Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox?

Abstract

Objective To systematically compare transthyretin with primary amyloid neuropathy to define their natural history and the underlying mechanisms for differences in phenotype and natural history. Methods All patients with defined amyloid subtype and peripheral neuropathy who completed autonomic testing and EMG at Mayo Clinic Rochester between 1993 and 2013 were included. Medical records were reviewed for time of onset of defined clinical features. The degree of autonomic impairment was quantified using the composite autonomic severity scale. Comparisons were made between acquired and inherited forms of amyloidosis. Results 101 cases of amyloidosis with peripheral neuropathy were identified, 60 primary and 41 transthyretin. 20 transthyretin cases were found to have Val30Met mutations, 21 had other mutations. Compared to primary cases, transthyretin cases had longer survival, longer time to diagnosis, higher composite autonomic severity scale scores, greater reduction of upper limb nerve conduction study amplitudes, more frequent occurrence of weakness, and later nonneuronal systemic involvement. Four systemic markers (cardiac involvement by echocardiogram; weight loss over 10 pounds; orthostatic intolerance; fatigue) in combination were highly predictive of poor survival in both groups. Interpretation These findings suggest that transthyretin has earlier and greater predilection for neural involvement and more delayed systemic involvement. The degree and rate of systemic involvement is most closely related to prognosis.

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

“…Impairment of the autonomic nervous system is common in patients with hATTR amyloidosis and can manifest as disturbance of GI motility, sexual dysfunction, bladder dysfunction, cardiovascular (CV) symptoms, pupillomotor impairment, and/or vasomotor impairment [13][14][15][16]. Dysfunction of the peripheral autonomic nerves occurs more frequently in hATTR amyloidosis than in other types of amyloidoses (e.g., immunoglobulin light chain [AL] amyloidosis or amyloid A [AA] amyloidosis) [8,13,14,17], with autonomic neuropathy reported in approximately half of patients with hATTR amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry. Autonomic dysfunction occurs with a variety of TTR mutations including those not historically associated with neuropathic manifestations (e.g., V122I) [8,18].…”

The Pathology of Amyloidosis in Classification: A Review

“…A diagnosis of amyloid peripheral neuropathy is often delayed because the clinical features may mimic many other neuropathies. Overall, amyloidosis is a relatively rare cause of peripheral neuropathy -in the Mayo Clinic peripheral nerve laboratory, amyloid peripheral neuropathy accounted for only 3% of cases [81][82][83].…”

Amyloid Proteins and Peripheral Neuropathy

“…Although the prevalence of peripheral neuropathy in the various amyloid diseases may be quite variable (see [ 83 ]) and the relevance of amyloid protein aggregation for the development of peripheral neuropathy in these disease may also vary, some common characteristics do emerge. Peripheral amyloid neuropathy usually presents as symmetric polyneuropathy, which is length-dependent, i.e., beginning in the lower extremities and extending more proximally as the disease progresses [ 84 , 85 , 86 ].…”

“…In addition to peripheral sensory nerves and DRGs [ 74 , 90 , 91 ], amyloid has also been detected in autonomic nerves [ 92 ] and autonomic ganglia [ 21 ]. As a consequence, autonomic dysfunction is present in several of the amyloid diseases ( Table 1 and [ 83 ]). Development of signs and symptoms of autonomic dysfunction, however, usually occurs later than the peripheral polyneuropathy [ 93 ].…”