Neuromuscular and Movement Disorders Division

Division Director: Rick Barohn, MD
Associate Director; Paul Cheney, PhD

Goal: to improve the lives of people with neuromuscular and movement disorders through advances in understanding basic disease mechanisms and advances in diagnosis and therapy.

Strategy: to enhance translational research programs through communication and collaboration between research teams of preclinical and clinical investigators.

Background and Focus

The Institute for Neurological Disorders, based on the KUMC campus, has a substantial research effort devoted to many aspects of brain health and disease. The Institute is devoted to bringing together research teams to focus on developing new knowledge concerning the mechanism, diagnosis and treatment of disorders that affect the nervous system, including those that affect the motor system of the brain. These disorders deprive us of the ability to make purposeful movements and interact effectively with our environment. What is lost are some of the most basic abilities that have contributed to the success of the human species. This not only includes many functions that are shared with other species, such locomotion, but also functions that make us uniquely human such as speech and skilled use of the hands in tool use and playing musical instruments.

The brain controls skeletal muscles through specialized nerve cells - lower and upper motoneurons. Lower motoneurons are located in the spinal cord and brainstem and send axons (cable like extensions) to muscles where they make specialized contacts called neuromuscular junctions. During movement of a body part, signals are sent from the upper motor neurons located in the cerebral cortex of the brain to the lower motoneurons located in the brainstem (for head and facial muscles) and spinal cord (for limb and trunk muscles). Lower motoneurons then send signals to muscles to cause contraction.

Injury and dysfunction at any point in this network can result in disorders of movement and muscle contraction. Not surprisingly, these disorders include a large number of highly varying conditions depending on what part of the network is injured or dysfunctional. However, what all of these conditions have in common is that they affect some aspect of motor function. Symptoms may include weakness, muscle wasting, pain, spasticity (exaggerated reflexes and muscle spasms), rigidity (muscle stiffness), tremor, involuntary movements, slow movements, inability to initiate voluntary movements, inaccurate movements and unstable gait. Genetic mutations, viral infections, autoimmune disorders, hormonal disorders, metabolic disorders, drugs, toxins and trauma are among the known causative factors but in many cases a cause cannot be identified. Common diseases affecting the peripheral motor apparatus include myasthenia gravis and muscular dystrophy. Moving more centrally, amyotrophic lateral sclerosis (Lou Gehrig’s disease) is a disease in which the lower and upper motoneurons degenerate resulting in severe paralysis and ultimately death. Finally, dysfunction of basal ganglia is known to be responsible for a number of movement disorders, the most common of which is Parkinson’s disease. Similarly, dysfunction of the cerebellum produces a wide range of movement disorders including balance and postural instability, tremor and difficulty making accurate movements.

The prevalence of all disorders affecting the neuromuscular and brain motor system is difficult to estimate because there are so many different conditions. However, some of these conditions are quite common. For example, Parkinson’s disease affects about 1.5 million people in the United States, and its estimated annual total cost in the United States is $5.6 billion dollars. Clearly, advances in prevention and treatment could have a major health impact not only financially but also in improving the lives of the many Americans who suffer from these conditions.

KUMC has been a leader in the field of motor system disorders. This division currently consists of basic and clinical scientists whose accomplishments have been widely recognized nationally and internationally, including contributions to understanding basic motor system function and for treatment of Parkinson’s disease using deep brain electrical stimulation. There is a unique opportunity to build upon our past success by strengthening the division through recruitments targeting basic brain motor function, neuromuscular diseases and Parkinson’s disease.

Translational program focus areas and rationale

Neuromuscular and movement disorders are summarized in the following tables. Although our Institute has active clinical research programs relevant to each of these areas, we have chosen to focus our translational research program on five conditions – amyotrophic lateral sclerosis, peripheral neuropathy, myopathies, myasthenia gravis and Parkinson’s disease. In all of these conditions, limitations to the development of effective diagnostic and treatment strategies stem from an inadequate understanding, not only of the basic disease mechanism, but also of the basic physiology of the neuronal elements that become damaged or dysfunctional as part of the disease process. In some cases this involves molecular events attacking brain elements at a cellular and subcellular level. In other cases, disease related perturbations produce dysfunction of entire neuronal circuits that then translates into abnormal behavior including loss of motor control. Understanding the normal physiology as well as the pathophysiology underlying various disorders will enable a rationale approach to the development of effective intervention and treatment strategies as well as markers for early disease detection. It is also essential to understand each disorder in terms of its symptoms and to be able to quantify the symptoms. This knowledge then provides additional tools for the early detection of disease as well as measures that can be applied to evaluating the effectiveness of new therapeutics. We have mobilized research teams to provide expertise at all the levels of investigation described above. Basic, preclinical and clinical members work as a team to inform each other, identify critical research questions, and bring the power of current cutting edge methodologies to bear on improving the lives of individuals afflicted with neurological disorders.

Table 1. Neuromuscular Disorders

Motor Neuron Disease

Amyotrophic Lateral Sclerosis/Primary Lateral Sclerosis
Spinal muscular Atrophy
Post-polio Syndrome

Peripheral Neuropathy

Acquired
Hereditary (Charcot-Marie-Tooth Disease)

Neuromuscular Junction Disorders

Myasthenia Gravis
Lambert-Eaton Myasthenic Syndrome
Botulism

Myopathies

Hereditary

Muscular Dystrophies
Channelopathies

Acquired

Inflammatory – PM/DM/IBM
Toxic – drug-induced

Table 2. Movement Disorders
Hyopokinetic Parkinson’s Disease Progressive Supranuclear Palsy Parkinson’s Disease “Plus” Multiple System Atrophy Corticobasal Ganglionic Degeneration Diffuse Lewy Body Disease Ataxias Spinocerebeller degenerations	Hyperkinetic Huntington’s disease Dystonias Blepharospasm Torticollis Focal limb distonias Dystonic spasticity Tremor Disorders Essential tremor Cerebellar outflow tract Drug-induced

Amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) is a degenerative disorder involving the neuromuscular system. It affects approximately 1 in 100,000 adults, and is disabling as a result of loss of muscle strength and mobility. Death frequently results from complications related to loss of control of muscles related to respiration and swallowing. The average life expectancy of a patient with ALS is three years.

