Rare Spinocerebellar Ataxia Types in Canada: A Case Series and Review of the Literature

Abstract:

Background:

There is limited information on rare spinocerebellar ataxia (SCA) variants, particularly in the Canadian population. This study aimed to describe the demographic and clinical features of uncommon SCA subtypes in Canada and compare them with international data.

Methods:

We conducted a case series and literature review of adult patients with rare SCA subtypes, including SCA5, SCA7, SCA12, SCA14, SCA15, SCA28, SCA34, SCA35 and SCA36. Data were collected from medical centers in Ontario, Alberta and Quebec between January 2000 and February 2021.

Results:

We analyzed 25 patients with rare SCA subtypes, with onset ages ranging from birth to 67 years. Infantile and juvenile-onset cases were observed in SCA5, SCA7, SCA14 and SCA34. Most patients presented with gait ataxia, with no significant differences across groups. Additional common features included saccadic abnormalities (22 of 25), dysarthria (19 of 25) and nystagmus (12 of 22, except in SCA7). Less common findings included dystonia (8 of 25), cognitive impairment (7 of 25), tremor (9 of 25) and parkinsonism (3 of 25).

Conclusion:

Our study highlights the heterogeneity of rare SCA subtypes in Canada. Ongoing longitudinal analysis will improve the understanding, management and screening of these disorders.

Résumé :

Variantes rares d’ataxie spinocérébelleuse au Canada : une série de cas et une revue de la littérature.

Il existe peu de renseignements portant sur les variantes rares de l’ataxie spinocérébelleuse (ASC), en particulier au sein de la population canadienne. Cette étude vise à décrire les caractéristiques démographiques et cliniques des sous-types rares de l’ASC au Canada et à les comparer aux données internationales.

Nous avons fait appel à la méthode de série de cas et effectué une revue de la littérature portant sur des patients adultes atteints de sous-types rares de l’ASC, notamment l’ASC de type 5, l’ASC de type 7, l’ASC de type 12, l’ASC de type 14, l’ASC de type 15, l’ASC de type 28, l’ASC de type 34, l’ASC de type 35 et l’ASC de type 36. Les données ont été recueillies dans des centres médicaux de l’Ontario, de l’Alberta et du Québec entre janvier 2000 et février 2021.

Nous avons analysé 25 patients atteints de sous-types rares de l’ASC dont les âges d’apparition de la maladie allaient de la naissance à 67 ans. À cet égard, des cas d’apparition infantile et juvénile ont été observés en ce qui regarde les sous-types suivants : l’ASC de type 5, l’ASC de type 7, l’ASC de type 14 et l’ASC de type 34. La plupart des patients présentaient une ataxie de la marche, et ce, sans différence significative entre les groupes. Parmi les autres caractéristiques communes, citons les anomalies saccadiques (22 sur 25), la dysarthrie (19 sur 25) et le nystagmus (12 sur 22, sauf dans le cas de l’ASC). Parmi les caractéristiques moins fréquentes, on trouve la dystonie (8 sur 25), les troubles cognitifs (7 sur 25), les tremblements (9 sur 25) et le parkinsonisme (3 sur 25).

Notre étude a mis en évidence l’hétérogénéité des sous-types rares de l’ASC au Canada. Une analyse longitudinale continue permettra d’améliorer la compréhension, la gestion et le dépistage de ces troubles.

Highlights

• We report 23 patients with rare SCA subtypes in Canada, highlighting diverse demographic and clinical profiles.

• Key findings include early-onset in SCA5, SCA7 and SCA14, gait disturbances across all subtypes and visual impairments in SCA7.

• These findings emphasize their heterogeneity, contributing to improved understanding of these disorders in Canada.

Introduction

According to the latest data from the Online Mendelian Inheritance in Man (OMIM) database, 51 distinct subtypes of spinocerebellar ataxia (SCA) have been identified. ¹ These subtypes are systematically categorized based on their associated genetic loci, following the order in which they were discovered. While the genetic underpinnings of these disorders are well understood, the exact pathogenesis remains elusive.

