Neuromuscular Diseases and Amyotrophic Lateral Sclerosis (ALS)

Neuromuscular diseases

The difference between ALS-nerve cells and muscle and normal nerve cells and muscle.

The difference between ALS-nerve cells and muscle and normal nerve cells and muscle.

Mayo Clinic researchers are conducting innovative research on the myriad of complex diseases of the muscles and nerves that range from carpal tunnel syndrome to muscular dystrophy--and making strides in developing treatments to reduce discomfort, improve quality of life for patients, and lead to cures. Key areas of research include:

  • Motor neuron diseases--a group of progressive, degenerative nerve disorders that includes amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease)
  • Diseases of the neuromuscular junction such as myasthenia gravis, a chronic but highly treatable condition causing weakness in the voluntary muscles
  • Nerve injuries and peripheral neuropathies--damage to the nerves that transmit crucial information from the spinal cord and brain to the rest of the body
  • Entrapment neuropathies, such as carpal tunnel syndrome, caused by compression of nerves
  • Hereditary neuropathies, the effects of aging on neuropathic conditions, entrapment neuropathies (such as carpal tunnel syndrome), and neurotoxicology
  • Inherited degenerative disorders of skeletal muscle, including muscular dystrophies and myofibrillar myopathies

Ongoing research

Andrew Engel, M.D., studies the neurobiology of congenital myasthenic syndromes (CMS). CMS are heterogeneous and disabling disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). CMS are not uncommon but are commonly misdiagnosed or treated incorrectly. Clinical, morphologic, and electrophysiologic analysis can determine whether a CMS is presynaptic, synaptic, or postsynaptic in origin and point to a defect in an endplate (EP)-specific protein, such as the acetylcholine receptor (AChR), acetylcholinesterase (AChE), or choline acetyltransferase. CMS are investigated by the following:

  • Clinical assessment, including electromyography and tests for anti-AChR antibodies
  • Morphologic assessment, including immunocytochemical localization of AChR, AChE, and other EP-specific proteins; estimate of the number of AChR per EP; ultrastructural analysis of the EP; and evaluation of the density and distribution of AChR on the junctional folds
  • Electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimate of parameters of quantal release, and evaluation of AChR channel kinetics through single-channel patch-clamp recordings
  • Mutation analysis when the preceding studies point to an EP-specific protein
  • Expression studies using genetically engineered mutants

CMS studies are important for diagnosis and prevention of CMS, for investigating disease pathophysiology, for developing strategies for therapy, and for gaining insights into structure-function relationships of EP-specific proteins.

Collaborative studies are ongoing with Steven Sine, Ph.D., on the kinetic analysis of mutaions involving AChR.

Selcen Duygu, M.D., is investigating myofibrillar and related congenital myopathies. The myofibrillar myopathies (MFMs) have a characteristic morphological signature: At the light microscopic and immunocytochemical level they are associated with progressive myofibrillar destruction and the deposition of composite protein aggregates that immunoreact for desmin, alphaB-crystallin, myotilin, dystrophin, CDC2 kinase, prion proteins, and other proteins. At the ultrastructural level, the myofibrillar degenerations begin at the muscle Z-disk. The elemental change is like that observed in minimulticore disease. The ultrastructural findings provide a clue that the MFMs are caused by mutations in Z-disk-related proteins. The investigation tests the hypothesis that mutations in Z-disk-related proteins cause MFM and that appropriate expression studies can provide insights into the pathogenesis of the disease. So far mutations in desmin, alphaB-crystallin, and in other key Z-disk-associated structural proteins including myotilin, ZASP, and Filamin C have been detected in MFM patients.

Anthony J. Windebank, M.D., maintains an active basic science research laboratory investigating mechanisms of cell death and cell recovery associated with ALS. Recent projects have included collaborative efforts with the hematology group in the creation of mesenchymal stem cell lines from subjects with ALS. Animal studies are currently underway, and human clinical studies will begin once adequate safety and efficacy data are obtained from the animal studies.

Eric J. Sorenson, M.D., continues his clinical human research in ALS. The ALS study group has recently completed a large NIH-funded phase III study of IGF-1 in ALS. Additional clinical studies include ongoing epidemiology and genetic studies of the motor neuron diseases. Ongoing human clinical trials remain a focus of the clinical research group.

Recent advances

Mayo Clinic researchers found an unprecedented method to predict brain aging disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease. Investigators studied common variations within axon guidance pathway genes and identified several gene variations (DNA fingerprints) that collectively predicted people who are at a high risk for ALS (2,000 times greater than the average risk). They also identified several gene variations that collectively predicted people at a high risk for Parkinson's disease (nearly 400 times greater than the average risk). The research goal is to predict, prevent, and halt brain aging disorders, such that physicians will be able to do a simple blood test and predict whether a person is at high risk to develop brain aging disorders such as ALS, Parkinson's disease, and even Alzheimer's disease by studying common gene variations in disease pathways. The study was conducted primarily by the Mayo Clinic investigators, with bioinformatic support from Spiridon Papapetropoulos, M.D., Ph.D., and Lina Shehadeh, Ph.D., at the Miller School of Medicine, University of Miami.