Limb girdle muscular dystrophy

Limb girdle muscular dystrophies (LGMD) are a rare, heterogeneous group of progressive muscular dystrophies that mainly involve the muscles of the pelvic and shoulder girdles. There are many subtypes of LGMD, which can be categorised by gene and mode of inheritance.

• Typical clinical features of LGMD include progressive muscle weakness and atrophy of the muscles in the pelvic and shoulder girdles. Weakness in the lower limbs usually precedes progression to the upper limbs.
• There is significant variability in age of disease onset, phenotype and presentation, even between individuals within the same family with the same genetic alteration (see Tables 1 and 2).
• Depending on age of onset, some individuals may first experience difficulties in walking, which can present as a Trendelenburg (or ‘waddling’) gait due to weakness in hip and leg muscles. They may experience frequent falls and difficulties in running, climbing stairs and/or getting up from the floor, and may require assisted mobility devices.
• Weakness in shoulder girdle may present as difficulty reaching above the head (such as when combing the hair), carrying heavy objects and/or holding the arms outstretched.
• Facial and bulbar weakness may occur in some types of LGMD, often presenting as dysarthria and dysphagia.
• Cardiac involvement, such as cardiomyopathy, conduction anomalies or arrhythmias, can present in some types of LGMD, along with respiratory involvement, which can lead to difficulties with breathing.
• Most cases of LGMD present with symmetrical weakness; however, some types may have an asymmetrical onset.
• Other symptoms may include:
  • joint stiffness;
  • contractures;
  • muscle cramping;
  • myalgia;
  • fatigue;
  • calf hypertrophy (or pseudohypertrophy due to fatty replacement);
  • involvement of distal muscles of the upper and lower limbs; and
  • learning difficulties and developmental delay.
• Though this is not specific to LGMD, creatine kinase (CK) levels are increased and are usually more mildly elevated (from two-fold to twenty-five-fold) in autosomal dominant forms in comparison to autosomal recessive forms, which can present with much higher levels of CK (from two-fold to one-hundred-and-fifty-fold). Muscle biopsies and genetic analysis may help establish the specific subtypes.

LGMD can be divided into the autosomal dominant form (known as LGMD D) and the autosomal recessive form (which is more common and is known as LGMD R). These two types are then further subcategorised by a number (see Table 1 below), based on the chronological order in which the chromosomal locus was discovered. For example, LGMD D1 was mapped before LGMD D2. The causative gene in each type of LGMD completes the description (though in some cases, a genetic alteration has yet to be identified). Tables 1 and 2 below describe the LGMD types and causative genes that are currently known.

Table 1: Dominant forms of LGMD

Table 2: Recessive forms of LGMD

Individuals affected by LGMD D have a one-in-two (50%) chance of passing the gene change on to any children they may have.

The parents of most individuals affected by LGMD R are carriers for the condition, which means that they have a one-in-four (25%) chance of having another affected child. Recessive LGMD conditions are very rare, so the chance of an unrelated partner also being a carrier for the same condition is very low – their carrier risk will be that of the general population. An affected individual’s risk of having an affected child depends on their partner’s carrier status but, in the absence of consanguinity, the risk is usually considered to be so low that carrier testing is unlikely to be offered.

For those families in whom recurrence risk is thought to be significant, and in whom a pathogenic variant or variants have been identified, prenatal options should be discussed.

There is currently no cure for LGMD. Management of individuals is complex and a multidisciplinary approach to care should be undertaken, involving neurologists with expertise in neuromuscular disease, clinical geneticists, physiotherapists, speech and language therapists and occupational therapists, with lung function and cardiac surveillance considered. Other specialties, such as orthopaedics, may also be required. A number of disease registries exist, and patients may wish to enrol on these (see the resources section below).

For clinicians

• NHS England: National Genomic Test Directory
• The John Walton Muscular Dystrophy Research Centre: Diagnostic and advisory service for limb girdle muscular dystrophies

For patients

• LGMD Awareness Foundation
• Muscular Dystrophy Association
• Muscular Dystrophy UK
• TREAT-NMD Neuromuscular Network: Members of the registry network