A systematic review (not including Canada) estimated the global prevalence of dominantly inherited cerebellar ataxias to be 2.7 per 100,000, finding SCA3 as the predominant subtype, followed by SCA2 and SCA6. ² Our recent publication in three Canadian provinces estimated the prevalence of SCA to be 2.25 per 100,000, finding SCA3 predominantly in Ontario, whereas SCA2 was the most common in Alberta and Quebec. Notably, in Quebec, SCA6 was observed to be the third most frequent SCA subtype, with a prevalence not paralleled in the other provinces. ³ This prevalence distribution of SCAs was established before the identification of SCA27B, which has since been recognized as the most common SCA among French Canadians in Quebec. ⁴

We aimed to perform a secondary analysis of the previously published data in this present study. Our objective is to describe the characteristics of these rarer SCA subtypes and compare our findings with those derived from other demographic groups from different geographic regions.

Methods

The study employed a supplemental descriptive analysis, drawing upon data from a preexisting retrospective chart review of patients with various SCA subtypes. This multicenter study was conducted across five large medical institutions in Canada, specifically in Quebec, Alberta and Ontario. Patients who attended outpatient movement disorder clinics within the period extending from January 1, 2000, to February 1, 2021, were included in the study, prior to the identification of the GAA repeat responsible for SCA27B. ⁴ The inclusion criteria stipulated that all participants must be adults, specifically those aged 18 years and above, diagnosed with rarer SCA subtypes for which sufficient data were available. The diagnosis was established through molecular genetic testing or based on clinical findings in patients with a first-degree relative with a genetically confirmed diagnosis. We included nine subtypes of SCA: SCA5, SCA7, SCA12, SCA14, SCA15, SCA28, SCA34, SCA35 and SCA36. In a deliberate attempt to focus on these less common subtypes, this study excluded the more prevalent subtypes: SCA1, SCA2, SCA3, SCA6, SCA8 and SCA17, which were reported previously. ³

Data collection from all sites was performed using a standardized data collection sheet. This form included demographic details such as age, sex and race, in addition to disease-specific information such as age at disease onset, age at the time of evaluation or death, estimated duration of the disease and presence of a genetically confirmed family history of the same disease. Clinical manifestations included presenting complaints, the presence of ataxia (axial or truncal, appendicular or limb or mixed), oculomotor findings (nystagmus, gaze palsy, saccadic abnormalities and square-wave jerks [SWJ]), dysarthria, upper motor neuron signs (spasticity, weakness, hyperreflexia and extensor plantar response), movement disorders (tremor, dystonia, parkinsonism, chorea), hyporeflexia, sensory changes and cognitive function using the Montreal Cognitive Assessment (MoCA) test, when available. During the data collection and analysis stages, any absent or incomplete data were systematically identified and annotated as “missing” or “incomplete.” The mean and median values were calculated for the age of onset and estimated disease duration.

The Research Ethics Board at each participating institution granted approval, and a formal agreement on data transfer was executed among the involved parties. The center in Toronto, Ontario, used an opt-out consent approach.

Results

The study encompassed a total of 23 patients with a diagnosis of 8 distinct SCA subtypes: SCA5 = 3 (12%), SCA7 = 3 (12%), SCA12 = 3 (12%), SCA14 = 4 (16%), SCA15 = 2 (8%), SCA28 = 3 (12%), SCA34 = 2 (8%), SCA35 = 3 (12%) and SCA36 = 2 (8%). Among the 25 patients reported, 12 (48%) were from Ontario, 9 (36%) were from Alberta and 4 (16%) were from Quebec. Demographic and clinical characteristics are shown in Table 1 and Table 2, respectively.

Table 1. Demographic data of rare SCA subtypes in Canada

Note: SCA = spinocerebellar ataxia; SD = standard deviation.

*Missing or incomplete data. ^aOne case of death. ^bIncludes Southeast Asians and Middle Eastern.

