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The inter- and intraindividual variability of the frequency power density spectral and surface EMG amplitude parameters and of the muscle fiber conduction velocity (MFCV) is studied in 26 healthy volunteers during fatiguing isometric ischemic intermittent exercise of the m. biceps brachii at 80% of the maximal voluntary contraction level, with a contraction rate of 30/min. No significant age effects were found. Males were significantly stronger compared with females. The higher initial SEMG amplitude and the stronger shift of the frequency power density spectrum (PDS) to lower frequencies appear to be significantly correlated with males. Fatigue induces an almost proportional compression of the SEMG frequency content. The muscle fiber conduction velocity has the highest intraindividual reproducibility (r = 0.81). Despite the definite and strong influence of the MFCV on the PDS, the shift of the PDS can not be explained by a change of MFCV alone.

A patient with exertional rhabdomyolysis and continuously elevated serum creatine kinase (CK) was investigated. The known causes of recurrent attacks of rhabdomyolysis were ruled out by appropriate histochemical and biochemical investigations. During ischaemic exercise tests an abnormal K(+)-efflux from exercising muscles was observed. The patient was found to have a deficiency of muscular Ca(2+)-ATPase. Dantrolene sodium therapy gave relief of muscle symptoms and improved the exercise tolerance. Both the CK level and the K(+)-efflux in ischaemic forearm testing became normal on this therapy.

Clinical, electroneurographic and myographic studies were performed on 99 patients of 13 families having hereditary neuropathy with liability to pressure palsies (HNPP) and on 116 relatives. Diagnosis was confirmed in all families by a nerve biopsy of the index case. Large focal myelin thickenings (tomacula) were found in nerve biopsies of affected persons, whether or not pressure palsies had occurred. By using three electroneurographical parameters it was possible to discriminate between asymptomatic patients and unaffected relatives. Complaints sometimes mentioned in literature as being associated with HNPP such as low back pain, brachialgia and short lasting paraesthesia are not related to HNPP. The hereditary transmission is autosomal dominant with total penetration but variable expression.

The most frequently found mutation in autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) is a large duplication on chromosome 17p11.2 containing probes VAW409R3, VAW412R3, and EW401. We investigated a family with severe features of HMSN I, and demonstrated the absence of this duplication by a quantitative analysis of the hybridization signals of VAW409R3 and VAW412R3. Linkage analysis, however, revealed linkage with probe VAW409R3a (lod score, 3.22), which demonstrates the existence of allelic heterogeneity within the HMSN Ia locus. These findings have implications for clinical practice and for investigating the identity of the HMSN Ia gene.

We report on 3 siblings with an adult-onset, predominantly distal muscle weakness. In the female index patient this was associated with epilepsy and a progressive spastic ataxic gait, while the 2 other siblings had no appreciable clinical nervous system involvement. Additional investigations revealed muscular dystrophy and leukoencephalopathy in all 3 siblings. We conclude that this familial adult-onset muscular dystrophy associated with leukoencephalopathy represents a newly recognized autosomal recessive syndrome.

We studied pathologic changes in sural nerve biopsies from four patients with probable autosomal recessive (AR) hereditary motor and sensory neuropathy (HMSN) type I with a median motor nerve conduction velocity greater than 10 m/sec, comparing them with the pathologic features in autosomal dominant (AD) HMSN type I. The four recessive and two sporadic cases showed segmental demyelination. However, the classic onion bulbs of concentric Schwann cell processes, which occur in AD type I, were rare; many axons, also of a smaller size, were surrounded by onion bulbs of basal laminae. Schwann cells of the myelinated and unmyelinated types were involved in these onion bulb formations. Patients with HMSN type I who have many basal lamina onion bulbs should be considered as having AR inheritance.

Four children, index cases of families in which autosomal dominant neuropathy with liability to pressure palsies (HNPP) was diagnosed, are presented. Only one child was admitted for evaluation of an acute peroneal palsy, three presented with other symptoms. Polyneuropathy was diagnosed in all four children, in one of their parents and in some sibs. On inquiry, one child and several members of the four families had experienced transient palsies before. Morphological studies of the sural nerves showed frequently large tomacula and a neuropathic process of segmental de- and remyelination, and axonal degeneration. Attention is drawn to the atypical presentation without pressure palsies of HNPP.

