Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217




Limb and waist muscular dystrophy, also known as the shoulder girdle syndrome or myopathic shoulder girdle syndrome, forms a group of diseases that cause weakness and atrophy of the muscles of the arms and legs. The most affected muscles are the proximal muscles, specifically the muscles of the shoulders, arms, pelvic area and thighs. The severity, the age of onset and the characteristics of the disease vary among the many subtypes of this disorder, even within the same family. Signs and symptoms may appear at any age and generally get worse over time, although in some cases they remain mild.

In the early stages of the disease, affected individuals may have an unusual gait and difficulty running. As the disease progresses, affected people may eventually require a wheelchair. Muscular atrophy can cause changes in posture or in the appearance of the shoulders, back and arms. In particular, weakness in the shoulder muscles causes scapular separation. Other signs and symptoms of the disease may include lordosis, scoliosis, and contractures that may limit the movement of the hips, knees, ankles or elbows. Some individuals develop hypertrophy of the calf muscles, cardiomyopathy and mild or severe respiratory problems related to the weakness of the muscles needed to breathe. In addition, in rare forms of the disease, developmental delay and intellectual disability have been described.

The various forms of muscular dystrophy of extremities and waist are caused by mutations in many different genes. These genes encode proteins that are involved in muscle maintenance and repair. Some of the proteins produced from these genes bind with other proteins in larger protein complexes that maintain the physical integrity of muscle tissue and allow muscles to contract. Other proteins participate in cell signaling, cell membrane repair or removal of potentially toxic wastes from muscle cells.

Limb and waist muscular dystrophy is classified according to its inheritance pattern and genetic cause. Type 1 includes forms of the process that have an autosomal dominant inheritance pattern, while type 2 includes forms that have an autosomal recessive inheritance pattern. Within type 2, the various forms include 2A, 2B, 2C, 2D, 2E, 2F, 2I, 2J, 2K, 2L, 2M and 2N.

Type 2A, known as calpainopathy, is the most common type and is due to mutations in the CAPN3 gene (calpain 3). This type represents approximately 30 percent of cases. The CAPN3 gene, located on the long arm of chromosome 15 (15q15.1), encodes an enzyme called calpain-3, which is found in sarcomeres. Although the function of the enzyme calpain-3 is not clear, it is believed that it can help cleave damaged proteins into shorter segments to facilitate their removal from the sarcomere. In addition, it has been shown that calpain-3 is added to the proteins involved in the elasticity of muscle fibers and cell signaling. However, their specific functions in these processes are unknown. More than 300 mutations in the CAPN3 gene have been identified in people with muscular dystrophy of extremities type 2A. Most mutations change amino acids in the enzyme calpain-3. These mutations give rise to a calpain-3 enzyme that is abnormally unstable. Disruption of the enzyme´s ability to cleave proteins correctly for removal from the sarcomere may allow them to accumulate in muscle tissue and become toxic.

Other less frequent types are type 2B or dysferlinopathy, which is due to mutations in the DYSF gene (dysferlin); types 2D, 2E, 2C and 2F, also known as sarcoglucanopathies, which develop as a result of mutations in the SGCA (sarcoglycan alpha), SGCB (sarcoglycan beta), SGCG (sarcoglycan gamma) and SGCD (sarcoglycan delta) genes, respectively ; type 2J, due to mutations in the TTN gene (titin) and that has been identified only in the Finnish population; type 2L, due to mutations in the ANO5 gene (anoctamin 5); and types 2I, 2K, 2M and 2N, also known as dystroglicanopathies, due to mutations in other genes.

Other rare forms of limb and waist muscular dystrophy are caused by mutations in several others genes, some of which have not been identified. In addition, certain forms described as limb and waist muscular dystrophy have been grouped with different related processes, such as myofibrillar myopathy, Emery-Dreifuss muscular dystrophy, undulating muscle disease or Pompe´s disease.

Limb muscular dystrophy can have different inheritance patterns. In most cases it is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. Several rare forms of muscular limb dystrophy are inherited with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause the disease.

Tests performed in IVAMI: in IVAMI we detect the mutations associated with muscular dystrophy of the extremities and waist, by means of the complete PCR amplification of the exons of the genes involved according to the type suspected by the clinical manifestations, and their subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).