Miyoshi Myopathy: Clinical Features and Diagnostic Insights

Miyoshi myopathy is a rare inherited muscle disorder that primarily affects the distal muscles of the legs. It typically begins in late adolescence or early adulthood, leading to progressive weakness and difficulty with activities such as standing on tiptoes. The condition results from mutations in the DYSF gene, which encodes dysferlin, a protein essential for muscle membrane repair.

Early recognition is crucial for proper management and genetic counseling. Since its symptoms resemble other muscular dystrophies, accurate diagnosis requires clinical evaluation, molecular testing, and muscle biopsy findings.

Key Clinical Features

Miyoshi myopathy presents with progressive weakness predominantly in the distal lower limbs, particularly the gastrocnemius and soleus muscles. The initial symptom often manifests as difficulty rising onto the toes due to calf muscle weakness. This can be subtle, with affected individuals noticing an increased tendency to stumble or struggle with activities requiring plantar flexion, such as climbing stairs or walking. Over time, weakness extends proximally, though the quadriceps and hamstrings are typically spared in early stages, distinguishing it from other muscular dystrophies with more generalized patterns of muscle involvement.

As the disease advances, muscle atrophy becomes apparent, particularly in the posterior lower legs, leading to a characteristic “stork leg” appearance. Despite the progressive nature of the condition, sensory function remains intact, and deep tendon reflexes, particularly the Achilles reflex, are often diminished or absent. Unlike inflammatory myopathies, there is no significant pain or tenderness, though some individuals report mild discomfort associated with muscle degeneration.

The rate of progression varies, with some individuals experiencing a slow decline and others a more rapid deterioration. The weakness may eventually extend to the upper limbs, particularly the forearm flexors, though this typically occurs later. Respiratory and cardiac involvement are uncommon, which helps differentiate it from limb-girdle muscular dystrophy type 2B, which shares the same genetic mutation but presents with a different pattern of muscle weakness.

Molecular Role Of Dysferlin

Dysferlin is a transmembrane protein essential for repairing skeletal muscle fibers, particularly in response to mechanical stress. Encoded by the DYSF gene, it is predominantly localized to the sarcolemma, where it facilitates the rapid resealing of microtears that occur during muscle contraction. Without functional dysferlin, muscle fibers accumulate persistent membrane lesions, leading to degeneration and impaired regeneration.

Dysferlin interacts with key proteins involved in vesicle trafficking and membrane fusion, including annexins and caveolins. Annexins, particularly annexin A1 and A2, coordinate the recruitment of intracellular vesicles to sites of membrane injury. In dysferlin-deficient cells, these vesicles fail to aggregate efficiently, preventing timely repair and exacerbating muscle fiber susceptibility to mechanical stress. Additionally, dysferlin interacts with caveolin-3, a protein associated with lipid raft domains in the sarcolemma. This interaction helps organize repair machinery, ensuring membrane resealing occurs in a coordinated manner.

Beyond membrane repair, dysferlin influences intracellular signaling pathways that regulate muscle homeostasis. Its deficiency alters calcium homeostasis, leading to dysregulated calcium influx and impaired activation of downstream repair mechanisms. This imbalance contributes to oxidative stress and chronic activation of proteolytic pathways, accelerating muscle degeneration. Dysferlin also modulates endocytic trafficking, affecting the recycling of membrane components necessary for sarcolemmal integrity. These dysfunctions explain why individuals with Miyoshi myopathy experience progressive muscle wasting despite the absence of direct structural defects in contractile proteins.

Diagnostic Assessments

Diagnosing Miyoshi myopathy requires clinical observation, laboratory testing, and imaging. Given the progressive distal muscle weakness, initial suspicion arises from a neurological examination assessing selective calf muscle involvement, diminished deep tendon reflexes, and difficulty performing plantar flexion tasks. While these findings provide important clues, they are insufficient for a definitive diagnosis, necessitating biochemical and genetic investigations.

Serum creatine kinase (CK) levels are typically elevated, often several times above the normal limit, reflecting ongoing muscle degeneration. However, elevated CK is not exclusive to Miyoshi myopathy and must be interpreted alongside other markers. Electromyography (EMG) can help differentiate the disorder from neurogenic conditions by revealing myopathic changes such as short-duration, low-amplitude motor unit potentials. While EMG contributes to the diagnostic picture, it is non-specific and must be supplemented with molecular analyses.

Genetic testing plays a decisive role in confirming the diagnosis by identifying pathogenic variants in the DYSF gene. Advances in next-generation sequencing have improved the detection of both common and rare mutations, facilitating earlier and more precise identification. Whole-exome sequencing is particularly valuable in atypical cases or when distinguishing Miyoshi myopathy from other inherited muscle disorders. In some instances, targeted gene panels focusing on limb-girdle muscular dystrophies, which share overlapping clinical features, can streamline the diagnostic process.

Histological Findings

Muscle biopsy analysis reveals patterns of degeneration consistent with the disease’s progressive nature. Affected muscle tissue frequently exhibits fiber size variability, with atrophic fibers interspersed among hypertrophic ones. This mosaic pattern reflects ongoing cycles of muscle breakdown and compensatory hypertrophy. Unlike inflammatory myopathies, there is no significant immune cell infiltration, reinforcing the primary degenerative nature of the disorder.

A defining histological feature of Miyoshi myopathy is the presence of rimmed vacuoles within muscle fibers. These vacuoles, lined with basophilic granules, indicate autophagic activity, a process by which cells degrade and recycle damaged components. Their accumulation suggests an impaired ability to clear dysfunctional proteins and organelles, contributing to muscle fiber degeneration. Electron microscopy often reveals disrupted sarcolemmal architecture, with irregular membrane folding and cytoplasmic vesicle accumulation, consistent with defective membrane repair mechanisms.

Distinguishing Factors From Other Myopathies

Miyoshi myopathy shares clinical and genetic features with other muscular dystrophies, making differentiation essential for accurate diagnosis and management. One of the primary distinctions lies in muscle involvement. Unlike limb-girdle muscular dystrophy type 2B, which results from mutations in the same DYSF gene but primarily affects proximal muscles, Miyoshi myopathy begins with distal weakness, particularly in the gastrocnemius and soleus. Many other dystrophies, such as Becker muscular dystrophy or facioscapulohumeral dystrophy, present with either proximal or mixed muscle weakness rather than an initial distal pattern. The relative sparing of the quadriceps in early stages further sets Miyoshi myopathy apart from conditions that preferentially affect anterior thigh muscles, such as Duchenne muscular dystrophy.

Serum creatine kinase levels, although elevated, do not provide a definitive distinction, as similar elevations occur in various dystrophic conditions. Genetic testing remains the most reliable method for differentiation, particularly in ambiguous cases. Muscle imaging using MRI can also aid in distinguishing Miyoshi myopathy by revealing selective atrophy patterns, with preferential involvement of the posterior lower leg muscles. The absence of significant cardiac or respiratory involvement differentiates it from conditions such as Pompe disease or myotonic dystrophy, which often feature systemic complications.