Limb girdle muscular dystrophy (LGMD)

Overview

Limb girdle muscular dystrophy (LGMD) isn't one single condition but a large group of rare genetic conditions that share a common pattern: gradual weakening of the 'limb girdle' muscles — those around the hips, thighs, shoulders and upper arms. Because each subtype is caused by a change in a different gene, there are dozens of recognised forms, and they vary a lot in severity, age of onset and which other systems (heart, lungs, joints) get involved.

Older naming used numbers and letters (LGMD2A, LGMD1D, and so on); more recently, subtypes have been renamed and regrouped so that similar conditions sit together, using a system based on inheritance pattern (LGMDR for recessive, LGMDD for dominant) — though the older names are still sometimes used, and both are listed below for each subtype.

A diagnosis of LGMD can affect daily life in all sorts of ways — independence, education, work and relationships among them. A specialist healthcare team can help with understanding and managing the specific subtype involved, and can point toward relevant local support.

Symptoms

Symptoms vary enormously by subtype, and even people in the same family with the same genetic change can be affected differently. Onset is often in the teenage years or early adulthood, but this varies widely by subtype — anywhere from early childhood to late adulthood is possible.

The most common thread is muscle weakness in the hips, thighs, shoulders and upper arms, developing at a pace that depends on the specific subtype. Leg and hip weakness usually appears before shoulder and arm weakness, and can show up as frequent falls, difficulty running, trouble with hills or stairs, and difficulty getting up from the floor; as it progresses, some people need a walking aid or wheelchair. Shoulder and arm weakness can make overhead tasks — like washing hair — harder, along with carrying heavy objects or holding the arms out in front.

Some, but not all, subtypes also affect breathing and the heart, more often in forms that start in early childhood, and in the more severe subtypes this can affect life expectancy. Breathing difficulty can cause poor sleep, morning headaches, daytime sleepiness and a higher risk of chest infections — regular specialist review, annual flu and pneumococcal vaccination, and sometimes overnight breathing support are recommended where this applies. Weakness in nearby muscles can also affect swallowing and speech, where a speech and language therapist can help. Heart involvement can cause breathlessness and fatigue; where a particular subtype carries a known heart risk, regular cardiology review — including ECG and echocardiogram — is recommended to catch and manage problems early.

Inheritance and cause

Genes carry the instructions cells use to build proteins; in LGMD, a change in one of many possible genes disrupts a protein that muscle needs to work properly, so muscle fibres are gradually damaged over time. The specific gene involved differs by subtype (see the tables below).

Most LGMDs are inherited in an autosomal recessive pattern, needing a changed copy of the gene from both parents; a smaller number follow an autosomal dominant pattern, where a single changed copy from one parent is enough. Occasionally a change arises fresh in a person with no family history, and that person can still pass it on to their own children.

Getting a diagnosis

A GP refers to a neurologist, who asks about symptoms and family history and carries out a physical examination of muscle function. Where a muscle-wasting condition is suspected, further tests may include a blood test for creatine kinase (CK) — levels vary but tend to run much higher in recessive than dominant LGMD — a CT or MRI scan to see which muscles are affected, an EMG (electrical muscle test), genetic testing to identify the specific gene involved, and sometimes a muscle biopsy.

Management and outlook

Care works best through a multidisciplinary team, usually led by a neurologist, bringing in heart and lung specialists where the subtype involved makes that relevant, with regular appointments to check on those systems and offer treatment as needed. In the UK, a Highly Specialised Service for LGMD operates at the John Walton Muscular Dystrophy Research Centre (part of Newcastle upon Tyne Hospitals NHS Foundation Trust) — a national centre a specialist can refer to for a second opinion or specialist advice, while day-to-day care stays with the local team.

Staying appropriately active helps keep joints flexible and muscles as strong as possible — generally, regular exercise is encouraged provided you feel recovered by the following day, and exercise shouldn't cause pain or weakness that limits everyday activity. A physiotherapist can tailor a plan combining stretching (ideally 4–6 times a week, to ease joint tightness and improve mobility), strengthening work against resistance — body weight, resistance bands or light weights, at a level allowing only around 12–15 repetitions, 2–3 times a week — and aerobic activity sustained for around 45 minutes at a time, 3–4 times a week (walking, Nordic walking, swimming, dancing, arm cycling or powered wheelchair driving, depending on ability).

