Frank Lehmann-Horn - Academia.edu (original) (raw)

Papers by Frank Lehmann-Horn

Journal of Bodywork and Movement Therapies, 2012

... Subcutaneous fat was not related to clinical severity. References [1] Olsen D, Gideon P, Dysg... more ... Subcutaneous fat was not related to clinical severity. References [1] Olsen D, Gideon P, Dysgaard Jeppesen T & Vissing J. Leg muscle involvement in fascioscapulohumeral muscular dystrophy assessed by MRI. J Neurol. 253 ...

Osteopathische Medizin, Zeitschrift für ganzheitliche Heilverfahren, 2008

Journal of neurology, neurosurgery, and psychiatry, Jan 16, 2015

To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic... more To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP). We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes. In 10 patients without TPP, we identified 9 heterozygous, novel variations (c.-3G>A, L15S, R81C, E273X, T309I, I340T, N365S, G394R, R401W) and a questionable heterozygous causative R399X stop variant. Studies on 40 relatives of these 10 patients showed that none of the variants were de novo in the patients and that R399X occurred in 3 non-affected relatives. Most affected amino acids lacked conservation and several clinically affected relatives did not carry the patient's variant. T309I, however, could be pathogenic under the pre-requisite of strongly reduced penetrance in females. Of the controls, 17 revealed 12 novel rare variants including the heterozygou...

Anaesthesia, 2014

Malignant hyperthermia is a dreaded complication of general anaesthesia. Predisposed individuals ... more Malignant hyperthermia is a dreaded complication of general anaesthesia. Predisposed individuals can be identified using the standardised caffeine/halothane in-vitro contracture test on a surgically dissected skeletal muscle specimen. Skeletal muscle is composed of muscle fibres and interwoven fascial components. Several malignant hyperthermia-associated neuromuscular diseases are associated with an altered connective tissue composition. We analysed adjacent fascial components of skeletal muscle histologically and physiologically. We investigated whether the fascial tissue is sensitive to electrical or pharmacological stimulation in a way similar to the in-vitro contracture test for diagnosing malignant hyperthermia. Using immunohistochemical staining, α-smooth muscle actin-positive cells (myofibroblasts) were detected in the epi-, endo- and perimysium of human fascial tissue. Force measurements on isolated fascial strips after pharmacological challenge with mepyramin revealed that ...

Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, 2014

We studied the consequences of the Nav1.4 mutation R1448H that is situated in the fourth voltage ... more We studied the consequences of the Nav1.4 mutation R1448H that is situated in the fourth voltage sensor of the channel and causes paramyotonia, a cold-induced myotonia followed by weakness. Previous work showed that the mutation uncouples inactivation from activation. We measured whole-cell Na(+) currents at 10, 15, 20, and 25°C using HEK293 cells stably transfected with wildtype (WT) and R1448H Na(+) channels. A Markov model was developed the parameters of which reproduced the data measured on WT and R1448H channels in the whole voltage and temperature range. It required an additional transient inactivated state and an additional closed-state inactivation transition not previously described. The model was used to predict single-channel properties, free energy barriers and temperature dependence of rates. It allowed us to draw the following conclusions: i) open-state inactivation results from a two-step process; ii) the channel re-openings that cause paramyotonia originate from enha...

Studies in health technology and informatics, 2014

For patients suffering from rare diseases it is often hard to find an expert clinician. Existing ... more For patients suffering from rare diseases it is often hard to find an expert clinician. Existing registries rely on manual registration procedures and cannot easily be kept up to date. A prototype data collection system for discovering experts on rare diseases using MEDLINE has been successfully deployed. Initial manual analyses demonstrate proof of concept and deliver promising results. Examining the associations between authors, diseases and MeSH-Terms is expected to open up a variety of possibilities beyond expert discovery.

Journal of Neurology Neurosurgery and Psychiatry, 1998

Clinical, electrophysiological, and molecular genetic features were investigated in two patients ... more Clinical, electrophysiological, and molecular genetic features were investigated in two patients from a family a with dominantly inherited myotonic disease, characterised by painful cramps, stiffness without weakness, fluctuation of symptoms, and cold sensitivity. A reduction in amplitude of the compound muscle action potential was demonstrated on cooling and administration of potassium, although no clinical exacerbation was seen. A heterozygote mutation

Transitions between distinct kinetic states of an ion chann el are de- scribed by a Markov proces... more Transitions between distinct kinetic states of an ion chann el are de- scribed by a Markov process. Hidden Markov models (HMM) havebeen success- fully applied in the analysis of single ion channel recordin gs with a small signal- to-noise ratio. However, we have recently shown, that the anti-aliasing low-pass filter misleads parameter estimation. Here, we show for the c ase

Orphanet Journal of Rare Diseases, 2014

Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-thr... more Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.

The Journal of Physiology, 2007

The voltage-gated potassium channels K V 7.2 and K V 7.3 (genes KCNQ2 and KCNQ3) constitute a maj... more The voltage-gated potassium channels K V 7.2 and K V 7.3 (genes KCNQ2 and KCNQ3) constitute a major component of the M-current controlling the firing rate in many neurons. Mutations within these two channel subunits cause benign familial neonatal convulsions (BFNC). Here we identified a novel BFNC-causing mutation (E119G) in the S1-S2 region of K V 7.2. Electrophysiological investigations in Xenopus oocytes using two-microelectrode voltage clamping revealed that the steady-state activation curves for E119G alone and its coexpressions with K V 7.2 and/or K V 7.3 wild-type (WT) channels were significantly shifted in the depolarizing direction compared to K V 7.2 or K V 7.2/K V 7.3. These shifts reduced the relative current amplitudes for mutant channels particularly in the subthreshold range of an action potential (about 45% reduction at −50 mV for E119G compared to K V 7.2, and 33% for E119G/K V 7.3 compared to K V 7.2/K V 7.3 channels). Activation kinetics were significantly slowed for mutant channels. Our results indicate that small changes in channel gating at subthreshold voltages are sufficient to cause neonatal seizures and demonstrate the importance of the M-current for this voltage range. This was confirmed by a computer model predicting an increased burst duration for the mutation. On a molecular level, these results reveal a critical role in voltage sensing of the negatively charged E119 in S1-S2 of K V 7.2, a region that -according to molecular modellingmight interact with a positive charge in the S4 segment.

