Clinical Description
The phenotypic spectrum associated with biallelic RFC1 AAGGG repeat expansions ranges from typical cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), to cerebellar, sensory and vestibular impairment, to more limited phenotypes involving predominantly or exclusively one of the systems involved in balance control.
Before its molecular basis was known, CANVAS was characterized as cerebellar dysfunction with predominant vermian atrophy, spinal and cranial sensory neuronopathy, and bilateral vestibular areflexia [Bronstein et al 1991, Migliaccio et al 2004, Szmulewicz et al 2011, Cazzato et al 2016, Szmulewicz et al 2016, Rust et al 2017, Burke & Halmagyi 2018, Infante et al 2018, Pelosi et al 2018, Taki et al 2018]. Following the discovery of the causative biallelic RFC1 repeat expansions, this genetic alteration was also identified in individuals with a progressive disorder of balance, but not full CANVAS, thus expanding the phenotypic spectrum to include phenotypes involving predominantly or exclusively one of the systems involved in balance control, as well as autonomic dysfunction [Wu et al 2014] and cough.
To date, more than 200 individuals – either simplex cases (i.e., a single occurrence in a family) or having a family history consistent with autosomal recessive inheritance – have been identified with biallelic AAGGG repeat expansions in RFC1 [Akçimen et al 2019, Cortese et al 2019, Rafehi et al 2019, Aboud Syriani et al 2020, Cortese et al 2020b, Gisatulin et al 2020]. The clinical features of 100 individuals with RFC1 CANVAS / spectrum disorder were recently evaluated in a retrospective study [Cortese et al 2020b] and are summarized in Table 2 and detailed in the text that follows.
After ten years of disease duration:
Clinical features of CANVAS were seen in two thirds of affected individuals;
A complex sensory ataxia with cerebellar or vestibular involvement was identified in 16 and six individuals, respectively;
A sensory neuropathy was the only clinically detectable diasease manifestation in 15 individuals.
Table 2.
RFC1 CANVAS / Spectrum Disorder: Frequency of Select Features
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| Feature | Frequency |
|---|
| Sensory neuropathy | 100% |
| Bilateral vestibular impairment | 69% (93% of those tested) |
| Cough | 64% |
| CANVAS | 63% |
| Cerebellar syndrome | 63% |
| Dysautonomia | 32% (50% of those undergoing specific investigations) |
CANVAS = cerebellar ataxia, neuropathy, vestibular areflexia syndrome
In the series of Cortese et al [2020b], the mean age of onset of neurologic manifestations was 52 years (range 19-76 years) and mean age at the time of the study (and at diagnosis) was 72 years. However, symptoms can present as early as the third decade and it is expected that in the future more affected individuals will be diagnosed at a younger age.
Sensory neuropathy. More than two thirds of individuals complain of sensory symptoms, including loss of feeling, pins and needles, and neuropathic pain – in many cases since the onset of disease. Neurologic examination shows impaired sensation to pinprick, vibration and joint position, more typically in a length-dependent distribution. Reflexes can be either reduced/abolished, retained, or brisk. Motor nerves are usually unaffected.
Imbalance. Progressive imbalance is the most common complaint and is the presenting symptom in half of the cases. Imbalance is often worse in the dark, indicating a prominent peripheral component. Upper-limb coordination and hand dexterity are better preserved than gait.
Vestibular dysfunction. Oscillopsia, defined as a visual disturbance in which objects appear to oscillate during head movements, is a common sequela of a bilaterally impaired vestibulo-ocular reflex; it is reported by one third of affected individuals and can be the presenting complaint in some. Vertigo and hearing loss are not part of the syndrome but (as they are common in the general population) can independently occur. Bedside head impulse test reveals bilateral vestibular function in up to 90% of individuals.
Cough. Notably, a chronic spasmodic dry cough is frequently associated and can be reported as early as the second decade of life, up to three decades before any neurologic symptoms develop. Gastroesophageal reflux may coexist.
Cerebellar dysfunction. Dysarthria and dysphagia, which are attributed to cerebellar dysfunction, frequently complicate the disease course in later stages. Abnormal eye movements of putative cerebellar origin, including gaze-evoked, downbeat, and horizontal nystagmus, saccadic pursuits, and dysmetric saccades, are common and can be observed earlier in the disease course.
Dysautonomia. Symptoms of autonomic dysfunction including postural hypotension, erectile dysfunction, chronic constipation, urinary dysfunction, and altered sweating are not infrequent but rarely disabling. Autonomic testing confirms the presence of a parasympathetic and/or sympathetic dysfunction in half of individuals undergoing specific investigations.
Disease course. Current data support a pattern of spatial progression from the early involvement of sensory neurons to the later appearance of vestibular and cerebellar dysfunction. The disease has a slowly progressive course. Half of individuals need a cane after ten years of disease duration and one fourth are wheelchair dependent five years later. Life expectancy does not appear to be affected.
