Abstract
After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren’s syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.
Highlights
Polyneuropathy is a common health problem leading to neurological consultation, with an estimated prevalence of 1–2.4% in the general population and up to 7% in people aged 465 years.[1,2]Even after extensive evaluation, 25–32% of patients remain undiagnosed and are often labelled as having chronic idiopathic axonal polyneuropathy (CIAP).[3,4,5,6] CIAP refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy.[7]
As sporadic CIAP is the focus of the study, patients previously diagnosed with CANVAS or with a family history of CANVAS were not included
We identified replication factor complex subunit 1 (RFC1) AAGGG biallelic expansions in 34% of patients with sensory CIAP suggesting that RFC1
Summary
Polyneuropathy is a common health problem leading to neurological consultation, with an estimated prevalence of 1–2.4% in the general population and up to 7% in people aged 465 years.[1,2]Even after extensive evaluation, 25–32% of patients remain undiagnosed and are often labelled as having chronic idiopathic axonal polyneuropathy (CIAP).[3,4,5,6] CIAP refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy.[7]. Family history in CIAP is usually negative and age at onset is significantly higher than in most known inherited neuropathies.[9,11] Previous attempts at identifying a genetic cause of CIAP were unsuccessful.[12,13]
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