-
Tremor and Other Hyperkinetic Movements... Oct 2020The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous...
The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.
Topics: Adult; Amifampridine; Ataxia; Chorea; Dystonia; Electroencephalography; Female; Hallucinations; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Ocular Motility Disorders; Potassium Channel Blockers
PubMed: 33178487
DOI: 10.5334/tohm.549 -
The Journal of Biological Chemistry 20213,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the...
3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-approved treatment for neuromuscular weakness caused by Lambert-Eaton myasthenic syndrome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the presynaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-target agonist effect on the Cav1 subtype ("L-type") of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAP's mechanism(s) of action, we first used the patch-clamp electrophysiology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-affinity (1-10 μM) partial antagonist effect of 3,4-DAP in addition to the well-known low-affinity (0.1-1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5- or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, independent of Cav1 calcium channels. Finally, we demonstrated that 1.5- or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv channels to mediate AP broadening and enhance transmitter release at the NMJ.
Topics: Acetylcholine; Action Potentials; Amifampridine; Animals; Calcium Channels, L-Type; Calcium Channels, N-Type; Dose-Response Relationship, Drug; Female; Gene Expression; Male; Mice; Microelectrodes; Neuromuscular Agents; Neuromuscular Junction; Potassium Channel Blockers; Presynaptic Terminals; Rana pipiens; Shaw Potassium Channels; Tissue Culture Techniques
PubMed: 33465376
DOI: 10.1016/j.jbc.2021.100302 -
Journal of Neurology, Neurosurgery, and... Oct 2013A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles...
BACKGROUND
A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement.
METHODS
We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations.
RESULTS
Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present.
CONCLUSIONS
These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.
Topics: 4-Aminopyridine; Adrenergic beta-2 Receptor Agonists; Adult; Age of Onset; Albuterol; Amifampridine; Biopsy; Cholinesterase Inhibitors; DNA Mutational Analysis; Diagnosis, Differential; Exome; Female; Genetic Testing; Glycosylation; Humans; Male; Middle Aged; Motor Neurons; Muscle, Skeletal; Myasthenic Syndromes, Congenital; N-Acetylglucosaminyltransferases; Neurologic Examination; Neuromuscular Junction; Phenotype; Potassium Channel Blockers; Pyridostigmine Bromide
PubMed: 23447650
DOI: 10.1136/jnnp-2012-304716 -
Biophysical Journal Aug 1994Ionic conduction in the axolemmal and septal membranes of the medial giant fiber (MGF) of the earthworm (EW) Lumbricus terrestris was assessed by impedance spectroscopy...
Ionic conduction in the axolemmal and septal membranes of the medial giant fiber (MGF) of the earthworm (EW) Lumbricus terrestris was assessed by impedance spectroscopy in the frequency range 2.5-1000 Hz. Impedance loci in the complex plane were described by two semi-circular arcs, one at a lower characteristic frequency (100 Hz) and the other at a higher frequency (500 Hz). The lower frequency arc had a chord resistance of 53 k omega and was not affected by membrane potential changes or ion channel blockers [tetrodotoxin (TTX), 3,4-diaminopyridine (3,4-DAP), 4-aminopyridine (4-AP), and tetraethylammonium (TEA)]. The higher frequency arc had a chord resistance of 274 k omega at resting potential, was voltage-dependent, and was affected by the addition of TTX, 3,4-DAP, 4-AP, and TEA to the physiological EW salines. When all four blockers were added to the bathing solution, the impedance locus was described by two voltage-independent arcs. Considering the effects of these and other (i.e., Cd and Ni) ion channel blockers, we conclude that: 1) the higher frequency locus reflects conduction by voltage-sensitive ion channels in the axolemmal membrane, which contains at least four ion channels selective for sodium, calcium, and potassium (delayed rectifier and calcium-dependent), and 2) the lower frequency locus reflects voltage-insensitive channels in the septal membrane, which separates adjacent MGFs.
