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Limb-girdle muscular dystrophy type 2A
LGMD2A is a form of muscular dystrophy that typically begins in childhood or adolescence, leading to difficulties with movements like climbing stairs, running, and lifting arms. It is a rare, inherited condition affecting both sexes.
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Overview
Limb-girdle muscular dystrophy type 2A (LGMD2A), also known as calpainopathy, is a progressive genetic condition that primarily affects muscles in the limbs. The term 'limb-girdle' refers to the areas most commonly impacted: the muscles of the pelvic girdle (hips and thighs) and the shoulder girdle (shoulders and upper arms). Over time, these muscles weaken and waste away, leading to increasing difficulty with mobility. The progression rate and severity can vary significantly among individuals, even within the same family [PMID:33671239].
LGMD2A is considered a rare disease, with its exact prevalence varying across different populations globally. In the UK, individuals with suspected muscular dystrophies are typically referred through NHS pathways for assessment and diagnosis. The condition is inherited, meaning it is passed down through families, and affects both males and females.
Symptoms & clinical features
The symptoms of LGMD2A typically begin in childhood or adolescence, although onset can range from early childhood to adulthood. Initial symptoms often include difficulty with activities that require strong hip and thigh muscles, such as running, jumping, climbing stairs, or getting up from a chair or the floor. An altered gait, sometimes described as 'waddling', may also be observed [PMID:33671239].
As the condition progresses, muscle weakness can extend to the shoulders and upper arms, leading to challenges with overhead activities like lifting objects or combing hair. Muscle pain and cramps can also occur. While LGMD2A primarily affects skeletal muscles, the heart and respiratory muscles are generally spared, although some individuals may experience mild cardiac involvement later in life [PMID:33671239]. The rate of muscle weakness progression varies, with some individuals experiencing a slow decline and others a more rapid loss of mobility.
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Affected organs
LGMD2A predominantly affects the voluntary muscles throughout the body, particularly those of the limb girdles. These include the muscles around the hips, pelvis, thighs, shoulders, and upper arms. Over time, these muscles experience progressive weakness and atrophy (wasting). While the skeletal muscles are the primary target, other organ systems are generally not severely impacted.
In some cases, mild cardiac involvement has been noted, but significant heart problems are less common than in some other forms of muscular dystrophy. Respiratory muscles are usually preserved, meaning breathing difficulties are not typically a primary feature of LGMD2A, though this can vary in very advanced stages.
Risks & severity
The severity of LGMD2A can range from a relatively mild, slowly progressing form to a more severe course leading to significant mobility limitations. Most individuals experience a gradual decline in muscle strength. Many people with LGMD2A may require walking aids, such as sticks or crutches, in adulthood, and some may eventually need a wheelchair for longer distances or full-time mobility [PMID:33671239].
The age of onset also varies, typically presenting between 8 and 15 years, but can be as early as 2 years old or as late as 50. The earlier the onset, the more likely the disease course may be more severe. Life expectancy is generally not significantly reduced for most individuals with LGMD2A, especially if cardiac and respiratory functions are routinely monitored.
Genetic causes
LGMD2A is caused by pathogenic variants in the CAPN3 gene. This gene provides instructions for making a protein called calpain-3, which is specifically found in muscle cells. Calpain-3 plays a crucial role in maintaining the structure and function of muscle fibres, particularly within structures known as sarcomeres, which are the basic contractile units of muscle [PMID:33671239].
The calpain-3 protein is involved in the breakdown of damaged proteins within muscle cells. This process, known as protein turnover, is essential for muscle repair and regeneration. When pathogenic variants occur in CAPN3, the calpain-3 protein may be non-functional, absent, or have reduced activity. Without properly functioning calpain-3, muscle cells are unable to effectively repair and maintain themselves, leading to progressive muscle damage, weakness, and atrophy [PMID:20301326].
- CAPN3 calpain 3The CAPN3 gene provides instructions for producing calpain-3, an enzyme essential for maintaining healthy muscle structure and function, particularly in skeletal muscles.
Inheritance pattern
LGMD2A follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the pathogenic CAPN3 variant - one from each parent - to develop the condition. People who have only one copy of the pathogenic variant are called carriers; they typically do not show symptoms of LGMD2A but can pass the variant on to their children.
If both parents are carriers of a pathogenic CAPN3 variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two copies of the variant and develop LGMD2A. There is a 50% (1 in 2) chance that their child will be a carrier like them, and a 25% (1 in 4) chance that their child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of LGMD2A often begins with a clinical evaluation by a neurologist, who will assess symptoms, conduct a physical examination, and review family medical history. Blood tests may show elevated levels of creatine kinase (CK), an enzyme that leaks out of damaged muscle fibres, which is a common finding in muscular dystrophies. Muscle biopsy, where a small sample of muscle tissue is taken for examination, can sometimes show characteristic changes, including a lack of calpain-3 protein.
