Congenital Myopathy: Symptoms, Types, Causes and Treatment

Congenital myopathies are a group of rare, inherited muscle disorders that often present at birth or early childhood. Defined by characteristic structural abnormalities in muscle fibers, these conditions can impact movement, motor development, and overall quality of life. Advances in genetics and muscle imaging have transformed our understanding of congenital myopathies, revealing a remarkable diversity in symptoms, causes, and management strategies. In this article, we provide a comprehensive overview of congenital myopathies, focusing on their symptoms, major types, underlying causes, and current as well as emerging treatment options.

Symptoms of Congenital Myopathy

Congenital myopathies manifest through a distinctive set of symptoms, although the severity and specific features can vary widely from one individual to another. Recognizing these symptoms is crucial for early diagnosis and effective management.

Symptom	Description	Onset	Key Sources
Hypotonia	Low muscle tone, "floppy" muscles	Birth/Infancy	3, 4, 11
Muscle Weakness	Reduced strength, often proximal	Birth/Early	2, 3, 4
Motor Delay	Delayed milestones (e.g., sitting)	Infancy	3, 4
Respiratory Issues	Breathing difficulties, weakness	Variable	3, 1, 13
Feeding Problems	Trouble sucking/swallowing	Infancy	1, 3
Facial Weakness	Poor facial movement, expression	Early	2, 4, 15
Stable/Slow Course	Little or slow progression	Childhood	2, 4, 15

Table 1: Key Symptoms

Common Symptoms and Their Impact

Most congenital myopathies are characterized by hypotonia—a state of decreased muscle tone often noticed at birth, leading to "floppiness" and reduced spontaneous movement. Muscle weakness typically affects the proximal muscles (those closest to the trunk) and can involve the neck, face, and limbs. This weakness often results in motor delays, with affected infants taking longer to sit, crawl, or walk compared to peers 3, 4, 11.

Respiratory and Feeding Difficulties

Respiratory muscle weakness is a significant concern, especially in severe cases. Some infants may struggle with breathing and require ventilatory support, while others develop respiratory problems later in life 1, 3, 13. Feeding difficulties, such as trouble sucking or swallowing, are also common and can necessitate feeding tubes for nutrition 1, 3.

Facial and Other Muscular Involvement

Facial weakness can give rise to poor facial expression and difficulties with eye movement. Involvement of extraocular muscles (those that control eye movement) is more common in certain subtypes 2, 4, 15. Despite these challenges, many patients experience a stable or slowly progressive course, with symptoms remaining unchanged or only modestly worsening over time 2, 4, 15.

Types of Congenital Myopathy

Congenital myopathies are classified into several main types based on characteristic features seen under the microscope (histopathology) and underlying genetic causes. Each type has its own clinical profile and challenges.

Type	Defining Feature	Key Genes/Proteins	Main Sources
Core Myopathies	Cores in muscle fibers	RYR1, SEPN1	1, 2, 13, 15
Nemaline Myopathy	Nemaline rods/bodies	ACTA1, NEB, TPM3, TNNT1	1, 8, 15
Centronuclear Myopathy	Centralized nuclei	MTM1, DNM2, BIN1	6, 9, 15
Fiber Type Disproportion	Small type 1 fibers	SEPN1, ACTA1, TPM3	1, 3, 10, 15
Myosin Storage Myopathy	Hyaline body inclusions	MYH7	10, 15

Table 2: Major Types of Congenital Myopathy

Core Myopathies

Core myopathies—including central core disease (CCD) and multi-minicore disease (MmD)—are the most prevalent subtype. They are defined by the presence of "cores," or regions lacking normal muscle structure, in muscle fibers. Most cases are linked to mutations in the RYR1 gene, which plays a crucial role in calcium regulation within muscles 1, 2, 13, 15. While some affected children have mild symptoms and can walk independently, others require assistive devices or respiratory support 1.

Nemaline Myopathy

Nemaline myopathy is characterized by the presence of rod-like structures (nemaline bodies) within muscle cells. It represents a heterogeneous group, with severity ranging from mild to life-threatening. Several genes have been implicated, most notably ACTA1, NEB, TPM3, and TNNT1—all involved in thin filament structure and function 1, 8, 15. Clinical features often include facial weakness, swallowing difficulties, and variable involvement of respiratory muscles.

Centronuclear Myopathy

Centronuclear myopathy (CNM) is defined by the abnormal central placement of nuclei within muscle fibers. The most severe form, X-linked myotubular myopathy, is caused by mutations in the MTM1 gene and often presents with profound weakness at birth. Other forms are related to DNM2 (autosomal dominant) and BIN1 (autosomal recessive) mutations 6, 9, 15. Newer research has shown that RYR1 mutations can also present as CNM 9.

Congenital Fiber Type Disproportion

This type is marked by a disproportionate reduction in the size of type 1 (slow-twitch) muscle fibers compared to type 2 fibers. Mutations in SEPN1, ACTA1, and TPM3 are common causes 1, 3, 10, 15. Symptoms are often milder, but respiratory complications can still arise.

Myosin Storage Myopathy

A rarer subtype, myosin storage myopathy, features the accumulation of hyaline bodies (protein inclusions) in muscle fibers. It is associated with mutations in MYH7, encoding slow/β-cardiac myosin 10, 15.

Causes of Congenital Myopathy

The causes of congenital myopathies are rooted in inherited genetic mutations that disrupt muscle function. Recent advances have greatly expanded our understanding of the genes and molecular pathways involved.

