Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

SYNOPSIS: Isolated amyloid myopathy is a rare disorder that can be distinguished from systemic amyloidosis with myopathy by clinical, biochemical, and muscle biopsy histologic criteria.

SOURCE: Liewluck T, Milone M. Characterization of isolated amyloid myopathy. Eur J Neurol 2017;24:1437-1445.

Amyloid myopathy is a rare and underdiagnosed disorder, unless muscle biopsy specimens are stained Congo red and evaluated with fluorescence optics. It is seen most often (75%) in patients with light-chain (AL) immunoglobulin amyloidosis, whether they have multiple myeloma, and presents with proximal weakness and elevated serum creatine kinase (CK) with or without dysphagia, myalgia, macroglossia, and enlarged muscles. Amyloid myopathy is also seen in familial amyloidosis with transthyretin and gelsolin mutations, whereas isolated amyloid myopathy occurs in limb-girdle muscular dystrophy type 2B (dysferlinopathy) and 2L (anoctaminopathy-5). Can isolated amyloid myopathy be differentiated from amyloid myopathy seen with systemic amyloidosis?

Patients seen at the Mayo Clinic between Jan. 1, 1998, and Sept. 20, 2016, and diagnosed with amyloid myopathy, defined by the presence of amyloid in intramuscular connective tissue or blood vessels on Congo red staining, were identified through the Mayo Clinic muscle biopsy database. They were classified as isolated amyloid myopathy or systemic amyloidosis-associated myopathy, based on the absence or presence, respectively, of monoclonal gammopathy, extra-muscular amyloid deposition, organomegaly by examination or computerized tomography, and peripheral neuropathy, clinically or electrodiagnostically. Patients were excluded if they had a coexisting independent myopathy. Statistical analysis comprised the Fisher exact test to compare frequencies of findings, and the Mann-Whitney U-test to compare continuous variables between the two groups.

Among 52 patients included in the study, 14 had isolated amyloid myopathy and 38 had systemic amyloidosis, the former including eight anoctaminopathy-5, two dysferlinopathy, and four genetically unknown cases, and the latter comprising 32 immunoglobulin AL amyloidosis, four familial amyloid polyneuropathy (three due to transthyretin-encoding gene mutations and one gelsolin-encoding gene mutation), and two senile systemic amyloidosis cases. Compared to those with systemic amyloidosis, patients with isolated amyloid myopathy had a younger age of onset (median 41.5 vs. 65 years) and a longer duration of symptoms until diagnosis (median 60 vs. 17.5 months). Although muscle strength was similar in both groups, with proximal weakness being the most common pattern, muscle atrophy, particularly of the calf muscles, was seen only in those with isolated amyloid myopathy, who also had no dysphagia or weight loss (vs. 26% in systemic amyloidosis group). Compared to systemic amyloidosis, isolated amyloid myopathy patients demonstrated small collections of inflammatory cells on muscle biopsy (43% vs. 0%) and had CK elevation at onset (100% vs. 29%). CK elevation < 2.5 times the upper limit of normal was seen only in systemic amyloidosis-associated myopathy. Among patients with amyloid myopathy, 27% are isolated to muscle, are usually due to anoctaminopathy-5, and may be differentiated clinically from amyloid myopathy seen with systemic amyloidosis.

COMMENTARY

Caused by a point mutation of the transthyretin gene, of which almost 100 mutations have been identified, transthyretin familial amyloid neuropathy (TTR-FAP) is rare, but is the most disabling hereditary neuropathy of adult-onset, fatal if untreated, affecting sensorimotor and autonomic function, as well as the eyes, heart, kidneys, and other organ systems. Seen worldwide, there is considerable phenotypic variability and course severity, depending on the particular point mutation. Early initiation of the TTR stabilizer tafamidis delays neuropathy progression in early-onset Val30Met TTR-FAP, and is the first-line therapy for stage 1 disease. Phase III clinical trials are ongoing using TTR gene silencing, which affects both mutant and wild-type TTR production, with results expected soon. Further research to allow early diagnosis, and early intervention, remains crucial.