Table 2. Clinical characteristics of rare SCA types in Canada

Note: SCA = spinocerebellar ataxia; SD = standard deviation.

*Missing or incomplete data. ^aOne case of death.

SCA5

We report three unrelated white female individuals. Two had a positive family history of the disease. The mean age of symptom onset was 31.33 ± 32.02 years, ranging from birth to 64, with an estimated disease duration averaging 24 ± 21.28 years, ranging from 5 to 47 years. Initial symptoms varied: two early-onset cases experienced gait and balance disturbances, whereas the advanced-onset had limb incoordination. Patients exhibited different patterns of cerebellar ataxia, including axial, appendicular and mixed ataxia. All had saccadic abnormalities; two also had associated nystagmus, dysarthria, tremor, upper motor neuron signs of spasticity, hyperreflexia and extensor plantar response. One patient distinctively reported muscle weakness, dystonia and cognitive impairment, along with sensory changes, while another showed additional hyporeflexia. Gaze palsy was observed in a separate case.

SCA7

Our cohort includes two unrelated male patients with SCA7, all of white ethnicity, with one female of French-Canadian descent. The male patients exhibited early symptom onset at ages 16 and 23, while the female patient first experienced symptoms at 49. The estimated disease duration averaged 16 ± 13.23 years, ranging from 6 to 31 years. All patients exhibited dysarthria. The males reported initial gait and balance dysfunction, mixed ataxia, saccadic abnormalities and hyperreflexia. One male also showed weakness, gaze palsy, cognitive impairment and sensory changes, while another had dystonia and spasticity, similar to the female patient. Among the three SCA7 patients, two had visual impairment, including one who was reported to be legally blind. The visual condition of the third patient is not known.

SCA12

We evaluated three patients of Indian/Punjabi descent, all with a family history of the same disease. The male patients showed symptoms in their sixth decade of life, at ages 60 and 67, while the female patient developed symptoms at age 40. Disease durations at the time of assessment were estimated to be 3, 12 and 14 years, yielding an average duration of 9.69 ± 5.86 years. The primary symptom reported by male patients was limb incoordination, while the female patient initially experienced tremors, although all three eventually developed tremors. Each individual displayed different patterns of cerebellar ataxia, including axial, truncal and mixed types, along with saccadic abnormalities and dysarthria. The two male patients also exhibited parkinsonism, with one case accompanied by dystonia, and both had clinically persistent sensory changes. One male patient had hyperreflexia without additional upper motor signs. Notably, nystagmus was only observed in the female patient.

SCA14

We assessed four patients diagnosed with SCA14: two white males and two related white females. A family history of similar conditions was noted among the female patients and one male participant. Symptoms onset varied, with males presenting at ages 10 and 29 years and females 37 and 49 years, resulting in a mean age of 31.25 ± 16.38 years. Evaluations were conducted after an average disease duration of 24.75 ± 14.27 years, ranging from 10 to 44 years, with the youngest patient experiencing the longest disease duration. Initial symptoms were gait dysfunction and imbalance in one male and one female patient, ages 29 and 49 years, respectively, while the others experienced limb incoordination at ages 10 and 37 years. Both males had evidence of mixed ataxia distribution, whereas the females showed appendicular ataxia. Two patients experienced concomitant tremors, and all had saccadic abnormalities. Dysarthria was present in all except for one female. Two patients of different sexes had nystagmus and spasticity; the female also showed weakness, hyperreflexia and an extensor plantar response. Another male patient had hyperreflexia without additional upper motor signs. Notably, both female patients showed signs of dystonia.

SCA15

We present two unrelated female patients aged 60 and 61 years of white and Asian ethnicities, with no reported familial history of similar conditions. Assessments conducted after 5 and 7 years of disease duration revealed that both individuals initially experienced progressive gait instability, later developing mixed-type cerebellar ataxia and dysarthria. Neurological examinations showed distinct oculomotor dysfunctions: the white patient exhibited nystagmus, while the Asian patient presented saccadic abnormalities. Both displayed upper motor neuron signs, including spasticity, muscle weakness and hyperreflexia, with the Asian patient also showing extensor plantar response. Persistent sensory deficits were common in both cases, and cognitive impairment was noted in the Asian patient.

