Spinal muscular atrophy, lower extremity dominant (SMA-LED) is a rare form of SMA. It is characterized by leg-muscle weakness, with symptoms being most severe in the thigh muscles (quadriceps). The condition usually develops in infancy or early childhood and has a slow rate of progression.

Symptoms of this SMA form include waddling or an unsteady walk, and difficulties in rising from a seated position and in climbing stairs. It is unclear why this condition only affects the lower extremities.

The genetic cause of SMA-LED

SMA-LED is caused by mutations in the DYNC1H1 gene (dynein cytoplasmic 1 heavy chain 1) and is inherited in a dominant way. This means that only one mutated copy of the DYNC1H1 gene (inherited from one parent) is enough to cause the disease.

The DYNC1H1 gene is located on chromosome 14 and provides instructions for making a protein that is part of a complex group of proteins, known as dynein, found in the cytoplasm (fluid inside the cell). Dynein is activated by binding to another complex of proteins known as dynactin.

The dynein-dynactin complex binds to various materials within cells, moving material along a system of small tubes called microtubules. Among many other cell processes, the dynein-dynactin complex has very important functions in protein transport, positioning of cell compartments, and mobility of structures within cells. In nerve cells (neurons), dynein helps neighboring cells to communicate by moving synaptic vesicles that contain chemical messengers.

In SMA-LED, the mutated DYNC1H1 gene causes changes in the amino acid sequence (single protein building blocks) in the heavy chain of the dynein complex. As a result, the movement of proteins and cellular materials is impaired, resulting in a decrease in chemical messaging between neurons that control muscle movement. This is thought to contribute to muscle weakness in patients.

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