KUMC has established strengths related to ALS in the basic, clinical and drug discovery realms, which position us well for more organized translational research program. Numerous clinical research trials are currently in progress and nearly all of these are multi-center trials involving 50 to 500 patients nationwide or worldwide. In addition to a large clinical research effort, there is a growing basic science research program in ALS. Excellent rodent models exist for this disease and these models are now being exploited by members of the team to investigate fundamental questions about disease mechanism. For example, Dr John Stanford has developed a novel tool to measure weakness of the tongue, facial and palate muscles, which frequently occurs in both humans and ALS rodent models. Dr Stanford can quantify the progression of the disease, and determine factors that influence this. He and his collaborators are also uniquely positioned to provide insight into the disease mechanism. Other translational research efforts are concerned with inflammatory processes in ALS and their role in neuronal death.

Unique to KUMC is the collaboration between basic science and drug discovery to identify new compounds with therapeutic activity in ALS. Researchers in the Higuchi Institute have developed a class of drugs that has been shown to slow or delay neurodegeneration and these compounds are being tested in Dr Stanford's animal model. If successful, they can potentially be brought into phase 1 trials at the KUMC ALS clinics.

Peripheral neuropathy

Peripheral neuropathy is a form of nerve damage that presents with numbness and weakness in the hands and feet. There are more than 150 causes of peripheral neuropathy. The most common cause is diabetes. In about 10% of patients, peripheral neuropathy has an immune cause. Members of the Institute are currently answering basic question about the mechanism of neuropathy, particularly diabetic neuropathy and conducting clinical trials on a number of very promising medications.

Myopathies and other diseases of muscle

The focus of this research group is on diseases that directly affect muscle cells including muscular dystrophy, idiopathic inflammatory myopathies and channelopathies. Muscular dystrophy refers to a group of muscle diseases that are inherited. The most common childhood forms are Duchenne muscular dystrophy. It weakens young boys early on and limits their survival. Duchenne muscular dystrophy is due to the absence of dystrophin, an essential muscle protein. The most common adult muscular form is myotonic dystrophy which results in muscle weakness, tiredness, heart rhythm problems and other related health issues. There are currently no available treatments to modify the outcome of these diseases.

Idiopathic inflammatory myopathies are a group of muscle disorders associated with muscle inflammation. Polymyositis, dermatomyositis and inclusion body myositis result in muscle degeneration and muscle weakness. Dermatomyositis manifests additionally with a typical skin rash. While there is no effective treatment for inclusion body myositis, many of the polymyositis and dermatomyositis patients do respond well to high dose prednisone.

The channelopathies are a group of disorders characterized by muscle stiffness or attacks of weakness. These are due to mutations affecting the genes that code for various ion channels in muscle cell membranes such the chloride, sodium and calcium channels.

There is a clear need for better understanding the pathophysiology of these disorders and for more effective interventions and therapies.

Myasthenia Gravis

Myasthenia gravis is a chronic autoimmune disorder of the neuromuscular junction. Antibodies directed to key receptors cause fatigue and weakness in various muscle groups. It commonly affects the eye muscles, the arms and legs, and the muscles involved in chewing, swallowing and breathing. Members of the Institute are currently working on basic aspects of neuromuscular junction function. Clinical trials focus on a number of very promising medications that suppress the immune system. Other efforts are concerned with development of effective outcome measures to evaluate quality of life.

Parkinson’s Disease, Huntington’s Disease and Tremor

Movement disorders are categorized as either hypokinetic or hyperkinetic. Hypokinetic conditions include Parkinson’s disease where movements are slow or absent. Hyperkinetic conditions include Huntington’s chorea and tremor where movements are involuntary and exaggerated. The Institute currently has a very active research program focusing on the pathophysiology and treatment of these conditions.

Parkinson’s disease is a neurodegenerative disorder with the primary symptoms of bradykinesia (slowness), rigidity (stiffness), tremor and postural instability that affects approximately 1,000,000 persons in the United States. The most common presenting motor symptoms of Parkinson’s disease include decreased arm swing on one side, decreased blink rate or burning eyes, cramping, decreased dexterity on one side, shorter, shuffling steps, soft or hoarse voice, “poker” face, dragging of one leg, tremor on one side when resting, shoulder pain and stooped posture. Early non-motor symptoms of Parkinson’s disease include anxiety, apathy, slowed thinking, constipation, depression, executive dysfunction, fatigue, reduced or loss of smell, sleep disturbances, urinary frequency/urgency and blurred or double vision. Parkinson’s disease is a result of the loss of the neurotransmitter dopamine in a part of the brain called the substantia nigra. The cause of this loss of dopamine is not known. There are multiple therapies available for Parkinson’s disease including carbidopa/levodopa, dopamine agonists, monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitor, amantadine, anticholinergics and in the appropriate patient, deep brain stimulation (DBS) surgery.

In addition to numerous drug trials, the research team has a long history of research excellence in deep brain stimulation as a treatment for Parkinson’s disease. Translational projects are concerned with better understanding brain circuits involved in Parkinson’s disease, how these circuits function normally and what goes wrong in Parkinson’s disease. Another major effort is directed at understanding the nature of the motor impairments associated with Parkinson’s disease, for example, early detection of movement disorders.