SCA28

Three unrelated individuals with SCA28 were assessed: a white female, an Asian and a white male. The white male and female patients had positive family histories. Ages at symptom onset were 32, 45 and 61 years, yielding a mean age of onset of 46 ± 14.53 years. Disease durations at the time of assessment were 13, 20 and 2 years, averaging 13.33 ± 6.51 years. The white male presented with gait imbalance, while the Asian male experienced limb incoordination, reflecting axial and appendicular ataxia. All patients demonstrated saccadic abnormalities. The female patient had bulbar symptoms, including dysarthria or dysphagia, mixed ataxia and signs of upper motor neuron involvement, such as spasticity, weakness and hyperreflexia. Oculomotor findings differed among the patients; nystagmus was noted in the female and the Asian male, and both males exhibited gaze palsy. Dystonia and cognitive impairment were present in the female patient and the Asian male, whereas persistent sensory changes were observed exclusively in the Asian male.

SCA34

Our study documented two distinct presentations of SCA34. The first case involved a male patient of French-Canadian descent with a family history, while the second case was a female Asian patient without a family history. The onset of symptoms appeared at different ages, with the male patient beginning to exhibit symptoms at age 60 years and the female patient at age 13 years. Their conditions were assessed after prolonged disease courses of 23 and 24 years, respectively. Both initially experienced gait dysfunction and imbalance, with evidence of mixed-distribution cerebellar ataxia and saccadic abnormalities. Distinctive neurological findings characterized their conditions further; the male patient displayed nystagmus, SWJ and persistent sensory changes, whereas the female patient experienced dysarthria, tremor and cognitive impairment, in addition to congenital ichthyosis at a young age.

SCA35

We identified three unrelated individuals with SCA35, including two white siblings (a male and a female), each with a family history of SCA35. Symptom onset was at 67 years for the male and 59 years for the female, with the disease duration of 12 and 13 years, respectively, at the time of assessment. Initially, the male presented with bulbar dysfunction, including dysphagia and dysarthria, while the female initially exhibited gait instability and recurrent falls. Neurological evaluations revealed that both patients exhibited cerebellar ataxia with both axial and appendicular involvement, nystagmus, saccadic abnormalities and dysarthria. The male patient also showed gaze palsy, parkinsonism, dystonia, sensory changes and cognitive decline.

SCA36

Two unrelated patients were diagnosed with SCA36. The first patient, a white male, initially presented with visual complaints at age 45. The second patient, a female of Asian descent, experienced progressive gait abnormalities and imbalance at age 54. Both exhibited axial and appendicular ataxia, along with saccadic abnormalities and dysarthria. Additionally, the male patient exhibited nystagmus, SWJ and profound deafness, while the female patient demonstrated tremor and hyperreflexia.

Discussion

Our multicenter study explored rare subtypes of SCA in Canada, focusing on demographic and clinical characteristics rather than molecular aspects. We evaluated 23 patients diagnosed with uncommon SCA subtypes but excluding SCA27B, for which testing was not available at the time of data collection. Age at symptom onset varied widely, from infancy to 67 years, with most cases manifesting in the third to fifth decades of life. Notably, SCA5 and SCA15 were exclusively female. A significant family history was present in 60% of cases, predominantly among white patients (72%), with 12% of French-Canadian descent and 28% from Asian backgrounds.

Patients reported gradual disease progression, with most being symptomatic for over 10 years at initial evaluation. However, six individuals with SCA5, SCA7, SCA12, SCA15 and SCA36 had a shorter disease duration, ranging from 2 to 7 years. The longest recorded duration was 47 years in a female with infantile-onset SCA5. Distinct clinical presentations at onset, often independent of ataxia, may remain as the primary symptoms throughout the disease. Some individuals initially show “pure” cerebellar symptoms before developing additional neurological issues. ⁵ Comparative demographic and clinical characteristics are detailed in Supplementary Table 1.

