Distinguishing hATTR Polyneuropathy From Its Common Mimics

Key Takeaways:

• hATTR-PN is commonly mistaken for chronic idiopathic axonal polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), or carpal tunnel syndrome, delaying diagnosis by several years.
• The combination of bilateral carpal tunnel syndrome, autonomic dysfunction, unexplained weight loss, cardiac involvement, and a suggestive family history should prompt consideration of hATTR-PN and TTR genetic testing.
• An axonal pattern on electrodiagnostic testing and lack of response to immunotherapy should prompt reconsideration of a diagnosis of CIDP.

Without treatment, hATTR-PN is progressive and can result in substantial disability and reduced survival. Early recognition is important because effective disease-modifying therapies are now available.¹

Yet in non-endemic regions, the diagnosis is typically delayed by 3 to 4 years, and hATTR-PN is suspected at only 26 to 38% of initial evaluations. For clinicians, the practical challenge is separating it from the far more common axonal and demyelinating neuropathies it resembles.²

The misdiagnosis problem

Many patients receive 1 or more alternative diagnoses before hATTR-PN is recognized. Misdiagnosis as CIDP is particularly important because it may lead to prolonged treatment with ineffective immunotherapy.²

A negative family history does not exclude hATTR-PN. In non-endemic areas, many patients have no known family history, particularly those with late-onset disease.²

Red flags that shift suspicion

Several clinical features should raise suspicion for hATTR-PN, particularly when they occur together. In a single-center cohort comparing 15 patients with hATTR-PN – all carrying the Val30Met variant – with 92 patients with chronic idiopathic axonal polyneuropathy, bilateral carpal tunnel syndrome and autonomic symptoms were substantially more common in patients with hATTR-PN.³

A first-degree family history of neuropathy and cardiac involvement were also more common in patients with hATTR-PN, although these findings come from a small, single-center study of patients with the Val30Met variant.³

In clinical practice, autonomic dysfunction in a patient with an otherwise unexplained axonal polyneuropathy should prompt consideration of hATTR-PN, particularly when accompanied by bilateral carpal tunnel syndrome, unexplained weight loss, cardiac disease, or a suggestive family history. A rapidly progressive course should further increase suspicion.^1,2

Expert consensus incorporates these findings into a suspicion index to help identify patients who should undergo TTR genetic testing. The index includes idiopathic rapidly progressive sensorimotor axonal neuropathy or atypical CIDP together with features such as family history, bilateral CTS, autonomic dysfunction, gait disturbance, unexplained weight loss of 5 kg or more, cardiac hypertrophy or rhythm disorder, vitreous opacities, or renal involvement. The presence of 2 or more of these features improves identification of patients with hATTR-PN while limiting unnecessary genetic testing.^1-3

Separating amyloid neuropathy from CIDP

The CIDP misdiagnosis is the most consequential because it can lead to prolonged, ineffective immunotherapy. Two features help resolve it.¹

First, electrophysiology: Although mild conduction slowing may be present, electrodiagnostic studies typically show an axonal neuropathy with reduced motor and sensory response amplitudes rather than the primary demyelinating features expected in CIDP.¹

Second, treatment response: Failure to respond to appropriate immunotherapy should prompt reassessment of the diagnosis rather than escalation of treatment.¹

Confirming the diagnosis

Diagnosis is established through TTR genetic testing together with confirmation of amyloid deposition and appropriate amyloid typing when tissue is obtained. Identification of a pathogenic TTR variant alone is insufficient because disease penetrance is incomplete. Additionally, a negative biopsy from a single site does not exclude the diagnosis.²

A confirmed diagnosis has important implications for family members because hATTR-PN is inherited in an autosomal dominant pattern. Genetic counseling and testing should be considered for at-risk relatives. Maintaining a high index of suspicion in patients with otherwise unexplained progressive axonal polyneuropathy remains one of the most important steps toward establishing the diagnosis before irreversible nerve injury occurs.^1,2