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, ^{Reference Ranum, Schut, Lundgren, Orr and Livingston6,Reference Cho and Fogel7} France, ^{Reference Stevanin, Herman, Brice and Dürr8} Germany ^{Reference Bürk, Zühlke and König9} and China. ^{Reference Bian, Wang and Jin10} Symptoms onset varied between infantile and adult onset, typically emerging in the third and fourth decades, with few juvenile-onset cases. ^{Reference Ranum, Schut, Lundgren, Orr and Livingston6– Reference Bian, Wang and Jin10} 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. ^{Reference Jacob, Ho, Martinez-Ojeda, Darras and Khwaja11} While our cohort consisted solely of white females, SCA5 has been also identified in male patients, ^{Reference Ranum, Schut, Lundgren, Orr and Livingston6– Reference Bürk, Zühlke and König9} 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. ^{Reference Ranum, Schut, Lundgren, Orr and Livingston6} One adult-onset patient exhibited cognitive impairment, consistent with two cases reported in China. ^{Reference Bian, Wang and Jin10} Unlike the French cohort, none of our patients showed gaze palsy, SWJ, facial myokymia or impaired sense of vibration. ^{Reference Stevanin, Herman, Brice and Dürr8}

Spinocerebellar Ataxia 7

SCA7 has been reported globally across diverse ethnic backgrounds, with a worldwide prevalence estimate of 5%. ^{Reference Teive, Meira, Camargo and Munhoz12} SCA7 was also the most common subtype SCA in Sweden and Finland, ^{Reference Jonasson, Juvonen and Sistonen13} 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. ^{Reference Kraft, Furtado and Ranawaya14}

The variability of the SCA7 phenotype is linked to the number of CAG repeats, ^{Reference Enevoldson, Sanders and Harding15,Reference Jonasson, Juvonen and Sistonen13,Reference Martin, Van Regemorter, Del-Favero, Löfgren and Van Broeckhoven16} which in our patients were 48, 45 and 45, respectively. All exhibited progressive cerebellar ataxia, dysarthria and saccadic abnormalities, consistent with international findings. ^{Reference Holmberg, Johansson, Forsgren, Heijbel, Sandgren and Holmgren17} 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. ^{Reference Enevoldson, Sanders and Harding15 Reference Miller, Tewari, Miller, Garbern and Van Stavern,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. ^{Reference Srivastava, Choudhry and Gopinath19} The condition is notably more common among individuals of Agrawal descent, indicative of a founder effect. ^{Reference Bahl, Virdi and Mittal20} SCA12 is less frequently observed among other ethnic groups, as evidenced by an investigation involving 211 patients from various ethnic origins. ^{Reference Cholfin, Sobrido, Perlman, Pulst and Geschwind21}

The characteristic presentation of SCA12 typically includes action tremor alongside moderate cerebellar ataxia, often leading to an initial misdiagnosis of essential tremor. ^{Reference Louis and Faust22} 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. ^{Reference Brussino, Graziano and Giobbe23,Reference Dong, Wu and Wu24} 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. ^{Reference Srivastava, Choudhry and Gopinath19,Reference Ganaraja, Holla and Stezin25}

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. ^{Reference Sun, Tang, Cao, Shao and Sun26}