Spinocerebellar Ataxia 5

In our cohort of three SCA5 patients, we observed a gradual clinical progression of cerebellar ataxia consistent with findings observed in prior studies in the USA, ^6,7 France, ⁸ Germany ⁹ and China. ¹⁰ Symptoms onset varied between infantile and adult onset, typically emerging in the third and fourth decades, with few juvenile-onset cases. ^{6– 10} We documented one infantile-onset case: a 12-year-old girl who exhibited global developmental delay, hypotonia, a wide-based gait, progressive intention tremor, nystagmus and facial myokymia, along with dysarthria and hyperreflexia. ¹¹ While our cohort consisted solely of white females, SCA5 has been also identified in male patients, ^{6– 9} indicating no specific gender predominance.

The primary clinical manifestation of SCA5 in our cohort was gait disturbance, observed in both infantile and adult-onset groups. Common findings included upper motor neuron signs, nystagmus and dysarthria. Adult-onset cases typically presented with appendicular ataxia; one case also showed truncal ataxia, tremors, saccadic abnormalities and sensory disturbances. Muscle weakness was noted in one adult patient, while hyporeflexia was observed in the eldest adult. Notably, bulbar involvement, documented in previous juvenile cases in the USA, was absent in this cohort. ⁶ One adult-onset patient exhibited cognitive impairment, consistent with two cases reported in China. ¹⁰ Unlike the French cohort, none of our patients showed gaze palsy, SWJ, facial myokymia or impaired sense of vibration. ⁸

Spinocerebellar Ataxia 7

SCA7 has been reported globally across diverse ethnic backgrounds, with a worldwide prevalence estimate of 5%. ¹² SCA7 was also the most common subtype SCA in Sweden and Finland, ¹³ potentially due to a founder effect from a shared geographic origin. In Canada, a study from 2005 identified 69 adult-onset SCA patients from Southern Alberta, southwestern Saskatchewan and southeastern British Columbia between January 1996 and December 2002, but none were found to have SCA7. ¹⁴

The variability of the SCA7 phenotype is linked to the number of CAG repeats, ^15,13,16 which in our patients were 48, 45 and 45, respectively. All exhibited progressive cerebellar ataxia, dysarthria and saccadic abnormalities, consistent with international findings. ¹⁷ Visual impairment due to macular or photoreceptor disturbances is a hallmark of SCA7. Moreover, previous studies demonstrated that visual loss often precedes ataxia in early-onset cases, while the reverse is true for adult-onset cases. ^{15 ,18} Similar to published reports, two of our three reported SCA7 patients had visual impairment.

Spinocerebellar Ataxia 12

We report two male and one female patients of Indian descent with SCA12, which is prevalent in this demographic, accounting for about 6.5% of SCAs. ¹⁹ The condition is notably more common among individuals of Agrawal descent, indicative of a founder effect. ²⁰ SCA12 is less frequently observed among other ethnic groups, as evidenced by an investigation involving 211 patients from various ethnic origins. ²¹

The characteristic presentation of SCA12 typically includes action tremor alongside moderate cerebellar ataxia, often leading to an initial misdiagnosis of essential tremor. ²² The tremor, usually affecting the upper limbs symmetrically, can also involve the head, jaw, tongue and voice, with reports of postural, intention and resting tremor. SCA12 commonly presents with cerebellar ataxia, dysarthria and upper motor neuron signs across different ethnic groups and regions. ^23,24 Other relatively common features include dysarthria, upper motor neuron signs, sensory changes, nystagmus and saccadic abnormalities. Our study confirmed the presence of associated parkinsonism and dystonia, consistent with previous reports, though myoclonus, chorea and facial myokymia were not observed. ^19,25