Where foot drop develops (weakness that makes it hard to lift the foot and toes, raising the risk of trips), an orthotics specialist can assess for a supportive device to improve walking and ease related knee, shoulder, back or posture problems — a GP or specialist can refer into a local orthotics service.

Because general anaesthesia can carry added risk with LGMD, it's important that any surgeon and anaesthetist know about the diagnosis, the specific subtype where known, and any heart or breathing problems well ahead of a procedure, so extra precautions can be arranged before, during and after.

Types of LGMD — autosomal recessive (LGMDR)

These subtypes need a changed gene copy from both parents; a person with one of these forms wouldn't usually pass the condition itself to their children (since the other parent would need to also carry a changed copy), though each child would typically inherit carrier status for the changed gene.

• LGMDR1 — calpainopathy (formerly LGMD2A; gene CAPN3): Onset usually age 8–15, though anywhere from 2–40 is possible. Develops slowly to moderately fast, mild to severe weakness, affecting pelvic muscles first then shoulders; can cause contractures and scapular winging (shoulder blades sticking out). Low chance of mild heart problems; possible mild breathing problems later in life.
• LGMDR2 — dysferlinopathy / Miyoshi myopathy (formerly LGMD2B; gene DYSF): Onset usually young adulthood, develops slowly. Can cause calf weakness alongside pelvic and shoulder weakness. Heart and breathing not usually affected.
• LGMDR3–R6 — the sarcoglycanopathies (formerly LGMD2D, 2E, 2C, 2F; genes SGCA, SGCB, SGCG, SGCD): Onset usually childhood, progressing at varying speed (can be fast in children), mild to severe weakness with possible contractures and scapular winging. Heart problems can be common and severe in most of this group but are rare specifically in LGMDR3; breathing problems are common.
• LGMDR7 (formerly LGMD2G; gene TCAP): Onset childhood or teenage years, starting with leg weakness; some need a wheelchair by around age 40. About half develop heart problems; breathing isn't affected.
• LGMDR8 (formerly LGMD2H; gene TRIM32): Onset young adulthood, starting with mild-to-severe leg weakness that can later involve the arms and sometimes mild facial weakness. May cause heart problems; breathing isn't affected.
• LGMDR9 (formerly LGMD2I; gene FKRP): One of the more common subtypes in the UK and northern Europe. Onset typically age 10–20, mild to severe, developing at varying speed (can be fast in young children). Can cause contractures and both heart and breathing problems.
• LGMDR10 — titinopathy (formerly LGMD2J; gene TTN): Onset age 10–30, causing severe weakness that develops quickly; identified so far only in Finland. Other changes in the same gene cause different muscle conditions. May cause heart problems.
• LGMDR11 (formerly LGMD2K; gene POMT1, part of the dystroglycanopathy group): Onset early childhood, develops slowly, causes severe learning difficulties. Identified in a small number of Turkish and English families; heart involvement is sometimes seen.
• LGMDR12 (formerly LGMD2L; gene ANO5): Onset adulthood, may cause calf weakness and thigh/upper-arm weakness that can be one-sided; develops very slowly. Muscle pain is more likely here than in most other LGMD subtypes. May cause heart and breathing problems.
• LGMDR13 (formerly LGMD2M; gene FKTN, dystroglycanopathy group): Onset early childhood, can cause eye problems and learning difficulties; some develop heart problems.
• LGMDR14 (formerly LGMD2N; gene POMT2, dystroglycanopathy group): Onset early childhood, mild to severe and varying widely between people; can cause learning difficulties, eye problems and, in some, heart problems.
• LGMDR15 (formerly LGMD2O; gene POMGnT1, dystroglycanopathy group): Onset early to late childhood, varying between people; can cause eye problems and, in some, heart problems.
• LGMDR16 (formerly LGMD2P; gene DAG1, dystroglycanopathy group): Onset early childhood, can cause learning difficulties. Heart/breathing risk is unknown given how rare this subtype is.
• LGMDR17 (formerly LGMD2Q; gene PLEC): Onset early childhood; heart/breathing risk unknown given rarity.
• LGMDR18 (formerly LGMD2S; gene TRAPPC11): Onset early to late childhood, weakness affecting the lower body more than the upper body; some develop breathing problems.
• LGMDR19 (formerly LGMD2T; gene GMPPB): Onset from birth to young adulthood, can cause mild learning difficulties; if it starts at birth, may include eye and brain involvement, and some develop heart or breathing problems. Symptoms can overlap with congenital myasthenic syndromes, so both may be considered during diagnosis.
• LGMDR20 (formerly LGMD2U; gene ISPD): Onset childhood, usually develops slowly; can cause low muscle tone and walking difficulty. If it starts at birth, may include eye and brain involvement; may cause mild heart problems.
• LGMDR21 (formerly LGMD2Z; gene POGLUT1): Onset usually young adulthood but can be from birth or in childhood; develops slowly, mainly affecting the legs, with possible scapular winging. Some start using a wheelchair between roughly 30 and 60. No reported heart problems; may cause mild breathing problems.
• LGMDR22 — recessive Bethlem myopathy (genes COL6A1, COL6A2, COL6A3): Onset from early childhood to adulthood, often with contractures and sometimes skin changes. No heart problems reported; breathing problems possible in some.
• LGMDR23 — LAMA2-related muscular dystrophy (gene LAMA2): Onset from childhood to mid-adulthood, may cause contractures and, in some, seizures. Some people over 40 develop heart problems; breathing problems are possible.
• LGMDR24 (formerly known as POMGNT2-related muscular dystrophy; gene POMGNT2, dystroglycanopathy group): Symptoms vary considerably — some people have none, others have learning and speech difficulties, and some have eye problems. Heart/breathing risk unknown given rarity.
• LGMDR25 (formerly LGMD2X; gene BVES): Onset between the teenage years and adulthood, slowly progressive, can cause walking difficulty and thigh/hip pain after exercise. May cause heart problems.
• LGMDR26 (gene POPDC3): Onset between the teenage years and adulthood, starting with leg weakness. No heart problems reported.
• LGMDR27 (gene JAG2): Usually slowly progressive, may cause facial weakness. May cause heart problems and mild breathing problems.