Seventeen cases of dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I) with infantile onset were studied. Not only clinical and electrophysiological data, but also the g ratio (axon diameter to fibre diameter), considered to be a distinguishing feature between HMSN type I and HMSN type III, showed overlap. Morphological and morphometrical investigations already revealed a lack of small and large diameter myelinated axons at an early stage, and a demyelinating process most active in early childhood followed later by axonal loss. It was concluded that the histopathology of HMSN type I cannot be sufficiently explained by axonal atrophy with secondary demyelination.

Cerebrotendinous xanthomatosis (CTX) is a familial sterol storage disease based on an inborn error of metabolism involving bile acid synthesis. Predominant clinical features are a chronic progressive neurological syndrome, mental deterioration, bilateral cataract and xanthomas. The presence of xanthomas usually leads to the diagnosis, and the reverse is probably also true: without xanthomas the diagnosis will often not be made. CTX may therefore be less rare than commonly thought, and the incidence of xanthomas in CTX may be overestimated. Four cases without xanthomas among the presenting symptoms are described, and the relevance of xanthomas in CTX is discussed.

Five case reports of neuromuscular disorders, presenting with frequent muscle cramps are discussed. Clinical diagnosis and pathophysiologic concepts are highlighted.

An isometric ischaemic intermittent m.biceps brachii exercise test is performed by 4 patients suffering from congenital myopathies which are characterized by a 100% type I fibre predominance, and by 26 healthy volunteers. Thirty contractions per minute are made at an 80% of maximal voluntary contraction level. It is found that type I muscle fibres have a fourfold lower force-generating capacity than type II muscle fibres. The EMG amplitude shows that more EMG voltage is needed per unit force in the patients with 100% type I fibres compared with controls. Under standardized fatiguing circumstances the power density frequency spectrum shows a weaker shift to lower frequencies in patients with 100% type I muscle fibres compared with controls. The muscle fibre conduction velocity (MFCV) of type I muscle fibres shows no decline during ischaemic exercise indicating an unimpaired muscle membrane excitability.

Myotonic dystrophy (DM) is well known for its highly variable clinical picture, including the age at which symptoms are first detected. In order to assess the proportion of asymptomatic gene carriers at different ages, we have used linked DNA markers to study individuals at 50% genetic risk of DM, in whom neurological examination, slit-lamp examination and electromyography (EMG) had failed to show diagnostic signs. A total of 139 asymptomatic offspring of DM patients were studied. Our analyses identified 11 out of these 139 as probable gene carriers. Our data show that penetrance of the DM gene increases with age. After correction for the possibility of genetic recombination between the DM gene and the DNA markers used, we calculated the residual chance of carrying the DM gene as 8.3% for clinically normal offspring aged between 20 and 39 yrs. We evaluated several factors that might influence this figure. Neither the sex of the propositus nor that of the affected parent modified the risk of carrying the DM gene. Presence of aspecific lens opacities also did not correlate with the risk of having inherited the DM gene. Since a significant proportion of DM gene carriers are not detected by neurological examination, including slit-lamp examination and EMG, these results confirm the need for DNA analysis in asymptomatic offspring of DM patients.

The relative proportions of fiber types within muscle and the characteristics of these fiber types are important determinants of the surface electromyogram (SEMG) during fatigue. In this study, patients suffering from congenital myopathy characterized by a strong type I fiber predominance were studied. Six patients with 95-100% type I fibers, 2 patients with 80% type I fibers, and 12 healthy volunteers participated in an ischemic, isomeric, intermittent exercise test of m. quadriceps femoris at 80% MVC. Considering the results of the morphometric analysis of muscle biopsy specimen and of the anthropometric estimated muscle-bone volume, it was found that type I muscle fibers had a lower force generating capacity than type II fibers. The initial conduction velocity along the muscle fiber membrane (MFCV) was low in patients with 95-100% type I fibers. During the ischemic exercise test, the 95-100% type I fibers showed less fatigability than type II fibers, which was reflected by a nearby absent decrease of the muscle membrane excitability as measured by the MFCV, and only a slight increase of the SEMG amplitude compared with patients having 80% type I fibers and controls. The absence of a definite MFCV decrease was related to the nearby lacking lactate formation in 95-100% type I fibers.

A few cases of non-anaesthetic-induced rhabdomyolysis in humans, predisposed to malignant hyperthermia (MH), have been described in literature. We studied a group of 6 consecutive patients with unexplained and recurrent attacks of rhabdomyolysis with the test used to determine susceptibility to MH, the in vitro contraction test (IVCT). The results of the IVCT showed 5 of these 6 patients to be MH susceptible. In cultured muscle cells from one of these patients a disturbed calcium homeostasis could be demonstrated. The relation between MH and recurrent rhabdomyolysis is discussed.