Proceedings of the National Academy of Sciences, 2000

Abbreviations: HypoPP, hypokalemic periodic paralysis; HyperPP, hyperkalemic periodic paralysis; ... more Abbreviations: HypoPP, hypokalemic periodic paralysis; HyperPP, hyperkalemic periodic paralysis; SCN4A, ␣ subunit of the adult skeletal muscle sodium channel; DHP, dihydropyridine; SSCA, single-strand conformation analysis; WT, wild type.

Neuromuscular Disorders, 2005

The purpose of this review is to alert non-anaesthesiologists to the various complications from w... more The purpose of this review is to alert non-anaesthesiologists to the various complications from which patients with neuromuscular disorders and those susceptible to malignant hyperthermia can suffer during anaesthesia. The patient's outcome correlates with the quality of consultation between anaesthesiologists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced administration of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants. This review provides a synopsis of pre-operative anaesthetic considerations and adverse drug effects on skeletal, cardiac and smooth muscle tissue. It describes the pathogenetic aspects of typical complications and introduces anaesthetic procedures for the various neuromuscular disorders, including regional anaesthesia for patients in whom a restriction of respiratory and/or cardiac function is predicted. q

Nature Genetics, 1994

... Rime1, A. Elbaz1, R. Heine4, J. Guimarães3, J. Weissenbach5, N. Baumann1,2, M. Fardeau2-6 &am... more ... Rime1, A. Elbaz1, R. Heine4, J. Guimarães3, J. Weissenbach5, N. Baumann1,2, M. Fardeau2-6 & F. Lehmann-Horn4 Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant muscle disease thought to arise from an abnormal function of ion channels. ...

Muscle & Nerve, 1987

To study the mechanism of periodic paralysis, we investigated the properties of intact muscle fib... more To study the mechanism of periodic paralysis, we investigated the properties of intact muscle fibers biopsied from a patient who had adynamia episodica hereditaria with electromyographic signs of myotonia. When the potassium concentration in the extracellular medium, [K],, was 3.5 mmol/l, force of contraction, membrane resting potential, and intracellular sodium activity were normal, but depolarizing voltage clamp steps revealed the existence of an abnormal inward current. This current was activated at membrane potentials less negative than -80 mV, reached a maximum within 50 msec, and was not inactivated with time. The inward current was completely and reversibly blocked by tetrodotoxin, which indicates that it was carried by sodium ions. In a solution containing 9 mmol/l potassium, normal muscle would depolarize to -63 mV and yet be capable of developing full tetanic force upon stimulation. The muscle from the patient depolarized to -57 mV and became inexcitable, i.e., it was paralyzed. A contracture did not develop. Lowering of the extracellular pH did not influence the resting potential, but it effectively antagonized or prevented the paralytic effect of high [K], by changing the inactivation characteristics of the sodium channels. Hydrochlorothiazide, which had a therapeutic effect on the patient, did not prevent paralysis in vitro. An abnormal rise of the intracellular sodium activity was recorded when the extracellular potassium concentration was raised to 10 mmol/l.

Muscle & Nerve, 1981

Three patients with paramyotonia congenita and 3 control persons were biopsied for an in vitro in... more Three patients with paramyotonia congenita and 3 control persons were biopsied for an in vitro investigation of the sarcolemmal membrane parameters and of the contractile properties of paramyotonic muscle. At 37 degrees C, paramyotonic muscle fibers had normal resting potentials, but on cooling to 27 degrees C they depolarized. Depolarization to -60 mV caused spontaneous activity, and further depolarization to -40 mV caused inexcitability. Depolarization could be prevented by the application of tetrodotoxin, a finding suggesting a defect in the Na channels. Analysis of the membrane current densities using voltage clamps with 3 microelectrodes revealed that in paramyotonic patients at 37 degrees C all component conductances were normal, except for a decreased Cl conductance in the patient who had myotonia in a warm environment. At 27 degrees C, the Na and Cl conductances were abnormally high. The K conductance was always normal. The results explain the clinical symptoms of weakness and paralysis. Potassium- and caffeine-contracture experiments gave normal results. The clinical symptom of paramyotonic stiffness, therefore, has not been explained by these studies.

Muscle & Nerve, 2000

Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic tri... more Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal muscle calcium homeostasis resulting in organ and systemic failure. Susceptibility to MH, an autosomal dominant trait, may be associated with congenital myopathies, but in the majority of the cases, no clinical signs of disease are visible outside of anesthesia. For diagnosis, a functional test on skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over 50% of the families show linkage of the IVCT phenotype to the gene encoding the skeletal muscle ryanodine receptor and over 20 mutations therein have been described. At least five other loci have been defined implicating greater genetic heterogeneity than previously assumed, but so far only one further gene encoding the main subunit of the voltage-gated dihydropyridine receptor has a confirmed role in MH. As a result of extensive research on the mechanisms of excitation-contraction coupling and recent functional characterization of several disease-causing mutations in heterologous expression systems, much is known today about the molecular etiology of MH.