Spinocerebellar Ataxia 14

In line with our own previous investigation, most case reports of SCA14 in the literature involved juvenile-onset, while our cohort had onset ages ranging from 10 to 49 years, primarily presenting with progressive, pure cerebellar ataxia. In contrast, SCA14 can present with an episodic course, as noted in a Chinese case. ²⁶

None of our patients reported cognitive issues, which have been described in early-onset cases. ²⁷ A neuropsychological evaluation of Norwegian patients indicated that potential verbal and executive function impairments might be associated with SCA14. ²⁸ Dystonia was noted in two individuals, reflecting the broad range of movement disorders associated with SCA14. ^{27,29– 33} However, we did not find other reported features in our cohort such as action myoclonus, ^{30– 36} chorea, ^30,37 postural tremor, ^27,30 facial myokymia, ³⁷ muscle rippling, ³⁵ parkinsonism ³³ and restless legs syndrome. ³⁰ Seizures were absent, although one case had a history of generalized epilepsy at age 14 with an unclear association to SCA14. ³⁸

Our patients did not exhibit visual changes, whereas a Japanese report described retinal degeneration in one individual. ²⁹ Additional distinctive signs associated with SCA14, not observed in our study, included gaze palsy, ^27,39 dysphagia, ^{33,35– 37} bilateral facial palsy, ²⁹ positional vertigo, ³⁴ failure to suppress vestibulo–ocular reflex, ⁴⁰ hearing impairment, ^33,41 sphincter and autonomic dysfunction, ^27,33 cataracts and pes cavus. ³⁹

Spinocerebellar Ataxia 15

SCA15 and SCA16 may not be separate entities but rather phenotypic variations due to ITPR1 haploinsufficiency, ⁴² leading to the combined designation SCA15/16 in scholarly literature. ⁴³ In our study, we report two females of White and Asian descent with SCA15. The prevalence of SCA15 varies by ethnicity, accounting for 8.9% of unexplained SCAs and 1.8% of all SCAs in the German population. ⁴⁴

Studies from various regions highlight the phenotypic diversity of SCA15. ^{44– 48,50} An Australian study reported a case with early unsteadiness and later movement-induced oscillopsia, indicating vestibulocerebellar involvement. ⁴⁵ Another study reported patients with variable deep tendon reflex responses within a single family, from hyperreflexia to hyporeflexia. ⁴⁶ As Italian cohort identified additional unique symptoms not described elsewhere such as buccolingual dyskinesias, facial myokymia, ⁴⁷ intermittent choreic movements ⁴⁸ and myoclonus responsive to levetiracetam, ⁴⁹ with similar findings in another Caucasian kindred. ⁵⁰ Our reported patients did not present with any of these described clinical features.

Spinocerebellar Ataxia 28

Our cohort included patients of White and Asian ethnicities, but the prevalence of SCA34 has not been extensively studied. A Japanese investigation estimated its occurrence to be 0.7% among unidentified degenerative ataxia index cases and 0.2% among a series of 506 Japanese index patients, describing two Japanese males and one English-Canadian patient. ⁵¹ In this study, patients developed symptoms at advanced ages, unlike prior reports of infantile and childhood onsets. ^{52– 55}

Most patients exhibited progressive cerebellar ataxia, nystagmus, gaze palsy and saccadic abnormalities, consistent with prior findings. ^52,53 However, we did not observe other reported features like ptosis and progressive external ophthalmoplegia. ^53,56 Two cases of dystonia were present in our cohort. SCA28 is associated with various hyperkinetic disorders, including myoclonus, chorea and dystonia, as well as rare cases of spastic paraparesis, sensorineural hearing loss and mild cognitive dysfunction. ^55,57 A Hungarian study showed additional features like hypotonia, impaired vision, diplopia and bulbar symptoms but no cognitive dysfunction, differing from our findings. ⁵⁴

Spinocerebellar Ataxia 34

SCA34 was initially recognized in 1972 as a neurocutaneous syndrome within a French-Canadian family with autosomal dominant inheritance. The condition is characterized by slowly progressive neurological features, including gait and limb ataxia, nystagmus, dysarthria and hyporeflexia, as observed in our patients. ⁵⁸ Our study identified an Asian female who presented with similar neurological signs along with congenital ichthyosis.

Additionally, we observed cognitive decline in one patient, with impairments observed in executive functions, visuospatial skills, attention and psychiatric symptoms, aligning with existing literature. ⁵⁹ Sensory changes were also detected in one case. ⁵⁹ Beyond the principal manifestations identified in our study and others from Europe, Japan, the USA and Canada, various distinctive features have been reported, including axial stiffness, ⁶⁰ parkinsonism, ⁶¹ autonomic dysfunctions such as urinary incontinence issues and constipation, ⁵⁹ retinitis pigmentosa and diplopia, ⁶² bilateral facial muscle weakness and forearm fasciculations. ⁵⁸

Spinocerebellar Ataxia 35

SCA35 was identified through a novel mutation in the Han Chinese population, associated with the transglutaminase six gene (TGM6). ⁶³ Its onset age for SCA35 varies, with most individuals showing a gradual disease progression. Our findings align with numerous studies reporting progressive cerebellar syndrome. Additional symptoms noted in other reports include pseudobulbar palsy, spasmodic torticollis, ⁶⁴ delayed speech, ⁶³ dysphagia, progressive urinary and bowel urgency, cognitive decline, ophthalmoplegia and sensory impairment. ⁶⁵ Case studies from India highlighted associated bilateral hand and voice tremors with dystonia, ⁶⁶ while a report from Puerto Rico described a patient with mild parkinsonism. ⁶⁷

Spinocerebellar Ataxia 36

Our study presents two cases of SCA36 affecting individuals of Caucasian and Asian descent. Similar reports have emerged from Asia, ^{68– 74} Europe ^{70,75– 77} and North America ⁷⁸ with typical symptoms onset occurring in the fourth and fifth decades of life. Symptoms include truncal and limb ataxia, dysarthria and saccadic abnormalities. One patient in our study exhibited profound deafness, consistent with previous findings, ^{75 ,70– 74} while the other patient showed tremor and hyperreflexia. Although motor neuron involvement was not observed in our cases, it has been documented elsewhere, often manifesting as tongue atrophy and fasciculations. SCA36 is linked to mutations in the GCCTG hexanucleotide repeat in the NOP56 gene, which can also appear in patients with amyotrophic lateral sclerosis and dementia. ⁶⁸ Additional features reported in the literature that were not present in our patients include oculomotor apraxia, ⁷⁵ other movement disorders (myoclonus, ⁷⁵ dystonia, ⁷⁶ and parkinsonism ⁷⁶ ), reduced vibration sense, ^{70– 74 77} urinary incontinence and autonomic dysfunction. ^75,77

We have collected data from multiple centers across Canada, enabling a comprehensive analysis of rare subtypes within the Canadian population, including those not previously studied. This study helps fill critical gaps in the understanding of neurological conditions within Canada, enhancing knowledge of the prevalence and unique clinical features of these rare subtypes.

However, our research has limitations. The small patient cohort may introduce selection bias and affect the generalizability of the results. Additionally, the retrospective nature of data collection resulted in missing and incomplete data, emphasizing cautious interpretation of our findings. The limited number of patients undergoing objective testing (electrophysiological studies and neuroimaging) restricts our ability to fully assess specific aspects of the conditions. Furthermore, the lack of standardized cognitive assessments across all patients poses an additional challenge. We recommend future multicenter longitudinal studies employing standardized assessment tools, further evaluation with neurophysiological tests and neuroimaging and the correlation with genetic profiling.

Conclusion

Our study highlights the heterogeneity and diverse demographic and clinical features of rare SCA subtypes among the Canadian population. These findings underscore the need for future longitudinal studies that integrate advanced testing to better understand disease progression and the link between phenotype and genotype. Exploring these dimensions will enhance our comprehension of these rare subtypes, ultimately leading to more targeted and effective management and screening strategies.