Limb-girdle muscular dystrophies (LGMD): subtypes, genetics and diagnosis

The term limb-girdle describes a distribution of weakness, not a mechanism. The girdles are the bony rings at the shoulders and hips, and the muscles around them are the ones that fail first. Many conditions can produce that pattern, including some acquired muscle diseases and other genetic myopathies, so the label is used only when a specific genetic cause has been found or is strongly suspected.

Current naming combines inheritance and a letter or number for the gene, so recessive forms are written R and dominant forms D. It is common to see older names in letters, for example LGMD2A for calpain-3 disease, alongside newer ones, and a report may use both.

MedlinePlus lists unusual gait, difficulty running and trouble rising from a squat as early signs. As the condition advances, shoulder blades may protrude, the spine may curve, joints may stiffen and the heart muscle may weaken. Some people eventually need a wheelchair, but this depends greatly on the subtype.

The age at onset ranges from early childhood to middle age. Severity can differ even within the same family, which makes it hard to give general predictions. Some subtypes are marked by very high creatine kinase levels, while others have much lower values.

• Waddling gait or difficulty climbing stairs

• Trouble lifting the arms above the head

• Calf enlargement in some subtypes

• Tight Achilles tendons or stiff spine in others

• A raised creatine kinase, sometimes very high

Calpain-3 is an enzyme that removes damaged proteins from muscle cells, and dysferlin is involved in repairing the muscle membrane. When either is deficient, muscle fibres are unable to deal with everyday damage. Other LGMD genes encode proteins that anchor the cell membrane to the fibre skeleton, modify sugar chains on structural proteins, or maintain the nuclear envelope.

The subtype matters because it predicts what to monitor. Some forms need regular heart surveillance for cardiomyopathy, while others are mainly skeletal. Some are associated with respiratory weakness that is out of proportion to limb weakness. A few are linked to treatable features or, in a small number of subtypes, to clinical trials. Knowing the gene also determines whether inheritance is recessive or dominant, which changes the advice given to siblings and children.

A GP will usually arrange a creatine kinase test and refer to neurology or a neuromuscular service. The NHS lists blood tests, genetic screening, electromyography, muscle biopsy and MRI as tools used in muscular dystrophy. Muscle MRI is particularly useful in LGMD because different subtypes have characteristic patterns of fat replacement in muscle.

Increasingly, a gene panel or exome test is done first. The NHS Genomic Medicine Service operates genomic laboratory hubs and a national genomic test directory that standardise which tests are available through the NHS. A muscle biopsy may still be helpful when genetic results are unclear because protein stains can show a missing protein. NHS genetic testing is free when arranged by a hospital specialist.

There is no specific cure for most LGMD subtypes. Care is supportive: physiotherapy and exercise advice, occupational therapy, mobility aids, orthopaedic input for contractures and scoliosis, cardiac review and respiratory monitoring when indicated. The NHS describes this approach for muscular dystrophy generally, including surgery for complications and respiratory support when needed.

Because the heart and lungs are involved in only some subtypes, individual surveillance schedules vary. Women with LGMD planning pregnancy should talk to the neuromuscular and obstetric teams in advance, since breathing capacity and heart function influence the plan.

In recessive LGMD both parents are usually carriers without symptoms, so siblings of a patient may be affected, carriers, or unaffected. In dominant LGMD, a parent is usually affected and each child has an equal chance of inheriting the change. Clinical genetics provides counselling and, where relevant, prenatal or pre-implantation options.