Human Anatomy Physiology I PSIO201 Fall 2015 Integration Lecture 2 Neuromuscular Diseases MJ Ramirez Contact Info office Ina Gittings Building room 3A email mjramire email arizona edu phone 621 0733 Office Hours By appointment SI Integration Session on December 13th Looking for an opportunity to practice applying and integrating the concepts that you have been learning all semester Come join your peers at our last final exam integration session on Sunday December 13th from 3 00 5 00 pm in the Javelina Room at Park Student Union for a cumulative applicationbased session involving fun collaboration with your fellow classmates and engaging group activities We hope to see you all there good luck with your final exams Integration Lecture 2 Objectives 1 Apply knowledge gained in this course to physiological scenarios problems 2 Integrate information across organ systems Voluntary muscle movement Key Features of Neuromuscular Function Action potential travels along axon of motor neuron to the presynaptic terminal on the muscle fiber Depolarization of terminal opens calcium channels to trigger release of acetylcholine Ach Acetylcholine binds to nicotinic Ach receptors on muscle Excess is destroyed by acetylcholinesterase Binding of Ach to receptors opens ligand gated sodium channel to cause large muscle depolarization EPSP which invariably triggers muscle action potential in healthy individual Action potential triggers calcium release from sarcoplasmic reticulum SR which allows sliding of actin myosin filaments due to cross bridges The latter is dependent on ATP as is subsequent sequestering of calcium back into SR Problem 1 Preliminary diagnosis Patient presents with muscle weakness Difficulty standing up from seated position or lifting objects Decreased stretch reflex Minor atrophy loss of muscle tissue Major Classes of Neuromuscular Disease Motor neuron transmission failure e g Amyotrophic Lateral Sclerosis or Multiple Sclerosis Efferent action potentials fail to reach synaptic terminal either due to motor neuron degeneration or loss of myelin on axons Neuromuscular transmission failure e g Lambert Eaton Syndrome or Myasthenia Gravis Motor neuron action potential arrives at neuromuscular junction but fails to cause sufficient muscle excitation Myopathies e g Muscular Dystrophy or McArdle s Myopathy Skeletal muscle weakness defects in muscle proteins loss of muscle fibers An inherited metabolic disorder in which genes encoding enzymes that aid in glucose metabolism are mutated Diagnostics The conduction velocity of the nerve is within the normal range 45 70 m s https youtu be xTHiqR45T8Y Diagnostics Interestingly muscle contracts when fiber is stimulated directly with electric shock https youtu be lXtB PqVHlY Which class of neuromuscular disease is suffered by our patient A Motor neuron transmission failure B Neuromuscular transmission failure C Myopathies 59 24 17 A B C Problem 2 What is the specific problem with patient s neuromuscular synaptic transmission Motor Neuron Muscle Lambert Eaton Syndrome Autoimmune disorder in which the body produces antibodies against voltage gated calcium channels in its own presynaptic terminals This results in decreased release of Ach from presynaptic terminals failure to cause an action potential in the muscle fiber and therefore muscle weakness Myasthenia Gravis Autoimmune disorder in which the body produces antibodies against nicotinic Ach receptors at its own neuromuscular junctions This results in failure of Ach to open enough ligand gated channels in postsynaptic membrane failure of muscle action potential and therefore muscle weakness Diagnostics https youtu be OA7gIFMzr2c In our patient musclesuch Acetylcholinesterase inhibitors are drugs activation is restored when as neostigmine physostigmine or acetylcholinesterase is blocked by a drug endrophonium https youtu be JPBCgQlrypk Does the patient suffer from Lambert Eaton or Myasthenia Gravis A Lambert Eaton Syndrome B Myasthenia Gravis 66 34 A B Sydney Funnel Web Spider Australia One of the deadliest spiders in the world Careful where you step Based upon the initial description of symptoms which divisions of the nervous system are being affected most by the Funnel Web Spider FWS venom A Somatic NS and Parasympathetic 43 B ANS C Enteric NS and Sympathetic 25 D Somatic NS ANS and Enteric NS 13 11 8 E ANS and Enteric NS A B C D E Why is the answer that these symptoms reflect the output of both branches of the ANS 1 Atracotoxin is triggering action potentials in all axons it reaches and most tissues are innervated by both branches of the ANS 2 Uncontrolled sympathetic output would explain excessive sweating heart palpitations and hypertension high blood pressure leading to excess fluid edema in the lungs 3 Uncontrolled parasympathetic output explains excessive salivation and lacrimation tearing The FWS venom has only one protein target found in the nervous system What could the protein target possibly be that it would result in such a huge variety of nervous system effects The toxin enhances the function of a single protein Which protein target might be a candidate for such a huge variety of nervous system effects A ACh gated sodium channel 42 B Potassium leak channel 27 C Sodium potassium ATPase 21 D Voltage gated sodium channel 10 A B C D About FWS Venom Contains an excitatory toxin called atracotoxin or ACTX ACTX is an excitatory toxin that binds to voltagegated sodium channels In mammals ACTX does two things 1 Prolong the action potential by generating a plateau of depolarization lasting up to 100ms 2 Cause spontaneous repetitive firing of action potentials with increasing frequency starting at 1 per second In 1981 was there Any Treatment for Severe Envenomation by the Australian Funnel Web Spider Yes Antivenom had just been approved for use in local hospitals the culmination of a lifetime of work by Dr Struan Sutherland After receiving 4 ampules from the very first batch of antivenom George Wheatley was rescued from certain death If it hasn t killed him just give him some more These were Dr Struan Sutherland s instructions concerning Gordon Wheatley the first recipient of Funnel Web Spider antivenom in 1981