Upper limb onset of hereditary transthyretin amyloidosis is common in non‐endemic areas

Abstract

Background and purpose The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. Methods The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early‐onset patients and 99 late‐onset patients without upper limb onset. Results Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty‐four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late‐onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. Conclusion Upper limb onset of hereditary ATTR neuropathy is not rare in non‐endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.

Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy

“…Misdiagnoses depend on the initial clinical presentation of neuropathy (symptoms and signs). Common misdiagnoses (Table 2) [13,[25][26][27][29][30][31][32] of patients before the correct diagnosis of ATTRv with PN include chronic inflammatory Table 1 Characteristics of Val30Met early-and late-onset ATTR amyloidosis at the time of diagnosis and clinical course Reprinted with permission from Adams [18] ATTR amyloid transthyretin a Endemic areas, Nagano and Arao Kumamoto, Japan b Patients with early-and late-onset disease are found in the endemic area in Sweden; all are believed to have a common Swedish founder [21] Early-onset Val30Met [7,19] Late-onset Val30Met [8,19,20] Age at onset, years < The disease course for late onset is more aggressive and has a shorter survival time than for early onset [18]. Initial symptoms of late-onset disease may also include sensory problems in upper limbs (33%) and walking disorders (11%) [24], and autonomic neuropathy may occur later in the disease in approximately 47-78% of these patients [24,28,30].…”

<p>Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care</p>

“…1 Clinical presentation of late-onset hATTR-Val30Met amyloidosis and other non-Val30Met variants is, by far, more variable, as it may manifest with sensory or sensorimotor symptoms, starting either distally in lower or all four limbs or even exclusively in the upper limbs, mimicking a carpal tunnel syndrome. 31,35 Autonomic impairment is frequently observed, especially in early-onset cases, and may present with gastrointestinal symptoms (including constipation, daily diarrhoea or alternating constipation/diarrhoea, early satiety, nausea, and vomiting), orthostatic hypotension, bladder and erectile dysfunction.…”

“…[42][43][44] Furthermore, clinical presentation, given its heterogeneity, may mimic various peripheral neuropathies, explaining the high frequency of misdiagnosis (Table 2). 35,42,[45][46][47] Common misdiagnoses include idiopathic axonal polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, lumbar spinal stenosis, diabetic neuropathies, Charcot-Marie-Tooth neuropathy or motor neuron disease. In patients with a peripheral neuropathy of otherwise undetermined aetiology, early search for associated clinical features, especially for cardiac involvement, can help reveal amyloidosis.…”

Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner

“…The wide spectrum of clinical presentation and inaugural manifestations makes amyloid neuropathy a "chameleon-like" neuropathy; consequently, early diagnosis of ATTRv-PN can be challenging for general practitioners and specialists. The most common presenting symptoms of neurologic involvement include progressive sensory polyneuropathy, autonomic dysfunction (eg, chronic or alternating diarrhea and/or constipation, erectile dysfunction, and postural hypotension), pain in the hands or feet, and gait disorders [1,14,16,65,66].…”