Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Abstract

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

Keywords: RFC1; cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS); chronic cough; repeat expansion; sensory neuropathy.

Figure 1

Disease onset and progression. (A) Symptoms at disease onset and during disease progression in 100 biallelic RFC1 expansion carriers. Patients reporting a combination of symptoms (unsteadiness, cough, sensory symptoms, oscillopsia, dysautonomia, dysarthria, dysphagia) are also represented in the last two columns (multiple symptoms). (B) Age distribution of symptoms and disease milestones. The ends of the boxes represent the upper and lower quartiles, the median is marked by a vertical line within the box. The whiskers extend to the highest and lowest observations with outliers represented as circles outside the whiskers.

Figure 2

Involvement of peripheral nerve, cerebellum and vestibular system in RFC1 biallelic expansion. (A) Symptoms and signs. Clinical involvement of peripheral nerve (PN), vestibular system (VS) and cerebellum (CBM) is defined as follows: (i) peripheral nerve: sensory neuropathy: sensory symptoms (loss of feeling, paraesthesia, dysesthesia, neuropathic pain) and/or abnormal sensory examination including sensory ataxia; (ii) vestibular system: bilateral vestibulopathy: presence of head movement-induced oscillopsia and/or abnormal head impulse test; (iii) cerebellum: cerebellar dysfunction: cerebellar dysarthria and/or dysphagia, abnormal eye movements (nystagmus, dysmetric saccades, broken pursuits). (B) Symptoms, signs and investigations. In addition to the clinical involvement as defined in A, investigational involvement of the three main system affected in CANVAS was further identified by (i) peripheral nerve: sensory neuropathy/neuronopathy on nerve conduction studies; (ii) vestibular system: bilaterally abnormal video head impulse test, bithermal caloric or motorized rotational tests; and (iii) cerebellum: cerebellar atrophy on brain MRI. *Abnormal in 55 of 59 (93%) with clinical information available. **Abnormal in 69 of 74 (93%) with clinical and/or investigational information available.

Figure 3

Nerve biopsy findings in RFC1 biallelic repeat expansions. Severe loss of large and small myelinated fibres with no evidence of ongoing axonal degeneration, no signs of regeneration and no features of demyelination is seen in all CANVAS patients with sensory neuropathy due to RFC1 biallelic expansion. (A, A1, B and B1) Resin-embedded, semi-thin sections stained with methylene blue azure-basic fuchsin are shown from two different patients. Occasional large remaining fibres in both cases are highlighted with a red arrow in A1 and B1. The unmyelinated fibres in the peripheral nerves from CANVAS patients are comparably much better preserved. (C) Axons in formalin-fixed paraffin-embedded tissue are shown on immunostaining with SMI31 antibody. (C1) A large residual axon is highlighted with red arrow and one of multiple clusters of small unmyelinated fibres is shown with a blue arrow. Scale bars = 100 µm in A–C; 40 µm in A1–C1.