Neuromuscular Transmission in Amyotrophic Lateral Sclerosis
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      Consistent data suggest that neuromuscular transmission is impaired in ALS patients.
      Neuromuscular junctions dysfunction may appear very early in the disease, as shown by data in
      animal models. The pathogenesis of this neuromuscular transmission impairment is unknown.
      Nogo A isoform, a possible marker of the disease over-expressed in skeletal muscle of ALS
      patients, can be involved. We will characterize the pathophysiological mechanisms implicated
      using a complete study of the structure and function of the NMJ on muscle biopsies, in a
      group of 20 ALS patients compared to 10 controls.
    

Detailed description: 
      Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder involving
      motor neurons of the motor cortex, brain stem and spinal cord. Its pathogenesis remains
      unknown, and the only drug currently available, riluzole, only modestly prolongs survival.
      Consistent data show that neuromuscular transmission is impaired in patients with ALS. The
      significance of these abnormalities remains unknown, but recent data suggest that they
      potentially play a key role in the pathogenesis of the disease. Neuromuscular junctions
      (NMJs) dysfunction may appear very early in the disease, as shown by data in animal models.
      The mechanisms of this neuromuscular transmission impairment are unknown. Nogo A belonging to
      the family of neurite outgrowth inhibitor proteins which is abnormally expressed in skeletal
      muscle of ALS patients, is probably involved as it has been shown that over-expression of
      Nogo A in wild-type muscle leads to destabilization of NMJs. A detailed study of the
      structure and function of the NMJ in ALS patient is mandatory to better characterize the
      pathophysiological mechanisms implicated.

      The aim of this study is to characterize the neuromuscular transmission dysfunction in ALS.
      For this purpose, we will study the structural and functional features of NMJs on muscle
      biopsies in a group of 20 ALS patients compared to 10 controls. Using biopsies of a vestigial
      muscle, the anconeus, we will perform a morphological study of the NMJ, including routine
      histochemistry, immunohistochemical studies for NMJ major proteins and immune IgG complexes
      and electron microscopy study. The number of acetylcholine receptors per endplate will be
      determined by radiolabeled alpha-bungarotoxin binding. Expression levels of Nogo-A will be
      determined in muscle specimens by western blot. Synaptic transmission at individual NMJs will
      also be studied ex vivo. We will record membrane potential over time using different nerve
      stimulation frequencies and we will analyze the properties of the miniature endplate
      potentials (spontaneous release of acetylcholine) and endplate potentials after stimulation
      of the nerve (evoked release of acetylcholine). The results of this structural and functional
      study of NMJ on muscle biopsy will be correlated with surface-EMG and clinical data.

      This study will help identifying new mechanisms involved in the pathophysiology of ALS and
      potential new targets for future treatments.
    

Intervention name(s): Anconeus Muscle biopsy
Intervention type(s): Procedure
Intervention description(s): Anconeus muscle specimens will be surgically removed. The biopsy will be performed under regional anaesthesia and will require an about 5 cm incision of the skin and muscle fascia from the lateral condyle to over the ridge of the proximal ulna, 3 or 4 cm distal to the tip of the olecranon. A triangular muscle flap will be removed, and then the fascia and skin will be closed with running dissolving suture.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: ALS; Motor neuron; Pathophysiology; Neuromuscular junction; Neuromuscular transmission; Microelectrodes