centronuclear myopathy 2

Centronuclear Myopathy 2 (CNM2) Description

Centronuclear Myopathy 2 (CNM2) is a rare genetic disorder characterized by progressive muscle weakness, ranging from mild to profound. It is an autosomal dominant disorder, meaning that a single copy of the mutated gene is sufficient to cause the condition.

Key Features:

• Progressive muscle weakness, which can be severe
• Centrally placed nuclei on muscle biopsy, a hallmark feature of CNM2
• Muscle atrophy and wasting
• Weakness in proximal muscles of the lower limbs, making it difficult for patients to stand up without using their hands

Causes:

• Homozygous or compound heterozygous mutation in the dynamin 2 gene (DNM2) is responsible for CNM2 [8]

References:

• [6] Description of centronuclear myopathy
• [7] Evidence that CNM2 is caused by mutations in the DNM2 gene

Symptoms of Centronuclear Myopathy

Centronuclear myopathy (CNM) is a rare congenital myopathy that affects the muscles, causing various symptoms to appear in individuals affected by this condition. The specific symptoms and severity can vary greatly among different forms and from one person to another.

• Muscle Weakness: One of the primary symptoms of CNM is muscle weakness, which tends to worsen over time [1]. This weakness can affect any part of the body, including the arms, legs, face, and other muscles.
• Hypotonia: Individuals with CNM often experience hypotonia, or decreased muscle tone, which can lead to difficulties in maintaining posture and movement [8].
• Delayed Motor Milestones: People with CNM may experience delayed motor milestones, such as sitting, standing, or walking [7].
• Facial Weakness and Ptosis: Facial weakness and ptosis (droopy eyelids) are common signs and symptoms of CNM [7].
• Extraocular Muscle Involvement: Extraocular muscle involvement is also a common symptom in all forms of CNM [7].

It's essential to note that the severity and specific symptoms can vary greatly among individuals with CNM, even within the same family. Some people may experience mild symptoms, while others may have more severe manifestations.

References: [1] - The specific symptoms and severity of CNMs can vary greatly among the different forms and from one person to another [1]. [7] - Delayed motor milestones, facial weakness, and ptosis are common signs and symptoms of CNM [7]. [8] - Hypotonia is a common symptom in individuals with CNM [8].

Diagnostic Tests for Centronuclear Myopathy

Centronuclear myopathy (CNM) can be diagnosed through a combination of clinical features, muscle biopsy, and genetic testing.

• Muscle Biopsy: A muscle biopsy is often the first step in diagnosing CNM. This involves taking a small sample of muscle tissue from the affected area, which is then examined under a microscope for characteristic changes such as central nuclei, type 1 fiber predominance, and hypotrophy [12].
• Genetic Testing: Genetic testing can confirm the diagnosis of CNM by identifying mutations in genes associated with the condition. These include DNM2, BIN1, TTN, and MTM1 genes [7]. Molecular genetic testing is available as a diagnostic service at specialized laboratories [1].
• Clinical Features: A diagnosis of CNM may also be based on typical clinical features such as muscle weakness (myopathy) and wasting (atrophy), droopy eyelids (ptosis), foot abnormalities, high-arched palate, and abnormal side-to-side curvature of the spine (scoliosis) [3].

Additional Diagnostic Tools

• Comprehensive Myopathy Panel: The Invitae Comprehensive Myopathy Panel analyzes genes associated with inherited myopathies, including CNM [9].
• Specialized Laboratories: Molecular genetic testing is available at specialized laboratories for diagnosing CNM and other related conditions.

Note: A diagnosis of X-linked myotubular myopathy (XLMTM) can be established through molecular genetic testing in a proband with suggestive clinical findings and identification of a hemizygous pathogenic variant in MTM1 [14].

Current Status of Drug Treatment for Centronuclear Myopathy

Centronuclear myopathies (CNMs) are a group of rare genetic muscle disorders affecting children and young adults, with no effective treatment or cure currently available. However, researchers have been exploring various therapeutic options to manage the condition.

• Investigational Antisense Drugs: Dynacure is developing an investigational antisense product candidate, DYN101, designed to reduce the expression of dynamin 2 protein for the treatment of Myotubular and Centronuclear Myopathies. This drug has received Fast Track designation from the FDA for the treatment of these conditions.
• Tamoxifen Administration: Research has shown that tamoxifen administration improves muscle contractility in animal models of myopathies caused by mutations in the DNM2 and BIN1 genes. However, this is still an experimental approach and not a standard treatment for CNM patients.
• No Specific Therapy Exists Yet: Despite ongoing research, there is currently no effective treatment or cure for centronuclear myopathies. Management of the condition relies on respiratory support and management, as well as physiotherapy to maintain muscle function.

Recent Developments

In 2023, researchers announced that tamoxifen administration improves muscle contractility in animal models of myopathies caused by mutations in the DNM2 and BIN1 genes [3]. Additionally, Dynacure has licensed an investigational antisense drug targeting dynamin 2 for the treatment of centronuclear myopathy (CNM), which has received Fast Track designation from the FDA [11][13].

References

[3] Researchers show that tamoxifen administration improves muscle contractility in animal models of myopathies caused by mutations in the DNM2 and BIN1 genes. [10] Centronuclear myopathies are characterized by muscle weakness that can range from mild to severe. [11] Dynacure has licensed an investigational antisense drug targeting dynamin 2 for the treatment of centronuclear myopathy (CNM), which has received Fast Track designation from the FDA. [13] Ionis earns $5 million license fee from Dynacure.

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