Eighteen cases of a chronic progressive motor and sensory neuropathy of neuronal type with early onset are described. Based on the presented data and literature reports a condition is distinguished, which is in clinical, genetic and morphological aspects different from autosomal dominant HMSN type II. The condition corresponds to that described by Ouvrier et al. (1981). It shows a congenital or early childhood onset and causes a severe disability usually with wheelchair dependency already in puberty or later in adult life. The condition is probably transmitted by an autosomal recessive gene. Morphological features of biopsied nerves are an extensive loss of large diameter fibres with a shift to smaller diameters in the histogram. Regenerative features are almost absent in contrast to the distinct cluster formation in autosomal dominant HMSN type II. A maturation disturbance of peripheral motor and sensory neurons with a concomitant or secondary process of chronic neuronal degeneration is suggested. One dominantly inherited case in our group with an infantile onset exhibits clinical and morphological features consistent with an autosomal dominant HMSN type II.

The diagnostic value of axilla skin biopsy has been investigated in a patient with adult polyglucosan body disease. The biopsy data have been compared with those of control subjects and with those from previously reported patients with Lafora's disease. In a patient with adult polyglucosan body disease and in patients with Lafora's disease, an abundance of polyglucosan bodies was found in the myoepithelial cells of the axillary apocrine glands. In the control group of subjects, polyglucosan bodies were only sporadically seen. Axilla skin biopsy is, therefore, an easy and reliable method for confirming the diagnosis of adult polyglucosan body disease.

The diagnosis of muscle cramp is based on clinical features. Algorithms are presented for the diagnosis of muscle cramp and cramp syndromes.

A girl of 14 year is presented with a distal spinal muscular atrophy (SMA) with autosomal recessive inheritance. The technical findings are in agreement with the diagnosis. Light microscopical examination of sural nerve biopsy, including teased fiber studies and morphometry, showed no abnormalities. Electron microscopical investigation however demonstrated axonal pathology. The question arises if distal SMA is a distal axonopathy mainly of motor nerves, but to some extent also of sensory nerves.

A nationwide two-phase survey was carried out of the adult population of the Netherlands regarding fasciculation, muscle pain and muscle cramp. We conducted a population-based telephone interview with 780 Dutch adults, followed by a questionnaire covering more clinical details, filled out by 311 subjects, who had been interviewed by telephone previously. From these data the frequencies of fasciculation (men 50%, women 61%), muscle cramp (men 28%, women 42%) and muscle pain (men 48%, women 60%) in the Dutch adult population in 1988 were estimated. The combined occurrence of frequent fasciculation and frequent muscle cramp as well as of frequent fasciculation and frequent muscle pain was reported only sporadically. Although the muscular pain-fasciculation syndrome and the muscular cramp-fasciculation syndrome represent combinations of common neuromuscular phenomena, their occurrence in the general population proved to be rare. This finding supports their clinical identity as distinct motor unit hyperactivity syndromes rather than mere coincidences of fasciculation, muscle cramp and muscle pain.

Five patients with McArdle's disease entered a double-blind, placebo-controlled, cross-over study of dantrolene sodium. None of the patients experienced beneficial effect of dantrolene sodium medication. Each patient performed 2 exercise tests. Surface EMG during exercise tests without medication showed a temporary increase in EMG activity during the adaptation phase. Quite unexpectedly however, in view of the negative clinical results, this electrophysiological manifestation of muscle fatigue during the adaptation phase diminished or disappeared in all patients investigated when dantrolene sodium was used.

Six patients (5 index cases and 1 sib) with a congenital motor and sensory neuropathy are described. The clinical, genetic and electrophysiological features resembled Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III. Sural nerve biopsy of 5 patients revealed segmental demyelination and remyelination with hypertrophic changes, although onion bulbs were not as ubiquitous as in classical HMSN type III. A striking discriminating feature from HMSN type III was an abundance of focal myelin thickenings (tomacula) present in nearly all teased fibres. Possible pathogenic implications are discussed. These cases corroborate the heterogeneity of congenital motor and sensory neuropathies.

