RFC1 expansions are a common cause of idiopathic sensory neuropathy

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.

Keywords: CANVAS; RFC1; chronic idiopathic axonal polyneuropathy; sensory neuropathy.

Figure 1

Flow chart for enrolment of patients with sensory and sensory-motor CIAP. ENMG = electroneuromyography; HSN = hereditary sensory neuropathy; PN = polyneuropathy.

Figure 2

Detailed neurological examination of RFC1+ patients. HIT = head-impulse test; LL = lower limbs; UL = upper limbs; vVOR = visually-enhanced vestibulo-ocular reflex.

Figure 3

Graphic representation of the distribution of abnormalities at sensory examination. The different shades of colour correspond to different percentages of patients with reduced sensation in the specific area.

Figure 4

Distribution of system involvement in RFC1 patients after clinical examination and investigations. Patients with isolated sensory neuropathy were further subdivided depending on the presence of cough; patients with complex neuropathy who did not have the full triad of CANVAS were further classified depending on the presence of vestibular or cerebellar dysfunction.

Figure 5

The ‘iceberg’ hypothesis for RFC1 spectrum disorders. Complex neuropathy was defined by the contemporary presence of neuropathy and vestibular or cerebellar involvement.