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Item does not contain fulltext On comparing multichannel surface electromyographic measurements of the m. biceps brachii with simulations performed with a previously developed two-layer volume conduction model, we found substantial discrepancies. To incorporate an apparent distorting effect of the skin tissue, the model was extended to three layers. This new model describes the potential resulting from an eccentric bioelectric source in a finite, cylindrical, and anisotropic volume conductor consisting of three layers, representing muscle, subcutaneous fat, and skin tissue. This contribution presents the governing mathematical equations of the three-layer volume conductor model as well as our approach to their solution. A comparison of various models shows that the three-layer model best describes measured potential distributions. Furthermore, we present the "ANVOLCON" (analytical volume conductor) software package. This package has been developed to facilitate the use of the model for scientific and educational purposes and is freely available from http://www.mbfys.kun.nl/knf

Item does not contain fulltext We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.

Item does not contain fulltext Aromatic L-amino acid decarboxylase (AADC) is a vitamin B 6 requiring enzyme involved in the biosynthesis of the neurotransmitters dopamine (DA) and serotonin. Lack of AADC leads to a combined deficiency of the catecholamines DA, norepinephrine (NE), epinephrine (E) as well as of serotonin. Here we describe premature twins who presented with severe seizures, myoclonus, rotatory eye movements and sudden clonic contractions. The patients showed an improvement of the clonic contractions under vitamin B 6 supplementation but died in the third week of life. In CSF and urine a biochemical pattern indicative of AADC deficiency was revealed. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were decreased, in association with increased concentrations of 3-ortho-methyldopa (3-OMD) in CSF and significantly increased vanillactic acid in urine. The AADC enzyme substrates L-dopa and 5-hydroxytryptophan (5-HTP) were elevated in CSF. Elevated concentrations of threonine as well as of an unidentified compound in CSF rounded off the biochemical pattern. AADC activity was found to be increased in plasma and deficient in the liver. Molecular studies effectively ruled out a genetic defect in the AADC gene. The basis for the epileptic encephalopathy in the twins may be located in the metabolism of vitamin B 6 and remains to be defined.

Item does not contain fulltext This article gives an overview of what multichannel surface electromyography can teach us about a motor unit. Background information is given about the generation of surface electromyography in general and surface motor unit potentials in particular. Furthermore, we describe how surface motor unit potentials are related to several motor unit characteristics, such as size, location, neuromuscular junction position, fiber length, fiber type, and metabolic fiber properties. In addition, we show how the spatial characteristics of multichannel surface electromyography can be used to obtain single-surface motor unit potentials. The possibilities, challenges, and problems are discussed. Finally, several examples of surface motor unit potential analyses are given.

Item does not contain fulltext After an uneventful pregnancy a girl was born with serious joint contractures and several fractures of the long bones. The family history was negative for congenital abnormalities. Based on the distinct clinical presentation the diagnosis was 'amyoplasia', which is a partial aplasia of skeletal muscles. The cause of amyoplasia is unknown. As well as the partial muscle aplasia, which is symmetrical and mainly affects the extremities, joint contractures and deep dimples in the skin around the joints are present. Several frequently associated abnormalities have been reported, including abdominal hernias, midface capillary haemangiomas and hypoplastic external genitalia. The condition is always sporadic; there is a striking discordance within monozygotic twins and the offspring of patients is normal. In contrast with the severe neonatal presentation, the clinical prognosis is relatively good owing to intensive multidisciplinary treatment and the normal intelligence of the patients.

Contains fulltext : 186508.pdf (Publisher’s version ) (Closed access) The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the anti-Jo-1 autoantibody (20%), followed by anti-tRNAHis (6%), anti-Mi-2 (6%), and anti-SRP (4%). The presence of certain MSAs was clearly associated with specific clinical characteristics. Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.