The origin of fatigue in McArdle's disease is still a matter of debate. Both a reduction of muscle membrane excitability and failure of excitation-contraction (E-C) coupling have been suggested as causes. We performed intermittent isometric biceps brachii contractions (80% maximal voluntary contraction, rate 30/min) under local ischaemia in 5 McArdle's disease patients and 26 healthy controls. Our results show that in McArdle's disease the exerted force is less, the surface EMG (SEMG) amplitude steadily increases, and that the power density spectrum (PDS) shifts to lower frequencies, the latter without significant differences when compared with normals. The most important finding is that muscle membrane excitability remains unimpaired during ischaemic exercise, establishing a dominant role for intramuscular lactic acid formation in the reduction of muscle fibre conduction velocity seen in normal subjects. As is indicated by the shift of the PDS towards lower frequencies, as well as by the increase in SEMG amplitude, it can be concluded that during ischaemic exercise in patients with myophosphorylase deficiency, fatigue occurs without alterations in muscle membrane excitability and is due to a failure of E-C coupling.

Using the fluorescence indicator, quin2, we compared the cytoplasmic Ca2+ concentration ([Ca2+]i) of cultured myotubes obtained from control subjects and myotonic dystrophy (MyD) patients. In Ca2(+)-free buffer the [Ca2+]i of the cultured MyD muscle cells was not significantly different from that of the control cells. In the presence of 1 mM external Ca2+ the cultured MyD muscle cells showed a significantly higher [Ca2+]i, which was due to the influx of Ca2+ through voltage-operated nifedipine-sensitive Ca2+ channels. In the presence of external Ca2+, MyD myotubes did not respond to acetylcholine, whereas control myotubes showed a transient increase in [Ca2+]i after addition of acetylcholine. This increase was inhibited by the addition of nifedipine. The differences in Ca2(+)-homeostasis between cultured MyD muscle cells and control cells were not due to differences in the resting membrane potential or the inability of the MyD cells to depolarize as a response to acetylcholine. Therefore, cultured MyD muscle cells exhibit altered nifedipine-sensitive voltage-operated channels which are active under conditions in which they are normally present in the inactive state, and which are unable to respond to depolarization caused by acetylcholine.

A case is reported of a patient with periodic persistent hiccups and secondary generalised epilepsy lasting for a period of five years following a right temporal brain abscess. The recurring episodes of hiccups had a ten day rhythmicity and unlike epileptic convulsions were unresponsive to treatment.

Historically relevant hypotheses on the pathophysiology of muscle cramp are reviewed. Psychosomatic, static, vascular, myogenic and neural theories are highlighted from a clinician's point of view. Modern neurophysiological research leaves little doubt that true muscle cramp is caused by explosive hyperactivity of motor nerves. Several mechanisms may be involved including spinal disinhibition, abnormal excitability of motor nerve terminals and spreading of muscle contraction by ephaptic transmission or axon reflexes.

A 20-year-old man with the characteristic findings of infantile onset Kearns syndrome is described. Morphological and biochemical investigations proved a mitochondrial disease which we believe to be the cause of the symptoms in various organs. We assume an autosomal-dominant inheritance, the marker sign of which is blepharoptosis in several family members. Characteristic clinical, morphological and biochemical findings, combined with an autosomal-dominant inheritance with very variable expression, mark the Kearns syndrome as an individual disease, not as a symptom complex (syndrome). Kearns disease can be divided into three forms--an infantile form ("Kearns-Sayre syndrome') with early onset, rapid progression, multisystemic involvement and a severe course; and a juvenile and an adult form with onset in the second, respectively third (or later) decades with a generally slower and more benign course and less widespread expression in various organ systems. Furthermore, the occurrence of a curious orthoptic abnormality is described, indicating one of the possible ways to avoid diplopia in chronic progressive external ophthalmoplegia: the coexistence of normal and gliding abnormal retinal correspondence.

Three patients from a large pedigree are described who had autosomal dominant spinal muscular atrophy that became manifest between the end of the fourth and the sixth decade. The disease progressed rapidly without evidence of corticospinal tract dysfunction, and within 3 years the patients died from respiratory failure.

A patient with recurrent attacks of exertional rhabdomyolysis and easy fatiguability was treated with dantrolene sodium. She experienced a complete prevention of myoglobinuric attacks and gained a better exercise tolerance. Biochemical findings in this patient suggest a loosely coupled oxidative phosphorylation in mitochondria. The question is raised as to whether dantrolene sodium exerts an effect on the mitochondrial calcium uptake and influences the state of coupling of the mitochondria.

A 17-month-old boy with infantile globoid cell leukodystrophy is presented. The diagnosis was made by enzymic assay. Atypical features of his disease included a delayed onset at 12 months and a slow course. At the time of diagnostic evaluation, 5 months after onset, the usual features of opisthotonos posture, slowing of nerve conduction and marked elevation of cerebrospinal fluid protein were still absent. Sural nerve biopsy showed no significant demyelination and only inconspicuous deposition of the characteristic storage products.