Cause Type	Description	Example Genes/Proteins	Key Sources
Genetic Mutation	Inherited or de novo gene changes	RYR1, ACTA1, MTM1, NEB	1, 2, 11, 15
Protein Deficiency	Loss/alteration of muscle proteins	βIV-spectrin (SPTBN4)	5, 8
Disrupted Pathways	Calcium handling, filament assembly	RYR1, SEPN1, DNM2	2, 13, 14
Inheritance Pattern	Dominant, recessive, X-linked	Varies by subtype	6, 11, 15

Table 3: Causes of Congenital Myopathy

Genetic Mutations and Inheritance

Congenital myopathies are primarily caused by mutations in genes that encode proteins critical for muscle structure, contraction, and maintenance. These mutations can be inherited in various ways—autosomal dominant, autosomal recessive, or X-linked—or can arise as new (de novo) changes 6, 11, 15. More than 30 genes have been identified, with ongoing discovery of new causative genes and variants 11, 15.

Disrupted Muscle Proteins and Pathways

Key protein families involved in congenital myopathies include:

• Ryanodine receptor (RYR1): Regulates calcium release, crucial for muscle contraction (1, 2, 13).
• Thin filament proteins: Such as ACTA1 (α-actin), NEB (nebulin), TPM3 (tropomyosin), and TNNT1 (troponin T), all vital for the contractile apparatus (8, 10).
• Myotubularin (MTM1), dynamin 2 (DNM2), and amphiphysin 2 (BIN1): Involved in muscle membrane trafficking and organization, especially in centronuclear myopathies (6, 12).
• Selenoprotein N (SEPN1): Linked to redox regulation and involved in some core myopathies and fiber type disproportion (1, 10).
• βIV-spectrin (SPTBN4): Associated with rare forms involving myopathy plus neuropathy and deafness (5).

These mutations disrupt pathways such as calcium homeostasis, thin/thick filament assembly, excitation–contraction coupling, and cellular maintenance (2, 14). The same gene can sometimes produce different pathological features, highlighting the complexity and overlap between subtypes (3, 11).

Expanding Genetic Landscape

With the advent of next-generation sequencing, clinicians can now identify mutations across the entire coding regions of relevant genes, increasing diagnostic accuracy and revealing novel forms of congenital myopathy (4, 11, 13). Still, in about one-third of cases, the underlying genetic defect remains unidentified (1, 15).

Treatment of Congenital Myopathy

While there is currently no cure for congenital myopathies, considerable progress has been made in supportive care and the development of targeted therapies. Management focuses on maximizing function, preventing complications, and improving quality of life.

Treatment Approach	Main Focus	Current Status	Key Sources
Supportive Care	Respiratory, nutrition, rehab	Standard of care	1, 2, 14, 15
Multidisciplinary Team	Neurology, pulmonology, PT/OT	Essential	15, 14
Emerging Therapies	Gene/molecular targeted	Clinical trials/Preclinical	12, 13, 14
Symptom Management	Devices, surgery, medications	As needed	1, 15

Table 4: Treatment Strategies

Supportive and Symptomatic Management

The backbone of treatment remains supportive care:

• Respiratory support: Non-invasive ventilation, airway clearance, and monitoring for sleep apnea or respiratory insufficiency are vital, especially in those with severe weakness (1, 14, 15).
• Nutritional support: Feeding tubes or dietary modifications may be necessary for those with swallowing difficulties (1, 15).
• Physical and occupational therapy: To maintain mobility, prevent contractures, and maximize independence (15).
• Orthopedic intervention: Surgery or bracing may be required to address scoliosis or joint deformities (1, 15).

A multidisciplinary team—including neurologists, pulmonologists, dietitians, and therapists—is crucial for optimal care (15, 14).

Emerging and Experimental Therapies

Advances in molecular genetics have paved the way for novel therapies:

• Gene-targeted approaches: Antisense oligonucleotides and gene therapy are under investigation, with promising results in animal models, especially for DNM2-related centronuclear myopathy (12).
• Disease-modifying drugs: Research is ongoing into agents that may improve muscle function or slow progression, targeting pathways such as calcium handling and muscle growth (13, 14).
• Personalized medicine: As more genetic variants are identified, treatments tailored to specific mutations are becoming a realistic future goal (14, 15).

Current Limitations and Future Directions

Despite these encouraging developments, no FDA-approved disease-modifying treatments are yet available (13, 15). Clinical trials are ongoing, and new strategies—including gene editing and molecular therapies—offer hope for the future (14, 12). In the meantime, comprehensive supportive care remains the standard, substantially improving life expectancy and quality of life for many patients (1, 15).

Conclusion

Congenital myopathies are complex, diverse disorders that require a nuanced approach to diagnosis and management. As our understanding grows, so does the potential for more effective, targeted therapies. Key takeaways include:

• Early recognition of symptoms such as hypotonia, weakness, and delayed milestones is vital for diagnosis.
• Major types include core myopathies, nemaline myopathy, centronuclear myopathy, fiber type disproportion, and myosin storage myopathy.
• Causes are rooted in genetic mutations affecting muscle structure and function, with an ever-expanding list of implicated genes.
• Treatment is currently supportive and multidisciplinary, but exciting advances in gene and molecular therapy are on the horizon.

Ongoing research promises to further unravel the mysteries of congenital myopathies and bring new hope to affected individuals and families.