Item does not contain fulltext We investigated whether the capacity for repetitive submaximal muscle contraction was reduced in a group of subjects (n=8) with a primary deficiency of myoadenylate deaminase (MAD). Quadriceps femoris muscle fatigue was evaluated using voluntary and electrically stimulated contractions during 20 min of repetitive voluntary isometric contractions at 40% of maximal force-generating capacity (MFGC). After 5 min of exercise, MFGC had declined significantly to 70.6+/-4.1% (mean+/-S.E.M.) and 87.2+/-1.6% of baseline values in MAD-deficient and sedentary control subjects (n=8) respectively (P=0.002 between groups). After 5 min of exercise, the half-relaxation time had increased significantly to 113.4+/-6.1% of baseline in MAD-deficient muscle, but had decreased significantly to 94.1+/-1.3% in control subjects (P=0.003 between groups). All control subjects completed the 20-min exercise test. Five of the MAD-deficient subjects had to stop exercising due to early muscle fatigue; however, three of the MAD-deficient subjects were able to complete the 20-min exercise test. In conclusion, although the capacity for repetitive submaximal isometric muscle contractions for the group of MAD-deficient subjects was significantly decreased, it remains uncertain whether MAD deficiency is the sole cause of pronounced muscle fatigue.

Contains fulltext : 185298.pdf (Publisher’s version ) (Open Access) Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, alpha-N-acetylgalactosaminidase (alpha-NAGA) and alpha-galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (GalNAc (alpha 1-->3)[Fuc alpha 1-->2]Gal(beta1-->4)GlcNAc(beta 1-->3)Gal(beta 1--> 4)Glc (beta 1-->1')Cer, IV(2)-alpha-fucosyl-IV(3)-alpha-N-acetylgalactosaminylneolactotetraosylcer amide), B-6-2 (Gal(alpha 1-->3)[Fuc alpha 1--> 2] Gal (beta 1-->4)GlcNAc(beta 1-->3)Gal(beta 1-->4)Glc(beta 1-->1')Cer, IV(2)- alpha-fucosyl-IV(3)-alpha-galactosylneolactotetraosylceramide), and globoside (GalNAc(beta 1-->3)Gal(alpha 1-->4)Gal(beta 1-->4)Glc(beta 1-->1') Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the alpha-NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary excretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to alpha-galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones. Relatively high-degree degradation of substrates with alpha-D-Galactosyl moieties hints at a possible contribution of other enzymes.

Item does not contain fulltext Changes in intracellular Ca2+-concentration play an important role in the excitation-contraction-relaxation cycle of skeletal muscle. In this review we describe various inheritable muscle diseases to highlight the role of Ca2+-regulatory mechanisms. Upon excitation the ryanodine receptor releases Ca2+ in the cytosol. During and after contraction the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) pumps Ca2+ back in the SR resulting in relaxation. An abnormal change in the intracellular Ca2+-concentration results in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. Malignant hyperthermia (MH) and central core disease (CCD) are both caused by mutations in the ryanodine receptor but show different clinical phenotypes. In MH an acute increase of Ca2+ results in excessive muscle contraction causing rigidity, while in CCD a chronic rise of cytosolic Ca2+ is seen, leading to mitochondrial damage, disorganization of myofibrils and muscle weakness. In Brody disease and also in mitochondrial myopathies, SERCA functions sub optimal causing a prolonged physiological Ca2+-elevation leading to slowing of relaxation. Defective actin-myosin interactions, as in nemaline myopathy and also in mitochondrial myopathies due to ATP-shortage, cause Ca2+-hyposensitivity and slowness of contraction. Information of Ca2+-kinetics in these inherited muscular diseases improves our understanding of the role of calcium in the physiology and pathophysiology of the skeletal muscle cell.