Topics: 4-Aminopyridine; Amifampridine; Animals; Axons; Electric Stimulation; In Vitro Techniques; Ion Channels; Membrane Potentials; Models, Neurological; Models, Theoretical; Nerve Fibers; Neural Conduction; Oligochaeta; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin
PubMed: 7524713
DOI: 10.1016/S0006-3495(94)80528-4 -
Neuroscience Dec 2012While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the...
While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the exploration of ectopic endometrium as a source of endometriosis pain. Rats were surgically implanted with autologous uterus in the gastrocnemius muscle. Within two weeks, visual inspection revealed the presence of a reddish-brown fluid-filled cystic structure at the implant site. Histology demonstrated cystic glandular structures with stromal invasion of the muscle. Immunohistochemical studies of these lesions revealed the presence of markers for nociceptor nerve fibers and neuronal sprouting. Fourteen days after surgery rats exhibited persistent mechanical hyperalgesia at the site of the ectopic endometrial lesion. Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic. Systemic administration of leuprolide also produced antihyperalgesia. In vivo electrophysiological recordings from sensory neurons innervating the lesion revealed a significant increase in their response to sustained mechanical stimulation. These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain. This model of endometriosis allows mechanistic exploration at the lesion site facilitating our understanding of endometriosis pain.
Topics: 4-Aminopyridine; Action Potentials; Amifampridine; Animals; Antineoplastic Agents, Hormonal; Biophysics; Calcitonin Gene-Related Peptide; Cells, Cultured; Chronic Pain; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Endometriosis; Endometrium; Estrous Cycle; Female; GAP-43 Protein; Ganglia, Spinal; Hyperalgesia; Lectins; Leuprolide; Muscle, Skeletal; Nerve Fibers; Patch-Clamp Techniques; Potassium Channel Blockers; Progesterone; Progestins; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Tetraethylammonium; Time Factors; Transplants; Uterus
PubMed: 22922120
DOI: 10.1016/j.neuroscience.2012.08.033 -
Journal of Neurology, Neurosurgery, and... Aug 1998To assess the distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome (LEMS) to identify the most sensitive muscle to use in routine...
OBJECTIVE
To assess the distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome (LEMS) to identify the most sensitive muscle to use in routine examination.
METHODS
Surface recorded compound muscle action potential (CMAP) amplitudes were made from abductor digiti minimi, abductor pollicis brevis, anconeus, biceps brachii, and trapezius in 10 patients with LEMS. The effect of 3,4-diaminopyridine (3,4-DAP) was recorded in each muscle in nine patients. CMAP amplitudes were measured at rest and immediately after 10 seconds maximal voluntary contraction in each muscle. Values were compared with results obtained from 12 healthy controls.
RESULTS
Resting CMAP amplitudes were reduced in at least one muscle in all patients compared with controls, most markedly in abductor digiti minimi and anconeus. The administration of 3,4-DAP resulted in significantly improved resting CMAP amplitudes in trapezius only. After maximal voluntary muscle contraction, characteristic increments in CMAP amplitude of over 100% above resting values were seen in abductor digiti minimi and abductor pollicis brevis in seven patients, anconeus and biceps brachii in five patients. No patient had this level of increment in trapezius.
CONCLUSION
Despite predominantly proximal limb weakness seen clinically in patients with LEMS, the most sensitive muscles for detecting characteristic electrophysiological abnormalities of low resting CMAP amplitude and increment of over 100% after 10 seconds maximal voluntary contraction are abductor digiti minimi, abductor pollicis brevis, and anconeus.
Topics: 4-Aminopyridine; Adult; Aged; Amifampridine; Diagnosis, Differential; Electric Stimulation; Electrodiagnosis; Evoked Potentials, Motor; Female; Humans; Isometric Contraction; Lambert-Eaton Myasthenic Syndrome; Male; Middle Aged; Muscle, Skeletal; Peripheral Nerves
PubMed: 9703174
DOI: 10.1136/jnnp.65.2.213 -
Journal of Neuroengineering and... Jan 2010The K+ channel blocking aminopyridines greatly improve skeletal muscle isometric contractile performance during low to intermediate stimulation frequencies, making them...
