Rfc1 Canvas / Spectrum Disorder

Clinical characteristics.

The phenotypic spectrum associated with biallelic RFC1 AAGGG repeat expansion encompasses a range including (1) typical cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS); (2) cerebellar, sensory, and vestibular impairment; (3) more limited phenotypes involving predominantly or exclusively one of the systems involved in balance control; (4) autonomic dysfunction; and (5) cough. Onset begins after age 35 years. In a retrospective study of 100 affected individuals after ten years of disease duration, two thirds had clinical features of CANVAS; 16 had a complex sensory ataxia with cerebellar or vestibular involvement; and 15 had a sensory neuropathy as the only clinically detectable manifestation.

Diagnosis/testing.

The diagnosis of RFC1 CANVAS / spectrum disorder is established in a proband with suggestive findings and biallelic intronic AAGGG pentanucleotide expansions in RFC1 identified by molecular genetic testing that is targeted to detect these expansions. Note that pathogenic RFC1 AAGGG repeat expansions cannot be detected by sequence-based multigene panels or exome sequencing. However, they can be suspected by genome sequencing.

Management.

Treatment of manifestations: The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists.

Surveillance: Routine follow up by multidisciplinary specialists to assess: progression of neurologic findings; mobility, self-help skills; need for alternative communication methods; and aspiration risk and feeding methods.

Agents/circumstances to avoid: Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides); chronic alcohol consumption.

Genetic counseling.

RFC1 CANVAS / spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RFC1 AAGGG repeat expansion, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once biallelic RFC1 AAGGG repeat expansions have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

RFC1 CANVAS / spectrum disorder should be suspected in individuals with onset after age 35 years of one or more the following clinical findings (with supportive electrodiagnostic, vestibular, and imaging findings and family history).

Establishing the Diagnosis

The diagnosis of RFC1 CANVAS / spectrum disorder is established in a proband with suggestive findings and biallelic intronic AAGGG pentanucleotide expansions in RFC1 identified by molecular genetic testing (see Table 1).

Note: Pathogenic AAGGG repeat expansions in RFC1 cannot be detected by sequence-based multigene panels or exome sequencing. However, they can be suspected based on genome sequencing.

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.

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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The heterozygote carrier frequency of RFC1 AAGGG repeat expansions ranges from 0.7% to 4% in populations of predominantly northern European origin [Akçimen et al 2019, Cortese et al 2019, Rafehi et al 2019]. A similar allele frequency (2.24%) was found in the Chinese Han population [Fan et al 2020].

Therefore, the estimated prevalence of RFC1 CANVAS / spectrum disorder ranges from 1:20,000 to 1:625.

Sensory Neuronopathy

As sensory neuronopathy was identified in all individuals with genetically confirmed diagnoses and tends to appear early in the disease course, the differential diagnosis should initially encompass causes of acquired sensory neuronopathy including:

• Paraneoplastic syndrome
• Sjogren syndrome
• Acute and chronic immune-mediated disorders
• Metabolic disorders (diabetes mellitus, vitamin B₁₂ deficiency, copper deficiency)
• Toxins (alcohol, pyridoxine, platinum derivatives, pyridoxine intoxication)

Late-Onset Cerebellar Ataxia

Multisystem atrophy (MSA), a rapidly progressive neurodegenerative disease, is the main differential diagnosis in an individual with late-onset cerebellar ataxia [Fan et al 2020, Sullivan et al 2020, Wan et al 2020]. The following clinical characteristics distinguish MSA from RFC1 CANVAS / spectrum disorder.

• The average time from first manifestations to death in MSA is 9.3 years, while disease progression in RFC1 CANVAS / spectrum disorder is very slow and life expectancy does not appear to be reduced [Fanciulli & Wenning 2015].
• Unlike RFC1 CANVAS / spectrum disorder, sensory neuropathy and vestibular dysfunction do not occur in MSA, or, if coexisting, are most likely unrelated.
• Autonomic dysfunction, a common and highly debilitating feature of MSA, is usually mild in RFC1 CANVAS / spectrum disorder.
• Presence of additional features that favor an MSA diagnosis include rapid eye movement sleep behavior disorder, parkinsonism, and MRI pattern (putaminal, pontine, and middle cerebellar peduncle atrophy and "hot cross-bun" sign cruciform T₂-weighted hyperintensity in the pons) [Chelban et al 2019].

Additional causes of progressive cerebellar impairment to consider include: paraneoplastic syndromes; toxic, nutritional, vascular, and inflammatory conditions; and idiopathic (i.e., idiopathic late-onset cerebellar) ataxia.

Wernicke's disease due to vitamin B₁ deficiency typically presents with mental status change, cerebellar ataxia, and altered eye movements as well as vestibular areflexia and chronic neuropathy. Exposure to chronic alcohol intake, the acute course, and the presence of delirium help distinguish this potentially reversible condition from RFC1 CANVAS / spectrum disorder.

Bilateral Vestibular Areflexia

The differential diagnosis of bilateral vestibular areflexia includes (among other conditions) aminoglycoside ototoxicity, Meniere's disease, bilateral vestibular neuritis, tumors compressing both vestibular nerves (e.g., bilateral schwannomas in neurofibromatosis 2), and infectious and/or inflammatory systemic disorders.

Bilateral vestibular hypofunction can be observed in several hereditary neurodegenerative conditions including spinocerebellar ataxia (SCA3 as well as SCA1, SCA2, and SCA6), Friedreich ataxia, Gaucher disease, and Charcot-Marie-Tooth (CMT) hereditary neuropathy. Although vestibular dysfunction is probably more common than previously thought in CMT, nerve conduction study, typically showing an alteration of motor and sensory conductions, can help in the differential diagnosis [Poretti et al 2013, Pérez-Garrigues et al 2014, Akdal et al 2020].

When bilateral vestibular hypofunction occurs with hearing and visual loss, Usher syndrome type I and Usher syndrome type II should also be considered.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with RFC1 CANVAS / spectrum disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists.