Spinocerebellar Ataxias (SCAs) are a group of autosomal dominant hereditary neurodegenerative diseases with an incidence of 1-5 cases per 100,000 globally. With advancements in molecular biology, 49 subtypes have been identified based on genetic diagnosis. This disease exhibits significant regional and genetic heterogeneity, with varying proportions of subtypes in different regions. In the mainland Chinese population, approximately 62.09% of SCA patients are diagnosed with SCA3, followed by SCA2, SCA1, SCA6, SCA7, SCA12, and SCA17. Besides typical motor disorders like ataxia, SCAs patients also exhibit numerous non-motor symptoms. For instance, SCA7 is characterized by visual impairment, and SCA17 is more prone to cognitive impairment than other subtypes. However, due to the low prevalence of SCAs, clinical awareness of the disease is limited, particularly regarding its non-motor symptoms. Most SCAs patients typically present symptoms in middle age, often noticing gait instability in their third or fourth decade of life. Nonetheless, non-motor symptoms may precede motor symptoms by several years. This article briefly describes some common non-motor symptoms in SCA patients and their adverse effects on patients’ lives and work. Recognizing and treating these non-motor symptoms is crucial for enhancing the overall quality of life for SCAs patients.
01 Sleep Disorders
Sleep disorders are very common among SCAs patients. Even SCA6, once considered purely a cerebellar disorder, has been re-evaluated to include sleep disturbances. Specific manifestations of sleep disorders in SCAs patients include insomnia, rapid eye movement (REM) sleep behavior disorder (RBD), restless legs syndrome (RLS), periodic leg movement (PLM) during sleep, excessive daytime sleepiness (EDS), and sleep apnea (SA).
1.1 Insomnia
Insomnia refers to a subjective experience where patients are dissatisfied with their sleep duration and/or quality, affecting daytime social functioning. Common symptoms of insomnia include difficulty falling asleep, poor sleep quality, frequent awakenings, forgetfulness, and daytime sleepiness. Studies have indicated that the incidence of insomnia varies among different subtypes, with insomnia being most common in SCA3 patients, accounting for about 80% of their sleep issues. Research has also confirmed that the incidence of insomnia correlates with the patient’s age and the severity of their motor disorders, being more prevalent in older patients with severe motor symptoms. Insomnia is reported to affect approximately 50% of SCA1 patients, 23.8% of SCA6 patients, and 12% of SCA2 patients, but these studies had small sample sizes and require further validation.
1.2 RBD
The main feature of RBD is acting out dreams through physical movements, such as talking in sleep, shouting, sleepwalking, or falling out of bed while still asleep. Multiple studies have found that SCAs patients exhibit RBD. Rodríguez-Labrada et al. studied 36 pre-symptomatic SCA2 gene carriers using polysomnography (PSG) and found that their REM sleep percentage and density were lower compared to healthy controls, indicating that sleep disorders in SCA2 patients may precede their motor symptoms. The incidence of RBD in SCA3 patients is also high, reaching up to 50% in studies by D’Abreu et al. Even in the absence of RBD, SCA3 patients show decreased REM sleep percentage, characterized by increased REM sleep latency and awakenings. Therefore, PSG is valuable for confirming RBD diagnosis in suspected SCAs patients. The pathogenesis of RBD may be related to complex damage in the locus coeruleus, cholinergic nuclei, substantia nigra, hypothalamus, and frontal cortex.
1.3 RLS
RLS is a sensory-motor disorder characterized by an irresistible urge to move the legs, often accompanied by uncomfortable sensations. It typically begins or worsens during periods of rest or inactivity and can be partially or completely relieved by movement, often occurring or worsening at night. The prevalence of RLS in SCAs patients is significantly higher than in the general population, but varies among different SCA subtypes. According to research by Pedroso et al., the highest prevalence of RLS is found in SCA3 patients at approximately 56.7%, followed by SCA6 at 23.8%, SCA1 at 23%, and SCA2 at 18%. The likelihood of developing RLS in SCAs patients may increase with age but is unrelated to the length of CAG repeat expansions or the age of ataxia onset. Research suggests that central dopaminergic dysfunction may be a potential mechanism leading to RLS in SCAs patients.
1.4 EDS
EDS is defined as an irresistible urge to sleep when one should be awake and alert. The global prevalence of EDS is about 20%. There is no large-scale sample statistic in the SCAs population, but EDS has been observed in SCA1, SCA2, and SCA3, with SCA1 and SCA2 being more common compared to SCA3. Studies on sleep in SCA6 patients have shown more pronounced EDS compared to healthy controls, indicating that the cerebellum plays a dynamic regulatory role in sleep. It is noteworthy that EDS can occur before the onset of motor symptoms. A 48-year-old female SCA1 patient reported significant daytime fatigue and sleepiness two years before being diagnosed with motor disorders by a neurologist at age 45. Research has found that EDS is primarily associated with damage to the brainstem’s ascending reticular activating system, particularly in areas like the thalamus, thalamic-mesencephalic junction, and upper medulla. Therefore, EDS is also an independent risk factor for various neurological diseases.
1.5 Other Sleep Disorder Manifestations
In addition to the common sleep disorders mentioned above, SCAs patients also experience snoring, nocturnal sleep apnea, fragmented sleep, increased nocturia, and leg cramps or pain at night. These sleep problems may be inherent consequences of neurodegenerative diseases, and the specific mechanisms still need further elucidation.