Item does not contain fulltext This study was performed to test two hypotheses: (1) ischaemic preconditioning (development of tolerance to ischaemia) influences muscle fibre conduction velocity (MFCV) during repeated ischaemic isometric exercise and (2) the increase in MFCV to supranormal levels during recovery from ischaemic exercise is caused by activation of Na(+)-K(+)-ATPase. For this purpose, MFCV was measured with surface electromyography (sEMG) during repeated ischaemic isometric exercise of the brachioradial muscle (2 min at 30 % of maximal voluntary contraction). The involvement of ischaemic preconditioning was tested by changing the duration of ischaemia and by intra-arterial infusion of adenosine (brachial artery, 50 microg min(-1) dl(-1)). The role of Na(+)-K(+)-ATPase was explored using ouabain (0.2 microg min(-1) dl(-1)). During the exercise, MFCV decreased from 4.4 +/- 0.2 m s(-1) to 3.7 +/- 0.2 m s(-1) (P < 0.01, n = 13). Similar reductions in MFCV were observed during repeated exercise, irrespective of the reperfusion time (10 min vs. 18 min) or duration of the ischaemia (2 vs. 10 min). However, initial MFCV gradually increased for each subsequent contraction when contractions were repeated at 10 min intervals (4.4 +/- 0.2 m s(-1) vs. 4.9 +/- 0.2 m s(-1) for the first and fourth contraction respectively; P < 0.01; n = 13). This increase was not observed when contractions were performed at 18 min intervals, nor when additional ischaemia was applied. Intra-arterial adenosine did not affect MFCV. Intra-arterial ouabain did not affect the reduction in MFCV during exercise but completely prevented the increase in MFCV during recovery: from 4.7 +/- 0.2 m s(-1) to 5.2 +/- 0.2 m s(-1) vs. 4.5 +/- 0.1 m s(-1) to 4.5 +/- 0.1 m s(-1) in the absence and presence of ouabain respectively (P < 0.05 for ouabain effect; n = 6). In conclusion, ischaemic preconditioning is not involved in changes in MFCV during repeated ischaemic isometric exercise. The increase in MFCV during recovery from repeated ischaemic isometric exercise is caused by rapid activation of Na(+)-K(+)-ATPase.

Contains fulltext : 186494.pdf (Publisher’s version ) (Open Access) The autoantigenic polymyositis/scleroderma (PM/Scl) complex was recently shown to be the human homologue of the yeast exosome, which is an RNA-processing complex. Our aim was to assess whether, in addition to targeting the known autoantigens PM/Scl-100 and PM/Scl-75, autoantibodies also target recently identified components of the PM/Scl complex. The prevalence of autoantibodies directed to six novel human exosome components (hRrp4p, hRrp40p, hRrp41p, hRrp42p, hRrp46p, hCsl4p) was determined in sera from patients with idiopathic inflammatory myopathy (n = 48), scleroderma (n = 11), or the PM/Scl overlap syndrome (n = 10). The sera were analyzed by enzyme-linked immunosorbent assays and western blotting using the affinity-purified recombinant proteins. Our results show that each human exosome component is recognized by autoantibodies. The hRrp4p and hRrp42p components were most frequently targeted. The presence of autoantibodies directed to the novel components of the human exosome was correlated with the presence of the anti-PM/Scl-100 autoantibody in the sera of patients with idiopathic inflammatory myopathy (IIM), as was previously found for the anti-PM/Scl-75 autoantibody. Other clear associations between autoantibody activities were not found. These results further support the conception that the autoimmune response may initially be directed to PM/Scl-100, whereas intermolecular epitope spreading may have caused the autoantibody response directed to the associated components.

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Item does not contain fulltext Aromatic L-amino acid decarboxylase (AADC - E.C. 4.1.1.28) converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Inherited deficiency of this enzyme leads to decreased brain levels of these neurotransmitters. Clinically this results in the development of a progressive neurometabolic disorder characterized by severe hypotonia, dystonic and choreoathetoid movements, oculogyric crises, and hypothermia from infancy. Here we describe the clinical, biochemical and molecular details of two affected brothers, one of whom, despite the lack of AADC, presented with hyperdopaminuria. In addition, we detail his reactions to treatment with dopaminergic agonists, monoamine oxidase inhibitors and pyridoxine.

