Sandbox:ivbalaraman

INTRODUCTION

Lambert Eaton Myasthenic syndrome is a rare disorder causing muscle weakness targeting the Neuromuscular junction.This disorder is usually seen with Small cell Lung cancer, which may be an indication to investigate for SCLC.

PATHOPHYSIOLOGY

Understanding the concept of Neuromuscular junction,Presynaptic Acetylecholine (ACh) concentration,end plate potential, post-synpatic ACh receptors, role of Calcium and Voltage gated Calcium channel(VGCC) and role of potassium is essential to understand the pathophysiology of Lambert Eaton Myasthenic syndrome.

Briefly, The disease is of autoimmune origin, that is, it is caused by antibodies that are directed against the antigens of the neuromuscular junction. In 1989, the previously anticipated antibodies were demonstrated to be directed against presynaptic calcium channels, which are located in neuromuscular junction (see synapse) and are responsible for the efficient release of acetylcholine

In cases with both LEMS and lung cancer (usually small cell type), the antibodies are suggested to be aimed at cancer cells and to bind and affect the antigens in neuromuscular junction accidentally.

====Voltage Gated Calcium Channel==== [[1]]

• Potassium channels and the concentration of potassium ions does not contribute to the ACh release.

The mechanism by which the ACh is released is by increasing the concentration of calcium ions and their influx into the nerve terminal viz Voltage gated calcium channel (VGCC)

VGCC is a transmembrane protein with many subunits that is the main target in LEMS.

The commonly associated subtypes are L-type,N-type,P/Q-Type of alpha-1 subunit of VGCC, of which the P/Q subtype is the most important target in the disorder. N-Type is usually associated with the paraneoplastic LEMS.

VGCC is responsible for releasing the accumulated ACh in nerve terminal. Thereafter ACh binds to its receptor that depolarizes the muscle fibre end plate leading to a muscle contraction by generating a action potential. IgG antibodies of LEMS acts on the VGCC leading to the disorder of the above mechanism resulting in muscle weakness.

In paraneoplastic LEMS, Small cell lung cancer expresses the VGCC on the sufrace of the tumor cells that acts as the antigen to trigger the antibody production causing profound clinical symptoms.No genetic predisposition seen.

In Non-paraneoplastic syndrome,the autoimmunity against the P/Q type VGCC are seen usually in HLA-B8(HLA-Class I) and HLA- DR3 & HLA- DQ2 (HLA -class II) genes.

There are also some patients who do not carry these antibodies in their serum samples and the exact cause of disease in these cases still remains to be determined.