Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.

# Introduction

Cerebellar ataxias are a heterogeneous group of neurodegenerative diseases, some of which are genetic, either caused by conventional variants or due to tandem repeat expansions. Despite recent advances in next-generation sequencing technologies, half of patients with late-onset cerebellar ataxia (LOCA) have no molecular diagnosis [1]. In early 2023, a new cerebellar ataxia was identified, spinocerebellar ataxia 27B (SCA27B) (MIM 620174). SCA27B is an autosomal dominant slowly progressive LOCA caused by a (GAA)
                     ≥
                     
                     250 repeat expansion in intron 1 of fibroblast growth factor 14 (FGF14) [2,3].

Over the past year, many hundreds of cases have been identified worldwide, and this new disease appears to be a frequent cause of LOCA. The prevalence of SCA27B among LOCA in Europe and Quebec is estimated at 10–60% depending on the series [2,4,5].

In this mini-review, we will discuss the phenotypic profile of SCA27B, diagnosis and the current therapeutic avenues.

# Genetic data

SCA7B is due to a (GAA)
                     ≥
                     
                     250 repeat expansion in intron 1 of FGF14. The lower pathological threshold for expansion is still under discussion [6,7]. In total, 250–300 repetitions may be pathogenic, albeit with reduced penetrance, whereas more than 300 appears to be pathogenic [2].

SCA27B is autosomal dominant, with familial history in the majority of cases (85% in the French-Canadian cohort while 15% are sporadic cases) [2]. To add complexity, the repeat is unstable upon intergenerational transmission and normally expands with maternal transmission and contracts with paternal transmission [2,7,8]. Moreover, the instability of the GAA repeat during parental transmission depends on its size and purity [7,8]. Given the expansion of maternal transmission, its (GAA)
                     ≥
                     
                     300 transmission is more frequent (76.9%) than paternal transmission (23.1%) [7].

The diagnosis of SCA27B is made individually based on clinical evidence and the identification of a GAA expansion in intron 1 of FGF14. Molecular testing for SCA27B relies on polymerase chain reaction (PCR)-based gene analysis to determine the length and purity of FGF14 GAA repeats. It is important to standardize the diagnostic strategy. One such strategy has recently been validated in a French cohort. It uses the combination of fluorescent long-range PCR (fLR-PCR) to determine allele size, bidirectional repeat-primed PCR (RP-PCR) to verify the presence and nature of the expansion, and in some cases, agarose gel electrophoresis of LR-PCR amplification products and/or Sanger sequencing depending on the profiles observed in fLR-PCR and RP-PCR, particularly for elucidating GAA-interruptions and non-GAA patterns [9]. This is crucial as non-GAA expansions are not pathogenic, and, in the presence of GAA interruptions, diagnosis is based on the size of the pure GAA repeat. Some cases carrying a double expansion on both alleles are described, in these cases, family segregation study finds expansion in both the maternal and paternal branches.

The PCR-based strategy reliably detects and sizes of the FGF14 GAA expansions and compares favourably to long-read sequencing.

# Clinical phenotype of SCA27B

The main clinical features of SCA27B in four large cohorts (French-Canadian, German, and two French cohorts) are summarized in Table 1
                     .

SCA27B is a late-onset cerebellar ataxia, by definition starting after the age of 30, although LOCA may have an onset earlier. However, in SCA27B onset is often much later, averaging 54 years in the French-Canadian cohort, 60 years in the German cohort, 67.5 years in the Strasbourg cohort, 55 in the cohort from Paris, and 64 years in Nancy [2,5,7,9,10]. The onset of the disease most often begins with instability in walking, visual disturbances, or vertigo [4].

One of the most important features of SCA27B is its episodic onset in almost half the patients (70% in the French-Canadian cohort [2], 48% in a French cohort [7]). These episodes can last from a few seconds to a few days. The majority of patients subsequently develop permanent ataxia after an average of 3–4 years [2,11], but some patients may remain with an episodic form for more than 10 years. Episodes may include paroxysmal ataxia, vertigo, visual disturbances with diplopia or visual blurring, or a sensation of “brain fog” [2,10–12].

In the progressive phase, the ataxia is mainly axial, with predominant impairment of walking, balance, and ataxia of the lower limbs, while dysarthria and truncal ataxia are less significant. This suggests a rostrocaudal gradient of ataxia severity, predominantly of the vermis [2,10].

Oculomotor disorders are frequently present, accounting in 95% of patients with (GAA)
                     ≥
                     
                     300 who had eye movement recordings in the Paris cohort [7]. The most frequently described abnormality is downbeat nystagmus (DBN) in up to 66% of patients [2,7]. In a cohort of patients with idiopathic DBN, the frequency of (GAA)
                     ≥
                     
                     250 was 48% [6] but increased to 56% when DBN was associated with additional cerebellar oculomotor signs and to 72% in the presence of overt cerebellar ataxia. This reinforces the strong association between DBN and SCA27B.