Item does not contain fulltext Transcranial magnetic stimulation (TMS)-induced corticospinal volleys can be investigated in detail by analysing the firing pattern modulation of active motor units (MUs) at close to threshold stimulation strengths. In amyotropic lateral sclerosis (ALS) these volleys are dispersed and prolonged, attributed to altered motor cortical excitability. Impaired intracortical inhibition, as found in ALS, is not unique to this disease, but is also a well-established finding in Parkinson's disease (PD). The present study explored whether reduced inhibition in the motor cortex in PD is accompanied by similar changes in motor unit firing modulation by TMS as are found in ALS. TMS was applied to the contralateral motor cortex during a low-force voluntary elbow flexion while 126-channel surface electromyography (SEMG) was recorded from the brachial biceps muscle. A recently developed method for SEMG decomposition was used to extract the firing pattern of up to five simultaneously active MUs. Sixteen MUs in 7 PD patients and 17 MUs in 5 healthy control subjects were analysed and peristimulus time histograms (PSTHs) and interspike interval change functions (IICFs) were calculated. The IICF provides an estimate of the modulation of the postsynaptic membrane potential at the spinal motoneuron, evoked by the stimulus. In PD the duration of the PSTH peak was significantly increased and the synchrony was decreased. The excitatory phase at 20-50 ms of the IICF was broader in PD, reflecting a longer duration of the TMS-evoked excitatory postsynaptic potential. It is proposed that these results are due to prolonged corticospinal volleys resulting from impaired intracortical inhibition.

Item does not contain fulltext Multichannel surface EMG recordings of a multiheaded skeletal muscle during cyclic locomotion combined with cineradiography were analysed in a chronic experiment. The resulting detailed two-dimensional activation pattern from the long and lateral triceps brachii heads of the rat during treadmill locomotion were combined with gait characteristics and fibre typing of the muscle. Shortly before ground contact of the forelimb, maximum muscle activity was found in the proximal part of the long head of the muscle. During the stance phase maximum activity was observed in the proximal part of the lateral head. The frequency dependent behaviour of cross-covariance functions over both muscle heads confirmed this selective shift in activation. In the lateral triceps brachii head of the investigated rats, exclusively type II fibres were found. In the long head the frequency of type I fibres was the highest in the deep muscle layers, proximally more than distally, whereas type II fibres were dominant in more superficial muscle layers. A combination of physiological and histological findings supports an anticipating mechanism whereby fine-tuning of the vertical foot down manoeuvre is mainly achieved by the (type I fibre dominated) proximal deep compartment of the biarticular long triceps brachii head and force generation is predominantly executed by the monoarticular lateral triceps brachii head.

Three urine samples from two prolidase-deficient patients were analysed using 1H NMR spectroscopy. One-dimensional 1H NMR spectra showed a characteristic pattern of overlapping resonances of the proline and hydroxyproline protons of the imidodipeptides. The model compounds Ala-Pro, Gly-Pro, Phe-Pro, Leu-Pro, Val-Pro, Gly-Hyp and Pro-Hyp were measured as well. The non-proline resonances of Val-Pro, Ala-Pro and Gly-Pro could be assigned in the urine spectra. These resonances could then be used for quantification of the corresponding imidodipeptids. The presence of Leu-Pro in the patients' urine was demonstrated by the results of COSY experiments. However, this imidodipeptide could not be quantified owing to overlap of the resonaces in the one-dimensional 1H NMR spectrum of the patients' urine. Phe-Pro, Pro-Hyp and Gly-Hyp could not be assigned in the spectrum of the patient's urine. The characteristic resonances in the urine from a prolidase-deficient patient, i.e. Ala-Pro, Val-Pro, Gly-Pro, and resonances of the (hydroxy)proline part of the imidodipeptides can be used to diagnose this disease.

Item does not contain fulltext Facioscapulohumeral muscular dystrophy is caused by partial deletion of the D4Z4 repeat array on chromosome 4q35. Genetic diagnosis is based on sizing of this repeat array, which is complicated by cross-hybridization of a homologous polymorphic repeat array on chromosome 10 and by the frequent exchanges between these chromosomal regions. The restriction enzyme XapI optimizes the diagnosis of facioscapulohumeral muscular dystrophy by uniquely digesting 4-derived repeat units and leaving 10-derived repeat units undigested, thus complementing BlnI, which uniquely digests 10-derived repeat units. A triple analysis with EcoRI, EcoRI/BlnI, and XapI unequivocally allows characterization of each of the four alleles, whether homogeneous or hybrid. This is particularly useful in the case of identical sized 4-derived and 10-derived arrays, in situations of suspected facioscapulohumeral muscular dystrophy with nonstandard allele configurations, and for assignment of hybrid fragments to their original alleles.