The K+ channel blocking aminopyridines greatly improve skeletal muscle isometric contractile performance during low to intermediate stimulation frequencies, making them potentially useful as inotropic agents for functional neuromuscular stimulation applications. Most restorative applications involve muscle shortening; however, previous studies on the effects of aminopyridines have involved muscle being held at constant length. Isotonic contractions differ substantially from isometric contractions at a cellular level with regards to factors such as cross-bridge formation and energetic requirements. The present study tested effects of 3,4-diaminopyridine (DAP) on isotonic contractile performance of diaphragm, extensor digitorum longus (EDL) and soleus muscles from rats. During contractions elicited during 20 Hz stimulation, DAP improved work over a range of loads for all three muscles. In contrast, peak power was augmented for the diaphragm and EDL but not the soleus. Maintenance of increased work and peak power was tested during repetitive fatigue-inducing stimulation using a single load of 40% and a stimulation frequency of 20 Hz. Work and peak power of both diaphragm and EDL were augmented by DAP for considerable periods of time, whereas that of soleus muscle was not affected significantly. These results demonstrate that DAP greatly improves both work and peak power of the diaphragm and EDL muscle during isotonic contractions, which combined with previous data on isometric contractions indicates that this agent is suitable for enhancing muscle performance during a range of contractile modalities.
Topics: 4-Aminopyridine; Amifampridine; Animals; Diaphragm; Extremities; Isotonic Contraction; Muscle Fatigue; Muscle, Skeletal; Organ Culture Techniques; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley
PubMed: 20064261
DOI: 10.1186/1743-0003-7-1 -
Journal of Applied Physiology... Nov 1996Among the aminopyridines, 3,4-diaminopyridine (DAP) is a more effective K+ channel blocker than is 4-aminopyridine (4-AP), and, furthermore, DAP enhances neuromuscular...
Among the aminopyridines, 3,4-diaminopyridine (DAP) is a more effective K+ channel blocker than is 4-aminopyridine (4-AP), and, furthermore, DAP enhances neuromuscular transmission. Because 4-AP improves muscle contractility, we hypothesized that DAP would also increase force and, in addition, ameliorate fatigue and improve the neurotransmission failure component of fatigue. Rat diaphragm strips were studied in vitro (37 degrees C). In field-stimulated muscle, 0.3 mM DAP significantly increased diaphragm twitch force, prolonged contraction time, and shifted the force-frequency relationship to the left without-altering peak tetanic force, resulting in increased force at stimulation frequencies < or = 50 Hz. During 20-Hz intermittent stimulation, DAP increased diaphragm peak force compared with control during a 150-s fatigue run and, furthermore, significantly improved maintenance of intratrain force. The relative contribution of neurotransmission failure to fatigue was estimated by comparing the force generated by phrenic nerve-stimulated muscles with that generated by curare-treated field-stimulated muscles. DAP significantly increased force in nerve-stimulated muscles and, in addition, reduced the neurotransmission failure contribution to diaphragm fatigue. Thus DAP increases muscle force at low-to-intermediate stimulation frequencies, improves overall force and intratrain fatigue during 20-Hz intermittent stimulation, and reduces neurotransmission failure.
Topics: 4-Aminopyridine; Amifampridine; Animals; Diaphragm; Electric Stimulation; In Vitro Techniques; Isometric Contraction; Male; Muscle Fatigue; Phrenic Nerve; Potassium Channels; Rats; Rats, Sprague-Dawley; Synaptic Transmission
PubMed: 8941547
DOI: 10.1152/jappl.1996.81.5.2214 -
The Journal of Physiology Dec 19901. The three-microelectrode voltage clamp technique and pharmacological agents were used to examine the properties and functions of potassium currents in squid giant...