Definitive diagnosis is confirmed through genetic testing, which looks for pathogenic variants in the CAPN3 gene. In the UK, genetic testing for muscular dystrophies like LGMD2A is available through the NHS Genomic Medicine Service (GMS). Referral for genetic testing is typically made by a specialist, such as a neurologist or clinical geneticist, using specific R-codes from the National Genomic Test Directory.
Management & lifestyle
Management for LGMD2A primarily focuses on supporting mobility, managing symptoms, and improving quality of life, as there is currently no cure. Physiotherapy is often recommended to help maintain muscle strength and flexibility, and to prevent contractures (permanent tightening of muscles or joints). Occupational therapy can provide strategies and adaptive equipment to assist with daily activities.
Regular monitoring by a neurologist is important to track disease progression and address any emerging complications. Although cardiac involvement is less common, heart function may be monitored. Referral to a genetic counsellor is often offered to individuals and families to discuss the inheritance pattern, implications for other family members, and reproductive options.
UK care pathway
In the UK, individuals suspected of having a genetic muscular dystrophy like LGMD2A typically enter the NHS Genomic Medicine Service (GMS) pathway. This usually involves an initial referral to a specialist, often a neurologist or a clinical genetics service, who can assess symptoms and determine the appropriate diagnostic tests. Genetic testing for LGMD2A, specifically looking for variants in the CAPN3 gene, is available through the National Genomic Test Directory under relevant R-codes.
If a diagnosis is confirmed, individuals and their families will have access to clinical geneticists and genetic counsellors. These professionals can provide detailed information about the condition, discuss inheritance patterns, and offer support and guidance. Multidisciplinary teams, including physiotherapists and occupational therapists, are often involved in ongoing care.
Frequently asked questions
What is the life expectancy for someone with LGMD2A?
For most individuals with LGMD2A, life expectancy is generally not significantly affected, particularly if heart and breathing functions are regularly monitored. The condition primarily impacts skeletal muscles, and severe cardiac or respiratory complications are less common compared to some other muscular dystrophies.
Can LGMD2A be prevented?
As LGMD2A is a genetic condition caused by inherited pathogenic variants in the CAPN3 gene, it cannot be prevented. However, for families with a known history of LGMD2A, genetic counselling can provide information about the risks of passing on the condition and discuss reproductive options.
Is there a cure for LGMD2A?
Currently, there is no cure for LGMD2A. Treatment focuses on managing symptoms, maintaining muscle function for as long as possible, and improving quality of life through interventions like physiotherapy, occupational therapy, and assistive devices. Research into potential therapies is ongoing.
Will my children inherit LGMD2A?
LGMD2A is inherited in an autosomal recessive pattern. If you have LGMD2A, your children will inherit one copy of the pathogenic CAPN3 variant. They will only develop the condition if they also inherit a pathogenic variant from their other parent. If your partner is not a carrier, your children will be carriers but are unlikely to develop the condition. Genetic counselling can provide personalised risk assessments.
What is the difference between LGMD2A and other types of LGMD?
Limb-girdle muscular dystrophies are a group of conditions that all cause weakness in the hip and shoulder muscles. The '2A' in LGMD2A indicates it is an autosomal recessive form (2) and specifically caused by pathogenic variants in the CAPN3 gene (A). Other types of LGMD are caused by variants in different genes and can have varying clinical features and inheritance patterns.
References
- Gallardo E, Saenz A, Illa I. Limb-girdle muscular dystrophy 2A. Handbook of clinical neurology. 2011. PMID: 21496626
- Pradhan S. Limb-girdle muscular dystrophy type 2A. Neurology India. 2010. PMID: 20739783
- Sáenz A, Leturcq F, Cobo AM. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain : a journal of neurology. 2005. PMID: 15689361
- Zheng J, Xu X, Zhang X. Variants of CAPN3 cause limb-girdle muscular dystrophy type 2A in two Chinese families. Experimental and therapeutic medicine. 2021. PMID: 33335567
- Di Ri K E, Aydin A, Kurul S. Limb girdle muscular dystrophy type 2A presenting with cardiac arrest. Pediatric neurology. 2001. PMID: 32018938
- Branca D. Calpain-related diseases. Biochemical and biophysical research communications. 2004. PMID: 15336956
- Ono Y, Ojima K, Shinkai-Ouchi F. An eccentric calpain, CAPN3/p94/calpain-3. Biochimie. 2016. PMID: 26363099
- Fanin M, Angelini C. Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: The yield and the pitfalls. Muscle & nerve. 2015. PMID: 25900067