Item does not contain fulltext We describe a family carrying the Thr148Met mutation in the P0 gene. Contrary to other neuropathies caused by myelin gene defects, no demyeliantion could be found in our biopsies. Based on follow up examinations, extensive morphometry and immunohistochemical analysis we suggest that the mild hypomyelination documented in our family secondarily causes axonal degeneration and axonal loss of large and small fibers which predominates the clinical picture.

The aim of this study was to investigate local muscle O2consumption (muscV˙o 2) and forearm blood flow (FBF) in resting and exercising muscle by use of near-infrared spectroscopy (NIRS) and to compare the results with the global muscV˙o 2 and FBF derived from the well-established Fick method and plethysmography. muscV˙o 2 was derived from 1) NIRS using venous occlusion, 2) NIRS using arterial occlusion, and 3) the Fick method [muscV˙o 2 (Fick)]. FBF was derived from 1) NIRS and 2) strain-gauge plethysmography. Twenty-six healthy subjects were tested at rest and during sustained isometric handgrip exercise. Local variations were investigated with two independent and simultaneously operating NIRS systems at two different muscles and two measurement depths. muscV˙o 2 increased more than fivefold in the active flexor digitorum superficialis muscle, and it increased 1.6 times in the brachioradialis muscle. The average increase in muscV˙o 2 (Fick) was twofold. FBF increased 1.4 times independent of the muscle or the method. It is concluded that NIRS is an appropriate tool to provide information about local muscV˙o 2 and local FBF because both place and depth of the NIRS measurements reveal local differences that are not detectable by the more established, but also more global, Fick method.

Item does not contain fulltext In vivo NMR spectroscopy was performed on the brain of a patient with a leukoencephalopathy, revealing unknown resonances between 3.5 and 4.0 ppm. In addition, urine and CSF of the patient were measured using high-resolution NMR spectroscopy. Also in these in vitro spectra, unknown resonances were observed in the 3.5-4.0 ppm region. Homonuclear (1)H two-dimensional J-resolved spectroscopy (JRES) and (1)H-(1)H correlation spectroscopy (COSY) were performed on the patient's urine for more accurate assignment of resonances. The NMR spectroscopic studies showed that the unknown resonances could be assigned to arabinitol and ribitol. This was confirmed using gas chromatography. The arabinitol was identified as D-arabinitol. The patient is likely to suffer from an as yet unknown inborn error of metabolism affecting D-arabinitol and ribitol metabolism. The primary molecular defect has not been found yet. Urine spectra of patients suffering from diabetes mellitus or galactosemia were recorded for comparison. Resonances outside the 3.2-4.0 ppm region, which are the most easy to recognize in body fluid spectra, allow easy recognition of various sugars and polyols. The paper shows that NMR spectroscopy in body fluids may help identifying unknown resonances observed in in vivo NMR spectra.

Background: Diagnostic criteria for the Guillain-Barré syndrome (GBS) have been available since 1978. Since then, several variants have been described. More recently, a distinction has been made between pure motor forms, severe sensory forms, primary axonal and primary demyelinating varieties. Associations of clinical characteristics, and specific infections and the presence of antiganglioside antibodies have been found. For further studies on GBS, it is therefore necessary to reconsider the available diagnostic criteria and add additional criteria for subclassification. Methods: A panel of (20) experts was formed. The literature representing the recent developments in GBS subclassification was reviewed. Following a consensus protocol, diagnostic and classification criteria were formulated. Results: The diagnosis of GBS can usually be made on clinical characteristics. A schedule for subclassification has been made to cover also the clinical variants in a systematic manner.

