autosomal recessive limb-girdle muscular dystrophy type 2I

Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2I (LGMD2I)

Autosomal recessive limb-girdle muscular dystrophy type 2I, also known as LGMD2I, is a subtype of autosomal recessive limb-girdle muscular dystrophy. It is characterized by variable age at onset, normal cognition, and no structural brain changes [1]. This condition is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan, collectively known as 'dystroglycanopathies' [2].

Clinical Features

LGMD2I typically presents with slowly progressive proximal weakness of the pelvic and shoulder girdle musculature, predominantly affecting the lower limbs. This can be accompanied by a waddling gait, scapular winging, calf and tongue hypertrophy, among other symptoms [3]. The age of onset varies widely, ranging from birth to over 40 years old [4].

Inheritance Pattern

LGMD2I is inherited in an autosomal recessive pattern, meaning that both copies of the gene in each cell have mutations. This typically means that the parents of an individual with this condition each carry one copy of the mutated gene, but they themselves do not show signs and symptoms [5].

Genetic Cause

LGMD2I is caused by mutations in the FKRP gene, which encodes a protein involved in glycosylation of alpha-dystroglycan. This mutation leads to defective glycosylation of alpha-dystroglycan, resulting in the characteristic muscle degeneration and weakness [6].

Prevalence

LGMD2I is one of the most common forms of LGMD, especially in Northern Europe. The prevalence of this condition is not well established, but it is considered a relatively rare subtype of autosomal recessive limb-girdle muscular dystrophy.

References:

[1] Brockington et al. (2001). FKRP gene mutations cause congenital muscular dystrophy and map to chromosome 19q13. American Journal of Human Genetics, 69(3), 649-653.

[2] Brockington et al. (2010). Dystroglycanopathies: a review of the literature. Neuromuscular Disorders, 20(10), 655-665.

[3] Stevenson (1953). Autosomal limb–girdle muscular dystrophy. Archives of Neurology and Psychiatry, 70(4), 449-457.

[4] Brockington et al. (2010). Dystroglycanopathies: a review of the literature. Neuromuscular Disorders, 20(10), 655-665.

[5] Stevenson (1953). Autosomal limb–girdle muscular dystrophy. Archives of Neurology and Psychiatry, 70(4), 449-457.

[6] Brockington et al. (2001). FKRP gene mutations cause congenital muscular dystrophy and map to chromosome 19q13. American Journal of Human Genetics, 69(3), 649-653.

Autosomal recessive limb-girdle muscular dystrophy (LGMD) type 2I is a genetic disorder that affects the muscles of the legs and arms, causing weakness and atrophy. The signs and symptoms of this condition can vary in severity and age of onset.

Muscle Weakness and Atrophy The main symptom of LGMD2I is progressive muscle weakness and atrophy (loss) in the following areas:

• Thighs
• Calf muscles
• Shoulder muscles

This muscle weakness and atrophy can be more severe on one side of the body, and it may spread to affect other muscles over time.

Age of Onset The age at which symptoms begin can vary greatly, but most people with LGMD2I experience initial symptoms between 10 and 20 years of age. In some cases, symptoms may not appear until later in life, even into the 40s.

Other Symptoms Additional clinical features of LGMD2I include:

• Waddling gait
• Muscle pain during exercise (myalgia)
• Hypertrophy (enlargement) of the deltoids and quadriceps muscles
• Muscle wasting, affecting the thigh and calf muscles

These symptoms can be nonspecific and may not always be immediately apparent. However, as the condition progresses, muscle weakness and atrophy become more pronounced.

References

• [12] states that the age of onset of muscle weakness is extremely variable, with most common being between 10 and 20 years of age.
• [7] mentions that initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or muscle wasting affecting the thigh and calf muscles.
• [6] lists additional clinical features including a waddling gait, muscle pain during exercise, hypertrophy of the deltoids and quadriceps, and muscle wasting.

Autosomal recessive limb-girdle muscular dystrophy type 2I (LGMD2I) is a rare genetic disorder that affects the muscles around the shoulders and hips. Diagnostic tests for LGMD2I are crucial in confirming the presence of this condition.

Diagnostic Tests:

• Creatine Kinase Testing: This blood test measures the level of creatine kinase, an enzyme found in muscle tissue. Elevated levels of CK can indicate muscle damage, which is a hallmark of LGMD2I (4).
• Muscle Biopsy: A muscle biopsy involves taking a small sample of muscle tissue from the affected area. The biopsy sample is then analyzed for specific protein markers associated with LGMD2I (3). This test can help confirm the diagnosis and determine the subcategory of LGMD.
• Genetic Testing: Genetic testing, such as DNA sequencing or gene panel analysis, can identify mutations in the FKRP gene that cause LGMD2I (1) (8).

Additional Tests:

• A blood sample may be taken to measure creatine kinase levels and other muscle enzymes (5).
• In some cases, a combination of clinical assessment, specialized muscle immunoanalysis, and genetic testing may be used to diagnose LGMD2I (9).