Episodic diplopia, with or without visual blurring and oscillopsia, is another frequent feature of SCA27B, found in almost 60% of patients in the French-Canadian cohort. This episodic diplopia may be one of the first symptoms of the disease at the episodic stage but may persist throughout the disease [2,5]. This element must be sought on questioning in the presence of LOCA to guide molecular diagnosis.

Pellerin et al. described a worsening of ataxia symptoms with even moderate alcohol intake or physical exercise [2]. More recently, other triggers for aggravation have been described, such as drinking tea or coffee, smoking [11,12], strong emotions and fatigue.

SCA27B appears to be among the most slowly progressive of all inherited LOCAs. Wirth et al. describe a worsening of 0.4 points per year in the SARA score [5], it was 0.23 for Wilke et al., 
                     [10]. For example, ataxia associated with RFC1-related CANVAS and disease spectrum (MIM 614575) shows a progression rate of 1.3 points per year in the SARA score [13]. The slow progression of SCA27B is further illustrated by the fact that 50% of patients require unilateral walking aids after eight years of evolution and bilateral walking aids after 15 years, respectively [10]. Use of a wheelchair remains uncommon, even with protracted disease evolution, and occurs in ∼10% of individuals [2].

Some studies find a link between the number of GAA expansions, age of onset, and disease severity (SARA score) [2,3,8,14], but this is not found by all teams [7].

# Paraclinical examinations

## Magnetic resonance imaging (MRI)

The radiological features of SCA27B are cerebellar atrophy predominating over the vermis (Fig. 1
                        ). This vermian predominance coincides with the predominantly axial clinical involvement. A recent study found cerebellar atrophy in 94% of cases, with vermis atrophy (94%) ranging from mild 13%, moderate 17% to severe 3% [15]. This vermian atrophy is also accompanied by atrophy of the cerebellar hemispheres to a lesser extent. Longitudinal studies suggest that atrophy in patients with SCA27B begins in the vermis before extending to the cerebellar hemispheres over time [15].

## Electroneuromyogram (ENMG)

The Strasbourg team found that the ENMG was impaired, though often only mildly, in 60% of SCA27B patients. In the majority of cases, it consisted of an axonal sensory-motor neuropathy [5]. This is the only team to have documented such a high prevalence of neuropathy among SCA27B patients. For example, in the French-Canadian cohort, out of 28 patients with ENMG, only seven had neuropathic involvement, the most a moderate axonal sensory neuropathy type [2]. So, it's also not yet clear whether the polyneuropathy is age-related or if it's pathologically related to SCA27B.

However, even in the absence of polyneuropathy, around half of SCA27B patients have reduced vibration sense in the distal lower extremities [10]. Peripheral involvement does not therefore appear to be a specific core of SCA27B, although it may be present in some cases.

# Differential diagnoses

Other alternative diagnosis should be entertained in LOCA patients, in particular multiple system atrophy cerebellar type (MSA-c), spinocerebellar ataxia 6 (SCA6), and RFC1-related CANVAS and disease spectrum (Table 2
                     ).

MSA is a fatal sporadic, progressive adult-onset (>30 years) neurodegenerative disorder characterized by autonomic dysfunction, poorly levodopa-responsive parkinsonism, and cerebellar ataxia. The classification as MSA-parkinsonian type or MSA-cerebellar type depends on the predominant phenotype. The disease is rapidly progressive and approximately 60% of patients become wheelchair-bound after five years. The mean survival is six to 10 years from symptom onset [16]. Compared to SCA27B, brain MRI of patients with MSA shows atrophy of the putamen, middle cerebellar peduncles (MCPs), pons, and cerebellum. Cruciform T2-weighted hyperintensity in the pons (hot-cross bun sign) is also seen on MRI of patients with MSA [16].

Spinocerebellar ataxia type 6 (MIM 183086) is an autosomal dominant disease caused by (CAG)
                     ≥
                     
                     20 repeat expansions in exon 47 of the CACNA1A gene. The mean age at onset is between 43 and 52 years [17]. Slowly progressive cerebellar ataxia and oculomotor signs are the main features. Nearly half of patients report visual disturbances, such as diplopia [17]. Whereas DBN in SCA27B is spontaneous, it is mainly positional in SCA6 [18]. The disease, which is allelic to episodic ataxia type 2 caused by exonic point and frameshift variants in CACNA1A, may occasionally be episodic at onset [19]. Brain MRI shows isolated cerebellar atrophy, predominant in the vermis.

In comparison, episodic ataxia type 2 typically develops in childhood or early adolescence. Patients experience paroxysmal attacks of ataxia, which may be associated with dystonia, hemiplegia, and tonic upward gaze, which are not observed in SCA27B. Interictal progressive cerebellar ataxia and downbeat nystagmus may eventually develop in some patients, although less commonly than in SCA27B [20,21].

RFC1-related CANVAS and disease spectrum (MIM 614575) is an autosomal recessive condition caused by biallelic pentanucleotide expansions in the RFC1 gene. The disorder typically begins after the age of 35 years. The phenotypic spectrum ranges from full-blown cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) to more limited phenotypes with sensory neuropathy and variable combinations of cerebellar and vestibular impairment [13]. Chronic cough is a common accompanying feature. Nerve conduction studies show sensory neuropathy or neuronopathy with little to no motor involvement. Bilateral vestibulopathy is possible with SCA27B but remains relatively mild, while it is almost always present in RFC1-related CANVAS and disease spectrum. Polyneuropathy is not a core feature of SCA27B, although some patients may develop mild axonal sensory or sensorimotor polyneuropathy. In comparison, motor neuropathy is typically mild or absent in RFC1-related CANVAS. The diagnosis of RFC1-related CANVAS and disease spectrum is highly unlikely in the presence of isolated cerebellar ataxia without sensory neuropathy. Disease progression in SCA27B, averaging 0.23–0.40 SARA points per year, is considerably slower than in other common late-onset genetic ataxias, such as SCA6 (0.80 SARA points per year) and RFC1-related CANVAS (1.30 SARA points per year).

# Therapeutic perspectives

Given its recent discovery, there are still currently no therapeutic recommendations for SCA27B.

A recent retrospective non-blinded study examined the response to acetazolamide in 34 patients with SCA27B. Out of 34 patients, only 15 (44%) described a subjective improvement of their episodic symptoms. This improvement persisted in 87% of them. However, the treatment response was most often slight to moderate. No patient had complete cessation of their symptoms. Moderate side effects were observed in five patients, including one patient who described an increase or even worsening of his episodic symptoms [11].

However, the episodic nature of certain ataxias has already been the target of therapeutics trials. Muth et al., described the effect of fampridine and acetazolamide in 30 patients with episodic ataxia type 2. Both treatments reduced attacks compared to placebo. Fampridine had a better tolerance [22].

In comparison, 4-aminopyridine may represent a promising treatment strategy for SCA27B. Aminopyridines, composed of 3.4-diaminopyridine (3.4 DAP) and 4-aminopyridine (4-AP), inhibit some potassium channels. This mechanism of action is used in particular in Lambert-Eaton with 3.4 DAP which allows the increase in the release of acetylcholine. The effect in cerebellar disorders would be due to their action on Purkinje cells. In a functional study on SCA6 mice, 4-AP restored the precision of Purkinje cell action potential discharge. The effect was visible acutely but also maintained chronically [23].

Aminopyridines seem particularly interesting in DBN. Downbeat nystagmus is caused by a decreased function of inhibitory Purkinje cells in the cerebellar flocculus. Roger Calla et al., studied the effect of 4-AP and 3.4-DAP on DBN 45minutes and 90minutes after administration. Both treatments were effective compared to a placebo, with no significant difference between the two. They found a decrease in the average speed of the slow phase of nystagmus [24].

Because of all these data, the team of Wilke et al. identified SCA27B patients treated with 4-AP. They report an improvement in quality of life in 86% of treated patients [10].

# Conclusion

This mini-review highlighted that spinocerebellar ataxia 27B (SCA27B) (MIM 620174) is among the most common causes of LOCA (Fig. 2
                     ). FGF14 heterozygous expansion with (GAA)
                     ≥
                     
                     250 could explain 10–15% of LOCA without diagnosis in Europe. However, further studies are needed to help in the interpretation of intermediate size alleles in the (GAA)250–299 range. Detailed phenotyping of patients is particularly important to establish in carriers of intermediate size alleles.

Clinicians should consider the SCA27B diagnoses in the presence of episodic ataxia with episodic diplopia, downbeat nystagmus, gait ataxia and sometimes, but not always, with a family history. Visual symptoms and cerebellar oculomotor anomalies are some of dominating features of the SCAB27 phenotype. New genetics sequencing methods can also help in the diagnosis. By using long-read sequencing, one can detect all pathological expansions in the same patient with only one test though the size of the expansion cannot always precisely be determined. Clinicians and geneticists need to collaborate to correlate the genotype and the phenotype to establish all the medical issues and symptoms of a patient.

Proper assessment and treatment of visual and cerebellar disorders is a major challenge in the management of SCAB27 patients. Given the numerous oculomotor abnormalities found in SCA27B, further studies by videonystagmography should be performed to document these findings more precisely and on a larger scale.

# Authors contributions

G.C., S.P. and D.P. wrote the first versions, B.B, C.B. and M.R. reviewed them. The final version was approved by all.

# Disclosure of interest

The authors declare that they have no competing interest.

We thank Dr. Virginie Roth (CHRU Nancy) and Dr. Marion Wandzel (CHRU Nancy) for their work in the genetics laboratory; Dr. Solène Frismand (CHRU Nancy) and Dr. Armand Hocquel (CHRU Nancy) for their help.