Item does not contain fulltext Sjogren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

Item does not contain fulltext In fetal lambs, severe hypoxia (SH) will lead to brain damage. Mild hypoxia (MH) is thought to be relatively safe for the fetal brain because compensating mechanisms are activated. We questioned whether MH, leading to mild acidosis, induces changes in cerebral metabolism. Metabolites in cerebrospinal fluid (CSF) samples, as analyzed by proton magnetic resonance spectroscopy, were studied in two groups of seven anesthetized near-term fetal lambs. In group I, SH leading to acidosis with an arterial pH

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Background: It is still a commonly held belief that many of the frequently found low cobalamin (Cbl, vitamin B12) levels in older people do not represent deficiency and are therefore without clinical significance and should not be treated. In this study this notion will be challenged. Methods: In this prospective observational cohort design we studied 28 patients aged 65 years and older with low plasma Cbl (≤150 pmol/l). A number of haematological (Hb, MCV, five- and six-lobed granulocytes), metabolic (plasma levels of methylmalonic acid and homocysteine), and gastrointestinal (plasma pepsinogen A and C and protein-bound and free Cbl absorption) parameters, and the response to Cbl treatment, were measured. Cbl deficiency was considered to be present when at least one of the following three criteria was fulfilled: (1) haematological or metabolic abnormalities compatible with Cbl deficiency; (2) Cbl malabsorption or atrophic gastritis; (3) a response to Cbl supplementation. Results: Haematological or metabolic abnormalities were identified in 27 patients. Atrophic gastritis and Cbl malabsorption were identified in, respectively, 15 and 23 patients. Each treated patient showed a haematological or metabolic response to Cbl supplementation. All patients were considered Cbl deficient: 18 patients (64%) fulfilled three criteria of Cbl deficiency, eight (29%) fulfilled two criteria and two (7%) fulfilled one criterion. Conclusions: According to the generally accepted and a wide variety of criteria, we found that older patients with low Cbl levels were cobalamin deficient. Therefore, these patients should receive Cbl supplementation.

Functional characteristics of electrically stimulated quadriceps muscles of patients with multiple sclerosis (MS) were determined to investigate whether adaptations in muscle properties contribute to the higher fatigability of these patients. The estimated maximal isometric force generating capacity of MS patients was only 11.2% (P < 0.05) lower than control subjects. However, the patients were only able to voluntarily exert 75 +/- 22% (n = 12) of their maximal capacity, against 94 +/- 6% (n = 7) for the control subjects. There were no differences in muscle speed, suggesting that muscle fiber distribution was not different in the MS patients due to reduced muscle usage. During a series of repeated contractions, greater decrements occurred in isometric force and in maximal rate of force rise in the MS patients (by 31.3 +/- 10.3% and 50.1 +/- 10.0%, respectively; n = 13) than control subjects (23.8 +/- 6.6% and 39.0 +/- 8.1%, n = 15), suggesting a lower oxidative capacity. The results indicate that increasing the mass of their muscles by training may help to reduce the excessive muscle fatigue of MS patients.

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For the first time we used Fourier transform-infra-red (FT-IR) spectrometry in the investigation of an inborn error of metabolism, i.e. alcaptonuria, which expresses itself by the excretion of high concentrations of homogentisic acid in urine. The 200 homogentisic acid-spiked urine samples, ranging from 0 to 60 mmol l−1, were analysed in the mid-IR region using an attenuated total reflection accessory. Quantification is performed with partial least squares regression analysis. The standard errors of calibration, cross validation and prediction in the IR-predicted homogentisic acid concentration are 0.64, 0.78 and 0.79 mmol l−1, respectively, with R2>0.998. The 2σ detection limit is 2.0 mmol l−1 and the intra- and inter-assay coefficients of variation are below 5% for three concentration levels. The clear difference in the concentrations of homogentisic acid in the urine of four alcaptonuria patients compared to seven control samples demonstrates the potential suitability of IR analysis for the diagnosis and monitoring of alcaptonuria patients.