Biochemical studies in liver, muscle, and cultured fibroblasts were carried out in seven patients with Friedreich ataxia. Lowered activity of pyruvate carboxylase was shown in liver and cultured fibroblasts in all instances.

A familial occurrence of chronic inflammatory demyelinating polyneuropathy is reported. The diagnostic problems in distinguishing the progressive form of this disease in childhood from hereditary motor and sensory neuropathy types I and III are discussed. Criteria for a definite diagnosis of chronic inflammatory demyelinating polyneuropathy are proposed.

Plasma adenosine, inosine and hypoxanthine concentrations were assayed in seven control subjects, five myoadenylate deaminase deficient (MADD) patients and six McArdle patients before and after ischaemic forearm exercise. The plasma adenosine increase was very low in all test groups and there were no significant differences. The MADD patients showed a significantly lower increase of plasma inosine and hypoxanthine after exercise as compared with the controls. In the McArdle patients the increase in plasma inosine and hypoxanthine after exercise did not differ significantly from the values measured in the controls. The ischaemic exercise test with measurement of plasma inosine and hypoxanthine might be of diagnostic value in MADD, but not in McArdle's disease.

Some clinical variants of oculopharyngeal dystrophy are known; a rare form is described in this article: the early-adult form of oculopharyngodistal myopathy. The diagnosis was made in 2 patients ((brother and sister) on the grounds of extensive clinical, biochemical and morphological (microscopical, histochemical and submicroscopical) investigations. Although oculopharyngeal dystrophy is generally considered to be a purely myogenic condition, in one of our patients some neurogenic indications were found (EMG and biopsy). The general picture, however, was that of a myopathy with the characteristic morphological signs of oculopharyngeal dystrophy in the skeletal musclebiopsy.

Fifteen well-documented Parkinson patients treated with Madopar were switched to Sinemet for 3 months. The results were measured with an objective test procedure and compared. The effects of Madopar and Sinemet were equal provided th amount of levodopa was the same. There was one drop-out, because of ventricular extrasystoles. Attention is paid to the occurrence of involuntary hyperkinesias and the on-off-effect.

Subjects with myopathies associated with certain enzyme defects often show abnormal concentrations of lactate (LA) and ammonia (NH3) in blood after ischemic exercise. Myoadenylate deaminase (MAD) deficient patients produce only small amounts of NH3, whereas LA rises to normal levels. On the other hand, patients with certain enzyme deficiencies in the glyco(geno)lytic pathway show the opposite. However, the concentrations in blood are dependent on the exercise performed. Standardization of tests for screening purposes, therefore, is necessary. For ischemic contractions, experiments were performed to find the optimal combination for force and frequency, using the highest LA and NH3 concentrations in blood as criteria. Eleven healthy subjects performed ischemic isometric contractions with a handgrip dynamometer at frequencies of 30 and 50/min(-1) and force levels of 50%, 65%, and 80% of maximal voluntary contraction (MVC). A combination of 30/min(-1) and 80% MVC was found to give the best results.

The presence of polyglucosan bodies was studied in intramuscular motor nerves of 292 muscle biopsies. These biopsies were classified into five diagnostic categories and investigated for the presence of polyglucosan bodies in relation to age and sex. Their presence was nonspecific in patients over 20 years, the only correlation being with ageing. Under 20 years, their presence pointed to the diagnosis of Lafora's disease. In cases in which both a muscle biopsy and a sural nerve biopsy were performed, the former appeared to contain these polyglucosans more frequently.

This report concerns a trisomy 4p in a mentally retarded girl with multiple congenital anomalies. A translocation between chromsomes Nos. 4 and 15 was discovered in three generations of the patient's pedigree.

Four children with congenital fibre type disproportion were described. It was shown that their type 1 fibres were at least 12% smaller than the type 11 fibres. There was no increase in the terminal innervation ratio (TIR), but a decreased number of terminal knobs was observed in the biopsy of one child. The distribution of fibre types in the biopsy of another child bears out the notion that the abnormalities as seen in the biopsy can be traced back to the spine.

Four patients are reported, 3 females and 1 male, with (as a prominent symptom of muscle disease) limitation of flexion of cervical and dorsolumbar spine. The nosological classification of these cases is discussed. In two patients there was evidence of an inclusion body myositis. At necropsy one of these patients had a remarkable distribution of muscle changes.