None of our patients reported cognitive issues, which have been described in early-onset cases. ^{Reference De Michele, Galatolo and Galosi27} A neuropsychological evaluation of Norwegian patients indicated that potential verbal and executive function impairments might be associated with SCA14. ^{Reference Wedding, Koht, Dietrichs, Landrø and Tallaksen28} Dystonia was noted in two individuals, reflecting the broad range of movement disorders associated with SCA14. ^{Reference De Michele, Galatolo and Galosi27,Reference Miura, Nakagawara and Kaida29– Reference Chelban, Wiethoff and Fabian-Jessing33} However, we did not find other reported features in our cohort such as action myoclonus, ^{Reference Vlak, Sinke, Rabelink, Kremer and van de Warrenburg30– Reference Chen, Cimino and Ranum36} chorea, ^{Reference Vlak, Sinke, Rabelink, Kremer and van de Warrenburg30,Reference Stevanin, Hahn and Lohmann37} postural tremor, ^{Reference De Michele, Galatolo and Galosi27,Reference Vlak, Sinke, Rabelink, Kremer and van de Warrenburg30} facial myokymia, ^{Reference Stevanin, Hahn and Lohmann37} muscle rippling, ^{Reference Klebe, Durr and Rentschler35} parkinsonism ^{Reference Chelban, Wiethoff and Fabian-Jessing33} and restless legs syndrome. ^{Reference Vlak, Sinke, Rabelink, Kremer and van de Warrenburg30} Seizures were absent, although one case had a history of generalized epilepsy at age 14 with an unclear association to SCA14. ^{Reference Hiramoto, Kawakami and Inoue38}

Our patients did not exhibit visual changes, whereas a Japanese report described retinal degeneration in one individual. ^{Reference Miura, Nakagawara and Kaida29} Additional distinctive signs associated with SCA14, not observed in our study, included gaze palsy, ^{Reference De Michele, Galatolo and Galosi27,Reference Duggirala, Ngo, Pagnoni, Rosa and Fogel39} dysphagia, ^{Reference Chelban, Wiethoff and Fabian-Jessing33,Reference Klebe, Durr and Rentschler35– Reference Stevanin, Hahn and Lohmann37} bilateral facial palsy, ^{Reference Miura, Nakagawara and Kaida29} positional vertigo, ^{Reference Yamashita, Sasaki and Yabe34} failure to suppress vestibulo–ocular reflex, ^{Reference Fahey, Knight and Shaw40} hearing impairment, ^{Reference Chelban, Wiethoff and Fabian-Jessing33,Reference Koht, Stevanin, Durr, Mundwiller, Brice and Tallaksen41} sphincter and autonomic dysfunction, ^{Reference De Michele, Galatolo and Galosi27,Reference Chelban, Wiethoff and Fabian-Jessing33} cataracts and pes cavus. ^{Reference Duggirala, Ngo, Pagnoni, Rosa and Fogel39}

Spinocerebellar Ataxia 15

SCA15 and SCA16 may not be separate entities but rather phenotypic variations due to ITPR1 haploinsufficiency, ^{Reference Gardner42} leading to the combined designation SCA15/16 in scholarly literature. ^{Reference Tipton, Guthrie, Strongosky, Reimer and Wszolek43} 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. ^{Reference Synofzik, Beetz and Bauer44}

Studies from various regions highlight the phenotypic diversity of SCA15. ^{Reference Synofzik, Beetz and Bauer44– Reference Castrioto, Prontera and Di Gregorio48,Reference Gazulla, Bellosta-Diago, Izquierdo-Alvarez and Berciano50} An Australian study reported a case with early unsteadiness and later movement-induced oscillopsia, indicating vestibulocerebellar involvement. ^{Reference Storey, Gardner and Knight45} Another study reported patients with variable deep tendon reflex responses within a single family, from hyperreflexia to hyporeflexia. ^{Reference Hara, Fukushima and Suzuki46} As Italian cohort identified additional unique symptoms not described elsewhere such as buccolingual dyskinesias, facial myokymia, ^{Reference Di Gregorio, Orsi and Godani47} intermittent choreic movements ^{Reference Castrioto, Prontera and Di Gregorio48} and myoclonus responsive to levetiracetam, ^{Reference Orsucci, Ienco, Rocchi, Siciliano, Mancuso and Bonuccelli49} with similar findings in another Caucasian kindred. ^{Reference Gazulla, Bellosta-Diago, Izquierdo-Alvarez and Berciano50} 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. ^{Reference Ozaki, Ansai and Nobuhara51} In this study, patients developed symptoms at advanced ages, unlike prior reports of infantile and childhood onsets. ^{Reference Cagnoli, Mariotti and Taroni52– Reference Caporali, Magri and Legati55}