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During human gait, transmission of cutaneous reflexes from the foot is controlled specifically according to the phase of the step cycle. These reflex responses can be evoked by nonnociceptive stimuli, and therefore it is thought that the large-myelinated and low-threshold Aβ afferent fibers mediate these reflexes. At present, this hypothesis is not yet verified. To test whether Aβ fibers are involved the reflex responses were studied in patients with a sensory polyneuropathy who suffer from a predominant loss of large-myelinated Aβ fibers. The sural nerve of both patients and healthy control subjects was stimulated electrically at a nonnociceptive intensity during the early and late swing phases while they walked on a treadmill. The responses were studied by recording electromyographic (EMG) activity of the biceps femoris (BF) and tibialis anterior (TA) of the stimulated leg. In both phases, large facilitatory responses were observed in the BF of the healthy subjects. These facilitations were reduced significantly in the BF of the patients, indicating that Aβ fibers mediate these reflexes. In TA similar results were obtained. The absolute response magnitude across the two phases was significantly smaller for the patients than for the healthy subjects. The TA responses for the healthy subjects were on average facilitatory during early swing and suppressive during end swing. Both facilitations and suppressions were considerably smaller for the patients, indicating that both types of responses are mediated by Aβ fibers. It is concluded that low-threshold Aβ sensory fibers mediate these reflexes during human gait. The low threshold and the precise phase-dependent control of these responses suggest that these responses are important in the regulation of gait. The loss of such reflex activity may be related to the gait impairments of these patients.

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Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

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The spatial and temporal distribution of compound muscle action potential (CMAP) amplitudes was mapped using 1 × 1-cm grids over thenar, hypothenar, dorsal foot, and foot sole muscles (seven maps each). The high-amplitude zone (HAZ, area where amplitudes were over 80% of the maximum amplitude) denoted susceptibility to changes in recording site. Thenar maps had one peak (spatially and temporally) with a HAZ of 3.5 ± 2.3 cm2. Hypothenar maps had two peaks (spatially and temporally) with a HAZ of 7.7 ± 3.6 cm2. Dorsal foot maps had one temporal peak, which could be split up spatially; the HAZ was smallest, at 1.7 ± 1.7 cm2. Foot sole muscles had one peak (spatially and temporally), with the largest HAZ at 18.4 ± 6.1 cm2. Wave-form differences were ascribed to differences in muscle anatomy, architecture, and variability. These explain differences in amplitude reproducibility between nerves and the differing effect that increasing electrode size has on reproducibility. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 378–389, 1999

Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, non-progressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

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The First Workshop of the European Consortium on Charcot–Marie–Tooth (CMT) disease brought together neuroscientists, molecular and cell biologists, neuropathologists, neurologists, and geneticists with a common interest in the understanding of the fundamental mechanisms that underlie the pathogenesis of CMT. The interdisciplinary group of 25 expert scientists discussed recent advances in (i) molecular genetics and histopathology of CMT, (ii) development of suitable animal models, (iii) understanding of the cellular function of CMT-related proteins, and (iv) studies using nerve biopsies from CMT patients. In this minireview, we summarize the key findings presented and discuss their impact on CMT research.

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Choroid plexus carcinoma is a rare intracranial neoplasm, affecting mainly very young children. The most common site of origin is within one of the lateral ventricles. The diagnosis of choroid plexus carcinoma is based on histological examination. Frequently subarachnoid seeding occurs and investigation at diagnosis should include examination of the cerebrospinal fluid and magnetic resonance imaging of the spinal cord. Extraneural metastases are rare. Prognosis for long-term survival ameliorates. Total surgical resection of the tumor should be attempted. Both radiotherapy and chemotherapy are used as adjuvant therapies for primary tumors. No clear difference in effectiveness of these therapies could be found. However craniospinal irradiation seems to be more effective when leptomeningeal seeding is present.

