Limb girdle muscular dystrophies

Limb girdle muscular dystrophies (LGMDs) are a group of rare genetic disorders characterized by a progressive dystrophic phenotype, mainly affecting the muscles of the shoulder and pelvic areas. Onset and severity of the symptoms are variable. Typical LGMD signs are difficulty in movements, wobbling gait and specific distribution of muscle atrophy. Several severe forms also affect cardiac and respiratory functions that can be lethal to patients.

LGMD is diagnosed via a deep clinical evaluation (identification of characteristic symptoms and patient history) coupled with microscopic examination and molecular analyses of muscle biopsies. Subsequently, a genetic analysis confirms the LGMD and the particular mutation of a determinant protein specifies the subtype. Knowing the exact LGMD subtype provides precious information which is necessary for an effective treatment. Most available therapies used nowadays for LGMD are only palliative and there is no definitive cure to date for affected patients.


Also known as calpainopathy, LGMD-R1 first symptoms appear in childhood or early adulthood. This LGMD subtype is caused by autosomal recessive mutations in the CAPN3 gene, which encodes for calpain-3, a skeletal muscle-specific calcium-activated cysteine protease. Patients affected by this condition usually experience symmetrical weakness in their pelvis, upper and lower limbs, causing joint stiffness, difficulties in walking, posture abnormalities and scoliosis. The severity of the symptoms often forces the patients to the use of a wheelchair.


LGMD-R2 is characterized by mutations in the dysferlin gene, usually presenting with a late teenage onset. Dysferlin is expressed mainly in skeletal muscle, heart and macrophages. This protein is involved in a process called cell membrane repair, which is a protective mechanism to reseal membrane disruption, maintaining homeostasis and preventing cell death. This form of LGMD presents with a slow progression of proximal weakness and atrophy of shoulder and pelvic muscles. Typically, there is no involvement of heart or respiratory muscles. Calves pseudohypertrophy and highly elevated levels of serum creatine kinase are frequent in LGMD-R2 patients.


LGMD-R3 and R5 are linked to autosomal recessive mutations in α- and γ-sarcoglycans, respectively. Sarcoglycans are a family of transmembrane proteins that are involved in the connection between the internal cytoskeleton and extracellular matrix. In muscles, they are part of the dystrophin glycoprotein complex and prevent sarcolemmal damage during muscle contractions. These 2 subtypes of LGMD share a childhood onset with typical symptoms of the disease involving progressive weakness and atrophy of scapular and pelvic muscles. The prognosis is similar in both disease forms and results in difficulties of movement and reduced quality of life. While for LGMD-R3, cardiac and respiratory symptoms are rare, in LGMD-R5, there is a more frequent involvement of both the heart and diaphragm. A feature, often present in LGMD-R3, is the hypercontraction of the Achille’s tendon leading to a peculiar tiptoe gait pattern.


LGMD-R9 is a recessive autosomal dystrophy caused by mutation in the fukutin related protein (FKRP) gene. FKRP is a ribitol-5-phosphatase transferase that participates in α-dystroglycan glycosylation to ensure matrix-anchoring of the muscle fiber.
LGMD2I/R9 affects an estimated 5,000 people in the US and Europe. Symptoms appear around late childhood or early adulthood. Patients suffer from progressive muscular weakness leading to loss of ambulation. They also are prone to respiratory impairment and myocardial dysfunction. There currently are no curative treatments.