed and myopathic changes were slight. The findings are consistent with a prolonged open time of the ACh-induced ion channel.

The mean duration of motor unit action potentials (AP m ) was measured in 40 patients with myasthenia gravis in different clinical conditions. Findings were obtained from the quadriceps and the deltoid muscles. In 16 patients a muscle biopsy specimen was taken from the contralateral quadriceps muscle. The findings warrant the following conclusions: 1. 1. The AP m is often shortened in patients with myasthenia gravis, in particular those with little muscle strength. 2. 2. The AP m is a parameter of low specificity, for important deviations from normal were observed in patients without organic neurological disease or neurological patients without peripheral motor neurone or muscle involvement. 3. 3. The shortening of the AP m does not seem to result from any anatomical change in the muscle. 4. 4. It is postulated that shortening of the AP m results from diminution of the single fibre potentials (Ekstedt et al. 1967, 1969), which simultaneously contribute to the motor unit action potential.

The average visual response (AVR) was recorded in thirty patients after a cerebrovascular accident and in fourteen control subjects from the same age group. The AVR was obtained with the aid of a 16-channel EEG machine, a Computer of Average Transients and a tape recorder with 13 FM channels. This made it possible to study different periods after the stimuli and to study the potential distribution of the various components. Primary and secondary parts of the response and the rhythmic response were considered separately and the AVR was also considered as a whole. There were large inter-individual differences in both the patients and the controls. Therefore no general criteria of abnormality of the AVR could be established from the control subjects; criteria of abnormality of the degree of asymmetry between the AVR from the affected and unaffected sides were defined. The absence of waves I or II could not be considered pathological. In our series wave III (peak latency approximately 80 msec) was not infrequently surface positive in the occipital region. The presence of such a positive wave III correlated with the age of the subject both in the patient group and in the group of controls. The primary and secondary responses and the AVR as a whole, recorded from the parietooccipital derivation, were more frequently abnormal in patients with severe cerebral pathology than in those with moderate pathology. Such a correlation could not be found for the AVR recorded from the occipital-to-ear derivation. Similar findings were obtained, independent of the degree of cerebral pathology, for the patients with a disturbance of the visual system. An abnormal asymmetry of the amplitude of the secondary response only occurred in patients with disturbance of the visual system. The amplitude of the rhythmic response was correlated with the amplitude of the alpha rhythm; such a correlation could not be demonstrated for the other components of the AVR. A normal AVR was found more often in controls and in patients with a normal EEG than in patients with moderate or severe EEG disturbances. Determination of the potential field of the AVR with the aid of multi-channel recording did not appear to furnish significantly more information for diagnostic purposes than recording from both parieto-occipital areas. The AVR from the parieto-occipital derivation appeared to provide a better picture of the disturbances of cerebral function than did the occipital-to-ear derivation. Three investigations have been carried out with support from the Netherlands Research Organisation TNO.