To establish the existence of predominant right leg involvement in Coxsackievirus B1-induced myositis (CB1 myositis) 189 neonatal CD1 Swiss mice were inoculated with 300 pfu CB1, and regularly observed for posture, mobility, and gait. After 2 and 4 weeks, quantitative comparison of motor dysfunction of right and left leg yielded an asymmetry score; on light microscopy mononuclear cell infiltration and muscle fiber necrosis were quantified in bilateral hamstring muscles, using a five-grade scale (0-4). Motor asymmetries were seen during acute viral myositis as soon as hind leg dysfunction appeared, and animals with a predominant dysfunction of one leg preserved that preference throughout the observation period. At 2 weeks, mice with predominant right leg dysfunction (n = 34) significantly outnumbered those with predominant left leg dysfunction (n = 11) (p = 0.01). At 2 and 4 weeks, infiltration and necrosis in hamstrings from legs with predominant dysfunction were not higher than in those from contralateral legs, and infiltration in right-sided hamstrings was not higher than in left-sided ones, nor was infiltration at 4 weeks. At 4 weeks right-sided muscles were more necrotic (mean +/- SD, 1.8 +/- 1.5) than left-sided muscles (1.1 +/- 1.2; p = 0.03). In the absence of predominant inflammatory disease of the right leg, we interpret the hind leg asymmetry as a preferential use of the left leg, due to left-leggedness, and suggest that in CD1 Swiss mice left-leggedness is associated with increased susceptibility to CB1 myositis.

Contains fulltext : 23663___.PDF (Publisher’s version ) (Open Access) A patient with a deficient voltage-dependent anion channel (VDAC) is reported, presenting clinically with psychomotor retardation and minor dysmorphic features. Biochemical studies on muscle mitochondria showed impaired rates of pyruvate oxidation and ATP production; however, no specific deficient activity of one of the mitochondrial enzymes was involved. Western blotting experiments indicated an almost complete VDAC deficiency in skeletal muscle. The only moderately decreased VDAC content in the patient's fibroblasts might indicate that VDAC is expressed in a tissue-specific manner. The deficiency is likely caused by a mutation in the HVDAC1 gene or by a distributed posttranslational modification. This is the first described deficiency of a component of the outer mitochondrial membrane associated with the pyruvate oxidation pathway. Defects in this membrane should be considered as a possible cause of otherwise unexplained mitochondrial disorders.

The aims of this thesis were: (1) to identify parental occupations with an increased risk of spina bifida in offspring; (2) to study whether parental occupational exposure to chemicals or radiation during or shortly before pregnancy is a risk factor for the occurrence of spina bifida. In order to answer these questions, an epidemiological case-referent study was designed. After an extensivere view of the literature on risk factors for neural tube defects, with emphasison occupational and environmental factors, methodological issues in the design of the survey are discussed. Subsequently the results of the case-referent study, in which questionnaires were used to assess the occupation of the parents at the time of conception, are discussed and compared with studies conducted in Sweden, Spain and Hungary. The most important finding of the core study was an increased risk of spina bifida for women who had an agricultural occupation around conception. Also, working as a cleaning women was found to be associated with spina bifida, although this association was less pronounced. The results with regard to paternal occupations suggest associations with welders and transport workers. However, occupational risk factors do not account for a large part of the prevalence of spina bifida in the total population.

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Item does not contain fulltext The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons.

Item does not contain fulltext A Dutch family with autosomal recessive early-onset parkinsonism showed a heterozygous missense mutation in combination with a heterozygous exon deletion in the parkin gene. Although the main clinical syndrome consisted of parkinsonism, the proband clinically had additional mild gait ataxia and pathologically showed neuronal loss in parts of the spinocerebellar system, in addition to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Lewy bodies and neurofibrillary tangles were absent, but tau pathology was found.

We report on a patient with recovery of activity of the left orbicularis oris and nasalis muscles 3 months after a complete left facial palsy. Stimulation of the affected facial nerve evoked no responses, whereas contralateral facial nerve stimulation showed polyphasic responses with very long latencies in the nasalis and orbicularis oris muscles. Needle electromyography (EMG) revealed abnormal spontaneous activity in the left orbicularis oris muscle. The motor unit action potentials on the left side of the face could be recruited only during marked contraction of the corresponding muscles on the right and were of low voltage and polyphasic ("nascent potentials"). Contralateral reinnervation is probably due to sprouting of terminal branches crossing the midline of the face and innervating bundles of muscle fibers on the affected side. This phenomenon seems unfamiliar to most clinicians. Whether the activity is due to conduction along nerve fibers or muscle fibers crossing the midline is discussed.

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