Types of LGMD — autosomal dominant (LGMDD)

These subtypes need only one changed gene copy, inherited from an affected parent, who will themselves have the condition; each child of an affected person has a 1 in 2 chance of inheriting it. When LGMD subtypes were renamed, a few conditions no longer fitted the pattern and were reclassified as their own separate conditions: myofibrillar myopathy (formerly LGMD1A, 1E and 2R), Emery-Dreifuss muscular dystrophy (formerly LGMD1B), rippling muscle disease (formerly LGMD1C), and Pompe disease (formerly LGMD2V).

• LGMDD1 (formerly LGMD1D; gene DNAJB6): Onset adulthood, slowly progressive, often starting in the hips and spreading to legs and arms. May cause heart and breathing problems.
• LGMDD2 (formerly LGMD1F; gene TNPO3): Onset anywhere from under a year old to the late 50s, developing at varying speed, mild to severe, with possible scapular winging. No heart problems reported; breathing problems uncommon.
• LGMDD3 (formerly LGMD1G; gene HNRNPDL): Onset adulthood, slowly progressive, may cause finger/toe contractures, cataracts in young adults, and scapular winging. No heart problems reported; breathing risk unknown given rarity.
• LGMDD4 — dominant calpainopathy (formerly LGMD1I; gene CAPN3): Onset young adulthood, usually milder and slower than the recessive form (LGMDR1); may cause forward spinal curvature, walking difficulty and scapular winging.
• LGMDD5 — dominant Bethlem myopathy (genes COL6A1, COL6A2, COL6A3): Onset childhood or adulthood, often with contractures; many people continue walking with aids such as a stick or frame. Some skin changes possible. No heart problems reported; breathing problems possible later on.