1. The three-microelectrode voltage clamp technique and pharmacological agents were used to examine the properties and functions of potassium currents in squid giant presynaptic terminals. 2. Outward currents consisted of two components: a slow component which activated over hundreds of milliseconds and was blocked by extracellular application of tetraethylammonium (TEA) ions and a more rapidly activating component which was relatively insensitive to extracellular TEA. 3. The more rapid component was studied in isolation by treating presynaptic terminals with extracellular TEA, as well as tetrodotoxin (to block sodium channel currents) and manganese (to block calcium channel currents). The magnitude of this current component was 1-2 mA cm-2 at 0 mV. Rates of activation and deactivation were voltage dependent and little evidence of inactivation was seen for depolarizations less than several seconds in duration. 4. The reversal potential of the current was -70 to -80 mV in normal saline and became more positive with elevated extracellular potassium concentrations, suggesting that potassium is the primary permeant ion. Accumulation of extracellular potassium appeared to be marked during depolarizations that produced significant activation of the current. 5. Extracellular application of 3,4-diaminopyridine (DAP) blocked the current with an apparent dissociation constant of 7 microM at 0 mV. Intracellular applications of DAP and TEA also were effective in reducing this current. These treatments, but not extracellular TEA application, broadened presynaptic action potentials and increased the magnitude and time-to-peak of postsynaptic currents elicited by the broadened presynaptic action potentials. Postsynaptic currents were a sensitive and linear function of action potential duration; a 30% increase in action potential duration increased postsynaptic current amplitude by 190%. 6. Estimation of the magnitude and time course of the presynaptic calcium current, based on previous measurements of calcium channel gating, indicated that action potential broadening produces a large increase in calcium current magnitude. These calculations predict that a 30% increase in presynaptic action potential duration will increase the peak amplitude of the calcium current by approximately 170% and the total amount of calcium entry by approximately 230%. This implies a linear relationship between transmitter release and calcium entry during an action potential and can be explained by assuming that calcium co-operatively triggers release within intracellular domains that do not overlap.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: 4-Aminopyridine; Action Potentials; Amifampridine; Animals; Cell Membrane Permeability; Decapodiformes; Ganglia, Sympathetic; In Vitro Techniques; Kinetics; Manganese; Neurotransmitter Agents; Potassium; Potassium Channels; Synapses; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin
PubMed: 1983120
DOI: 10.1113/jphysiol.1990.sp018333 -
Journal of Neurophysiology Feb 2003The physiological and pharmacological properties of the motoneuron membrane and action potential were investigated in larval zebrafish using whole cell patch...
The physiological and pharmacological properties of the motoneuron membrane and action potential were investigated in larval zebrafish using whole cell patch current-clamp recording techniques. Action potentials were eliminated in tetrodotoxin, repolarized by tetraethylammonium (TEA) and 3,4-diaminopyridine (3,4-AP)-sensitive potassium conductances, and had a cobalt-sensitive, high-threshold calcium component. Depolarizing current injection evoked a brief (approximately 10-30 ms) burst of action potentials that was terminated by strong, outwardly rectifying voltage-activated potassium and calcium-dependent conductances. In the presence of intracellular cesium ions, a prolonged plateau potential often followed brief depolarizations. During larval development (hatching to free-swimming), the resting membrane conductance increased in a population of motoneurons, which tended to reduce the apparent outward rectification of the membrane. The conductances contributing to action potential burst termination are hypothesized to play a role in patterning the synaptically driven motoneuron output in these rapidly swimming fish.
Topics: 4-Aminopyridine; Action Potentials; Amifampridine; Anesthetics, Local; Animals; Calcium Channels; Cobalt; Motor Neurons; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels; Sodium Channels; Swimming; Tetraethylammonium; Tetrodotoxin; Zebrafish
PubMed: 12574443
DOI: 10.1152/jn.00324.2002