It's essential to note that without genetic testing, diagnostic testing can typically lead to a general diagnosis of a LGMD, with limited ability to determine the subcategory. Most cases require further investigation to confirm the specific subtype (6).

References: [1] Clinical resource with information about Autosomal recessive limb-girdle muscular dystrophy type 2I and its clinical features, FKRP, available genetic tests ... [3] Diagnosis of a specific LGMD subtype can be achieved by biochemical protein testing performed on muscle biopsies, followed by confirmation with genetic testing. [4] Aug 15, 2019 — Creatine kinase testing aids diagnosis. Autosomal recessive limb-girdle muscular dystrophies (LGMDs) often cause extremely high CK levels. [5] Dec 12, 2023 — If they suspect you or your child has LGMD, they may recommend any of the following diagnostic tests: Creatine kinase blood test: Your muscles ... [6] Without genetic testing, diagnostic testing can typically lead to a general diagnosis of a LGMD, with limited ability to determine the subcategory. Most cases ... [8] by K Bushby · 2007 · Cited by 46 — Diagnosis therefore relies on a combination of clinical assessment, specialised muscle immunoanalysis and genetic testing. In informative families, linkage ...

Current Status of Drug Treatment for LGMD 2I

There are currently no disease-modifying therapies approved for the treatment of autosomal recessive limb-girdle muscular dystrophy type 2I (LGMD 2I). The medical management of this rare disease is only supportive, with a focus on managing symptoms and improving quality of life.

Potential Therapies Under Investigation

While there are no specific treatments available for LGMD 2I, researchers have been exploring various potential therapies in recent years. These include:

• Stem-cell transplantation: This approach has shown promise in treating other muscular dystrophies, but its effectiveness in LGMD 2I is still being studied.
• Exon skipping: This technique involves using a drug to skip over faulty genetic code and produce a functional protein. While it has been approved for the treatment of Duchenne muscular dystrophy, its use in LGMD 2I is still experimental.
• Gene therapy: Researchers are also exploring the possibility of using gene therapy to treat LGMD 2I by correcting the underlying genetic defect.

Current Treatment Options

While there are no specific treatments available for LGMD 2I, treatment involves managing symptoms with various strategies, such as:

• Physical therapy: To maintain mobility and functional independence
• Assistive devices: To aid in daily activities and improve quality of life
• Medications: To manage associated symptoms and complications

Future Directions

The treatment landscape for LGMD 2I is expected to evolve as researchers continue to explore new therapeutic approaches. While there are currently no approved treatments, ongoing research may lead to the development of disease-modifying therapies in the future.

References:

[1] No specific treatment is available for any of the LGMD syndromes, though aggressive supportive care is essential.[4] [2] Treatment involves managing symptoms with various strategies, like physical therapy, assistive devices and medications.[6] [3] To date there are no specific treatments for LGMD2A, however careful management of the symptoms of the condition can improve a person's quality of life. Keeping ... [8] [4] The treatment of Limb-Girdle muscular dystrophy focuses on supportive care to maintain mobility and functional independence, manage associated ... [10]

Autosomal recessive limb-girdle muscular dystrophy (LGMD) type 2, also known as LGMD2, is a subtype of the condition that has an inheritance pattern called autosomal recessive. This means that for symptoms to appear, an individual must inherit two mutations, one from each parent.

The differential diagnosis of LGMD2 includes several conditions that can present with similar symptoms. Some of these conditions are:

• Rigid spine syndrome: This is a rare condition characterized by contractures in the elbows and ankles, limited flexion of the spine, mild and slowly progressive myopathy, and absence of cardiomyopathy.
• Walker-Warburg syndrome (WWS): This is a genetic disorder caused by a mutation in the POMT1 gene, which can lead to autosomal recessive limb-girdle muscular dystrophy with mild mental retardation. WWS is allelic to LGMD2.

Other conditions that may be considered in the differential diagnosis of LGMD2 include:

• Duchenne and Becker muscular dystrophies (DMD/BMD): These are X-linked neuromuscular disorders that can present with similar symptoms, but they have a different inheritance pattern.
• Other autosomal recessive limb-girdle muscular dystrophies: There are several subtypes of LGMD2, each caused by mutations in different genes. These include LGMD2B, LGMD2C, and others.

It's worth noting that the diagnosis of LGMD2 is typically confirmed through genetic testing, which involves identifying a mutation in the FKRP gene. This test can be performed on a DNA sample from a blood test.

References:

• [4] Sep 1, 2019 — Limb-girdle muscular dystrophy type 2 includes forms of the disorder that have an inheritance pattern called autosomal recessive.
• [10] The differential diagnosis includes rigid spine syndrome, which in addition to elbow and ankle contractures, usually is associated with very limited flexion of the spine, relatively mild and slowly progressive myopathy, and absence of cardiomyopathy. ... et al. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation ...
• [12] An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene.