Spinal muscular atrophy with lower extremity predominance (SMA-LED) – DYNC1H1 and BICD2 genes

Spinal muscular atrophy with lower extremity predominance (SMA-LED), also known as Kugelberg-Welander disease or spinal muscular atrophy type III (SMA3), is a process characterized by muscular weakness and atrophy in the lower extremities, as a consequence of the loss of motor neurons.

Muscular difficulties in most people with SMA-LED are evident in childhood or early childhood. However, approximately one quarter of affected people do not develop muscular weakness until adulthood. These problems may include instability when walking; difficulty getting up from a sitting position and climbing stairs; contractures in the hips, knees, feet and ankles; and arthrogryposis in the shoulders, elbows and hands in some individuals.

This process is due to mutations in the DYNC1H1 gene (dynein cytoplasmic 1 heavy chain 1) or in the BICD2 gene (BICD charge adapter 2). Depending on its genetic cause, this disease is classified in SMA-LED type 1 when it is due to mutations in the DYNC1H1 gene or in SMA-LED type 2 when it is due to mutations in the BICD2 gene.

The DYNC1H1 gene, located on the long arm of chromosome 14 (14q32.31), encodes a protein that is part of the dynein complex. This complex is part of a network that transports proteins and other materials into cells. The protein encoded from the BICD2 gene, located on the long arm of chromosome 9 (9q22.31), binds to the dynein complex, activating it and facilitating its binding to other cellular materials for synaptic transport. Thus, the BICD2 protein and the dynein complex help neighboring neurons to communicate by transporting synaptic vesicles containing chemical messengers. The BICD2 protein also helps maintain the structure of the Golgi apparatus, in which newly encoded proteins are modified so that they can carry out their functions

At least, eight mutations in the DYNC1H1 gene and six mutations in the BICD2 gene have been identified in individuals with spinal muscular atrophy predominantly in the lower extremities (SMA-LED). The mutations identified in both genes consist of amino acid changes that inhibit the function of the dynein complex. Consequently, the transport of proteins, synaptic vesicles and other materials inside the cells is reduced. It is believed that reduced transport of synaptic vesicles in motor neurons damages the growth of neurons, which contributes to muscle weakness and atrophy. In addition, mutations of the BICD2 gene affect the ability of the BICD2 protein to maintain the structure of the Golgi apparatus inside cells. As a consequence, the Golgi apparatus is broken down into small fragments and the altered BICD2 protein is trapped inside these fragments. The loss of these cellular components is likely to contribute to the signs and symptoms of SMA-LED.

This disease is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. In some cases, affected people have inherited the mutation of an affected parent. However, other cases are due to new mutations in the gene that occur in people with no history of the disease in their family.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the spinal muscular atrophy with lower extremity predominance (SMA-LED), by means of the complete PCR amplification of the exons of the DYNC1H1 and BICD2 genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).