Most patients exhibited progressive cerebellar ataxia, nystagmus, gaze palsy and saccadic abnormalities, consistent with prior findings. ^{Reference Cagnoli, Mariotti and Taroni52,Reference Edener, Wöllner and Hehr53} However, we did not observe other reported features like ptosis and progressive external ophthalmoplegia. ^{Reference Edener, Wöllner and Hehr53,Reference Liu, Wang, Chen, Kang and Li56} 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. ^{Reference Caporali, Magri and Legati55,Reference Pierson, Adams and Bonn57} A Hungarian study showed additional features like hypotonia, impaired vision, diplopia and bulbar symptoms but no cognitive dysfunction, differing from our findings. ^{Reference Szpisjak, Nemeth and Szepfalusi54}

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. ^{Reference Giroux and Barbeau58} 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. ^{Reference Beaudin, Sellami and Martel59} Sensory changes were also detected in one case. ^{Reference Beaudin, Sellami and Martel59} 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, ^{Reference Cadieux-Dion, Turcotte-Gauthier and Noreau60} parkinsonism, ^{Reference Ozaki, Doi and Mitsui61} autonomic dysfunctions such as urinary incontinence issues and constipation, ^{Reference Beaudin, Sellami and Martel59} retinitis pigmentosa and diplopia, ^{Reference Xiao, Binkley and Rexach62} bilateral facial muscle weakness and forearm fasciculations. ^{Reference Giroux and Barbeau58}

Spinocerebellar Ataxia 35

SCA35 was identified through a novel mutation in the Han Chinese population, associated with the transglutaminase six gene (TGM6). ^{Reference Li, Pang, Song, Kung, Ho and Sham63} 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, ^{Reference Wang, Yang and Xia64} delayed speech, ^{Reference Li, Pang, Song, Kung, Ho and Sham63} dysphagia, progressive urinary and bowel urgency, cognitive decline, ophthalmoplegia and sensory impairment. ^{Reference Maass, Jamous and Biskup65} Case studies from India highlighted associated bilateral hand and voice tremors with dystonia, ^{Reference Fasano, Hodaie, Munhoz and Rohani66} while a report from Puerto Rico described a patient with mild parkinsonism. ^{Reference Lin, Gan, Gupta, Alaedini, Green and Kuo67}

Spinocerebellar Ataxia 36

Our study presents two cases of SCA36 affecting individuals of Caucasian and Asian descent. Similar reports have emerged from Asia, ^{Reference Kobayashi, Abe and Matsuura68– Reference Zou, Wang and Gong74} Europe ^{Reference Obayashi, Stevanin and Synofzik70,Reference García-Murias, Quintáns and Arias75– Reference Lam, Rocca and Ibanez77} and North America ^{Reference Valera, Diaz and Petty78} 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, ^{Reference García-Murias, Quintáns and Arias75 Reference Obayashi, Stevanin and Synofzik,70– Reference Zou, Wang and Gong74} 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. ^{Reference Kobayashi, Abe and Matsuura68} Additional features reported in the literature that were not present in our patients include oculomotor apraxia, ^{Reference García-Murias, Quintáns and Arias75} other movement disorders (myoclonus, ^{Reference García-Murias, Quintáns and Arias75} dystonia, ^{Reference Baviera-Muñoz, Carretero-Vilarroig and Muelas76} and parkinsonism ^{Reference Baviera-Muñoz, Carretero-Vilarroig and Muelas76} ), reduced vibration sense, ^{Reference Obayashi, Stevanin and Synofzik70– Reference Zou, Wang and Gong74 Reference Lam, Rocca and Ibanez77} urinary incontinence and autonomic dysfunction. ^{Reference García-Murias, Quintáns and Arias75,Reference Lam, Rocca and Ibanez77}

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.