Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP)

Abstract

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

“…Misleading CIDP presentations have been occasionally reported in TTR‐FAP14, 38; we found 20% of our cohort of French ancestry fulfilling CIDP criteria. This is to our knowledge the first study able to estimate the prevalence of pseudo‐CIDP presentation in a large cohort of non‐Portuguese FAP patients.…”

“…LateMet30 accounts for 40% of cases. The remaining patients carry 1 of the 29 known TTR mutations in France,13 leading to different patterns of neuropathy 14…”

Clinical and electrophysiological correlates of TTRala71 amyloid neuropathy

“…Unfortunately, we were not able to test the entire family in order to clarify this point. Recently, Plantée-Bordeneuve et al 10 demonstrated that sporadic cases are prone to late diagnosis and its deleterious consequences, like inappropriate treatments Our data emphasize the importance of performing nerve biopsy in atypical or unresponsive CIDP cases, and of sequencing the TTR gene if an amyloid infiltrate is found or if there are significant small nerve fiber manifestations, even in the absence of a positive family history 10 .…”

A Case of Atypical Amyloid Polyneuropathy with Predominant Upper-limb Involvement with the Diagnosis Unexpectedly Found at Lung Operation

“…The demyelinating feature suggested by NCS has been reported as the most common pitfall in diagnosing sporadic cases of FAP (10), and in some late-onset FAP patients with ATTR V30M, the slowing of conduction velocity and prolongation of distal latency were reported to be conspicuous (11). In fact, the electrophysiological findings of the right ulnar nerve observed in our patient also hampered the correct diagnosis in our patient.…”