Differential Diagnosis of genetic muscle diseases
common genetic muscle diseases that may be confused with metabolic myopathies and childhood or adult polymyositis
- • Dystrophinopathies:
- Duchenne dystrophy: X-linked disease due to a mutation in DMD , the gene for the protein, dystrophin, which connects the contractile proteins of muscle, the sarcomere, up to a protein complex at the muscle membrane, the sarcolemma. Onset of pelvic and shoulder girdle muscle weakness occurs by age 5. CK levels can be elevated to more than 50 to 150 times upper limit of normal at rest. Calf hypertrophy, scoliosis, loss of ambulation by age 13, and death from respiratory failure or cardiomyopathy in the third and fourth decades occurred in the past. Corticosteroids slow progression of skeletal and cardiac muscle dysfunction. Diagnosis is by genetic testing, and genetic therapies are now available to significantly slow the progression of disease.
- Becker dystrophy: X-linked disease due to a less severe mutation of the dystrophin gene resulting in a partially functional protein complex. Similar to Duchenne dystrophy, but milder, with patients able to walk beyond the age of 16 years. Age of onset ranges from the first through the seventh decade. The extent of skeletal muscle and cardiac muscle dysfunction may be quite discordant with some ambulatory Becker patients requiring cardiac transplantation.
- Female carriers: Females (10%–30%) with a mutation in DMD on one X chromosome (often mothers, sisters or daughters of males with a dystrophinopathy) can develop skeletal muscle weakness and myalgias. An equal percentage may manifest cardiac dysfunction, arrhythmias, or heart failure, clinically or on testing (heart monitors and echocardiograms). Whenever a woman with muscle disease has symptoms that do not fit into a typical diagnosis, genetic muscle disease can be considered.
- • Facioscapulohumeral dystrophy: Autosomal dominant disease due to a partial deletion located on chromosome 4. Variable disease expression with disease onset between adolescence and middle-adult years. Facial muscle weakness (cannot whistle) often occurs first. Scapulohumeral weakness leading to winged scapulae is a prominent feature. Lower extremities are less involved. CK is elevated up to five times normal, and inflammation can be seen on muscle biopsy.
- • LGMDs: There are now more than 100 genetic muscle diseases that present with proximal weakness in the hip and shoulder girdle muscles. Fortunately, with large genetic testing panels encompassing 80 to 500 genes, many of these genetic muscles disease can be cost-effectively diagnosed early in the evaluation. The most common LGMD confused with polymyositis include:
- LGMD2B— dysferlinopathy. Autosomal recessive disease. LGMD2B stems from a mutation in DYSF, the gene coding for dysferlin, a protein important in muscle repair. Patients present with progressive lower extremity followed by upper extremity proximal muscle weakness beginning in second to fourth decades. Facial muscles and heart are spared and winged scapulae are not seen. The disease slowly progresses leading to 50% of patients requiring wheelchair use in 10–30 years. This dystrophy is the one most readily confused with adult polymyositis because CK is elevated and inflammatory infiltrates may be seen on muscle biopsy. A diagnostic clue is that most patients have difficulty standing on their toes within the first 1–2 years of symptom onset due to early, concomitant calf muscle weakness. A trial of corticosteroids in dysferlinopathies failed to demonstrate any benefit.
- LGMD2C, 2D, 2E, and 2F— the sarcoglycanopathies: Autosomal recessive disorders due to mutations of sarcoglycans in the sarcolemma. The sarcoglycans are a family of transmembrane proteins (α, β, γ, δ) involved in the protein complex responsible for connecting the muscle fiber cytoskeleton to the extracellular matrix, preventing damage to the muscle fiber sarcolemma through shearing forces. Patients present with a limb-girdle and Duchenne/Becker-like phenotypes. Most present by the age of 6–8 years. Progression of weakness can be rapid. Cardiomyopathy occurs in 30%. Serum CK levels are high. Muscle biopsies may have inflammation, especially eosinophilic myositis. The sarcoglycanopathies do not respond to corticosteroids.
- LGMD2I, 2K, 2M, 2N, and others— the alpha-dystroglycanopathies: Autosomal recessive disorders due to mutations in the 17 genes involved in glycosylation of alpha-dystroglycan. Alpha-dystroglycan forms pivotal, carbohydrate links from the sarcolemma up to the extracellular matrix. Onset of proximal weakness is generally in infancy or childhood and may have associated brain and eye involvement. Cardiac and respiratory compromise occurs in many patients. CK levels are 2 to 10 times the upper limit of normal. Interestingly, associated with a febrile illness in early childhood, around one-quarter of alpha-dystroglycanopathy patients have an abrupt onset of weakness (often lose ambulation) along with respiratory compromise. Recovery ensues over 1 to 3 weeks. This acute illness-associated weakness occurs prior to onset of the muscular dystrophy in half the cases.
- • Myotonic dystrophies: Autosomal dominant diseases. Type 1 has temporal atrophy, sternocleidomastoid muscle wasting, ptosis, distal limb weakness, and systemic features (balding, cataracts, cardiorespiratory, and gastrointestinal involvement). Characteristic physical finding is delayed relaxation and muscles stiffness (myotonia). Inability to relax handgrip when shaking hands and myotonic contraction of thumb when thenar eminence musculature is percussed by a reflex hammer is commonly observed. EMG shows excessive insertional activity and a “dive bomber” sound with contraction of muscle. Ringed myofibers seen in 70% on muscle biopsy and atrophy of type I fibers is prominent. Type 2 has proximal muscle weakness, muscle pain, cataracts, intermittent and asymmetric myotonia, tremors, cardiac disturbances (heart block), and hypogonadism. Neck flexors, hip flexors, and triceps are affected most commonly. CK is elevated up to four times normal.
- • Lipin-1: Autosomal recessive disease due to mutations in LPIN1 , the gene for lipin-1. A common cause of rhabdomyolysis in children aged ≤6 years. Baseline muscle strength and CK levels are often normal, but rhabdomyolysis may be severe with CK levels 10,000–1,000,000 U/L with up to a 30% mortality rate. Attacks are most often triggered by febrile episodes, but also associated with exercise, fasting, and anesthesia. Intravenous high-concentration glucose solutions during attacks and increased caloric intake during situations of elevated energy demand (e.g., fever or exercise) resulted in decreased frequency and severity of episodes of rhabdomyolysis.
- • RYR1-associated myopathies: Autosomal dominant disorder. Mutations in RYR1 , the gene for the ryanodine receptor, may account for up to 30% of rhabdomyolysis episodes in otherwise healthy persons. Common triggers for episodes of rhabdomyolysis include exercise, heat, and viral infections. It is important to recognize and diagnose these patients since there can be concomitant malignant hyperthermia susceptibility with certain inhalational anesthetics. Modification of lifestyle through avoidance of overheating and modification of exercise programs can help reduce the frequency and severity of the rhabdomyolysis episodes.
