Systemic amyloidosis-associated myopathy

Systemic amyloidosis very rarely involves skeletal muscles. In AL amyloidosis, only 1.5% of patients are reported to develop myopathy. However, a clue to its being a muscle disease is that nearly 70% of these AL amyloidosis myopathy patients initially developed weakness without sensory or autonomic symptoms. In ATTR and AGel amyloidosis, myopathy is very rare. Amyloid myopathy is usually accompanied by peripheral neuropathy. Although amyloid myopathy patients may not experience neuropathy symptoms, especially at onset, careful neurologic exam and electrodiagnostic studies typically identify subclinical neuropathy in these patients. Peripheral neuropathy is observed in 40% of AL amyloid myopathy and 90% of ATTR amyloid myopathy.

In AL amyloid myopathy, 9% to 25% of patients may present with jaw claudication, due to amyloid deposition around the temporal artery, what may be misdiagnosed as temporal arteritis. Systemic amyloidosis-associated myopathy typically causes symmetrical proximal predominant weakness. Creatine kinase (CK) is normal in approximately two thirds of patients. Occasionally, amyloid myopathy can present with axial weakness, or muscle pseudohypertrophy, the latter of which has been reported in only AL amyloidosis. Approximately one third of patients with AL amyloid myopathy develop dysphagia, which can be the first manifestation of the myopathy. Respiratory muscles can be affected, albeit uncommonly. Needle EMG often shows short duration, low amplitude motor unit action potentials (MUPs) with rapid recruitment. Fibrillation potentials or myotonic discharges are observed in only a small proportion of patients. Muscle biopsy is fundamental for the diagnosis of amyloid myopathy. It is recommended to perform Congo red-staining for all muscle biopsies to look for amyloid myopathy. Routine performance of Congo red staining can result in a 10-fold increase in the number patients identified with amyloid myopathies. In our cohort, hematoxylin and eosin stained sections were suggestive of amyloid deposits in only 25% of patients with ATTR myopathy. The most common myopathological features of amyloid myopathy are rare necrotic and regenerating fibers, variation in fiber size, and interstitial amyloid deposition in intramuscular blood vessels or in the perimysium or endomysium, occasionally encasing muscle fibers. Denervation atrophy is also observed in 80% of patients confirming the observation of co-existing peripheral neuropathy. Amyloid myopathy is probably underdiagnosed in systemic amyloidosis as muscle biopsy is not typically pursued. In patients with peripheral neuropathy and both proximal and distal weakness, it is vital to perform careful needle EMG on paraspinal and proximal limb muscles as the identification of concomitant myopathic changes (neuromyopathy) significantly narrows the differential diagnosis.

Isolated amyloid myopathy

Skeletal muscle can be the only tissue involved by amyloidosis, so called isolated amyloid myopathy. It is considered a localized form of hereditary amyloidosis. In our institution, isolated amyloid myopathy ishe second most common cause of amyloid myopathy, accounting for 27% of patients with amyloidosis involving skeletal muscle. Among 14 patients with isolated amyloid myopathy, 10 patients carried mutation in the anoctamin-5 gene (ANO5) and 2 patients had mutations in the dysferlin gene (DYSF). Defects in both proteins are known to cause autosomal recessive limb-girdle muscular dystrophies and distal myopathies of Miyoshi type. In dysferlinopathy with interstitial congophilia, electron microscope confirmed the presence of amyloid fibrils and fragments of dysferlin were identified in the congophilic deposits using immunohistochemical technique. In anoctaminopathy with extracellular congophilia, mass spectrometry analysis identified amyloid chaperone proteins in congophilic deposits, but the amyloidogenic protein remains unknown. Patients with dysferlinopathy or anoctaminopathy may present with proximal weakness or distal weakness primarily affecting calf muscles, and markedly elevated CK levels. EMG typically shows rapidly recruiting short duration, low amplitude motor unit potentials with fibrillations potentials. Several key clinical features can help to differentiate between systemic vs isolated amyloid myopathy

Unlike systemic amyloidosis-associated myopathies, laser captured microdissection and mass spectrometry have failed to identify amyloidogenic proteins in anoctaminopathy and dysferlinopathy patients, which could be, at least in part, due to technical limitations. If the clinical presentation is typical for anoctaminopathy or dysferlinopathy, immunohistochemical study for dysferlin and genetic testing for ANO5 and DYSF are warranted. The exact frequency of amyloid deposition in dysferlinopathy and anoctaminopathy is uncertain, as Congo red staining is not routinely performed in many laboratories, but it is estimated at approximately 30% for dysferlinopathy and 50% for anoctaminopathy. The presence of amyloid deposits does not seem to alter the myopathy phenotype. There are no disease modifying treatments available for isolated amyloid myopathy.

Diagnostic work-up:

EMG/NCS,

CK, SPEP/SIFE, FLCs, UPEP/IFE.

In patients with a proximal myopathy of undetermined etiology, usually pursue a muscle biopsy. Congo red stain is routinely performed in our muscle laboratory. If muscle biopsy is negative for amyloid and monoclonal gammopathy screen is negative, the possibility of amyloid myopathy is ruled out. When amyloid myopathy is suspected, it is important to communicate this to the muscle biopsy laboratory to save specimen for potential paraffin embedding as amyloid subtyping can only be done on paraffin-embedded tissue. As mentioned above, in dysferlinopathy and anoctaminopathy with amyloidosis, the amyloid subtyping generally identifies amyloid-associated proteins, but not the known amyloidogenic proteins associated with systemic amyloidosis.