02 Cognitive Impairment
Cognitive impairment is relatively common among SCAs patients, often presenting with varying degrees of cognitive decline, dementia, or intellectual disability.
2.1 General Cognitive Impairment
General cognitive abilities include memory, language, visual-spatial function, calculation, attention, and executive function, among others. SCAs patients often show varying degrees of decline in these abilities. Kawai et al. assessed general cognitive function in 16 SCA3 patients and found impairments in memory, visual-spatial structure, and language fluency, with no correlation to CAG repeat length or the severity of motor symptoms. Burke et al. conducted neuropsychological tests on 36 SCA1, 2, and 3 patients, finding more pronounced executive function deficits in SCA1, while all subtypes exhibited mild deficits in language fluency and memory. Garrard et al. evaluated general cognitive function in 9 SCA6 and 6 SCA3 patients, revealing more pronounced memory and executive function impairments in SCA3 patients. Although the results vary, they all suggest that SCAs patients experience general cognitive impairment. Studies on the pathological mechanisms have revealed significant neuronal loss in the cholinergic neurons of SCAs patients, which may contribute to cognitive impairment. Additionally, the cerebellum may participate in cognitive function through the cerebellar-parietal-thalamic cortical pathway, and defects in cerebellar output to the cortex may lead to cognitive impairment.
2.2 Dementia
Dementia represents a severe degree of cognitive impairment, rendering patients unable to live independently. The clinical symptoms of SCA17 primarily include ataxia and/or dementia, with chorea being a common symptom. Its clinical phenotype sometimes overlaps with Huntington’s disease (HD), characterized by movement disorders, psychiatric manifestations, and dementia. Research by Toyoshima et al. found that the severity of cognitive impairment in SCA17 correlates with CAG repeat length. When the CAG/CAA repeat length is between 43-50, over 75% of patients experience intellectual decline, and within this range, dementia and chorea are more easily observed compared to individuals with higher repeat counts. When the CAG/CAA repeat is between 50-60, all patients exhibit ataxia, with approximately 75% showing intellectual decline; however, this repeat range also sees increased manifestations of pyramidal signs (e.g., deep tendon reflexes) and tone disorders. Other SCA subtypes are rarely diagnosed with dementia; Ishikawa et al. reported 4 SCA3 patients exhibiting dementia and delusional symptoms in late disease stages. Ikeda et al. reported an atypical SCA3 case presenting with retinal degeneration and dementia.
03 Depression Symptoms
Depression is a common accompanying symptom of neurodegenerative diseases. Depression symptoms are also prevalent among SCAs patients. A large-sample study found that over half of SCAs participants (52%) had suicidal thoughts, with SCA3 patients exhibiting the highest prevalence of suicidal ideation: SCA1: 44.9%; SCA2: 45.3%; SCA3: 65.0%; SCA6: 39.1%. The study also conducted a two-year longitudinal observation of SCAs patients, finding that depression symptoms remained stable over time, independent of the severity of ataxia. Furthermore, similar to other non-motor symptoms, depression symptoms can appear before other motor symptoms, leading some researchers to suggest that depression symptoms may also result from neurodegeneration. This hypothesis can be confirmed in the natural history of SCAs patients, as the progression rate varies among different SCA subtypes; however, the prevalence of depression does not follow the same developmental sequence, with SCA1 progressing the fastest, followed by SCA3, SCA2, and SCA6, indicating the influence of other factors.
Lesions in the cerebellum itself may be a significant cause of depression symptoms in SCAs patients, as evidenced in SCA6 patients. The pathology of SCA6 suggests that lesions are primarily localized to the cerebellum, and the prevalence of depression in SCA6 patients is higher than in other subtypes, supporting the notion that cerebellar networks are involved in the depression symptoms of SCAs. Some studies have proposed that the cerebellum has dense connections with the frontal lobe and various brainstem regions, suggesting that cerebellar degeneration may lead to cognitive impairment and emotional disorders, referred to as cerebellar cognitive affective syndrome. In cerebellar affective syndrome, depression reflects dysfunction or widespread neuropathology in the connections between the cerebellum and the limbic system.
Gender is correlated with depression symptoms in SCAs patients; Schmitz-Hübsch et al. found that male SCAs patients often exhibit more severe and frequent depression symptoms, though no significant relationship was found between CAG repeat length and the severity of depression.
The above research findings suggest that depression symptoms can be both an emotional response to the suffering caused by the disease and one of the symptoms of SCAs neurodegeneration, while depression symptoms may also influence the progression of ataxia.
04 Autonomic Nervous System Dysfunction
Autonomic nervous system dysfunction is a common clinical symptom among SCAs patients but is often overlooked. It mainly includes arrhythmias, urinary system disorders, gastrointestinal dysfunction, sexual dysfunction, orthostatic hypotension, abnormal sweating, drooling, and sensitivity to temperature changes, among others. The nuclei involved in regulating the autonomic nervous system are primarily located in the hypothalamus and brainstem, such as the locus coeruleus, nucleus of the solitary tract, ambiguous nucleus, dorsal nucleus of the vagus nerve, neurons in the lateral medulla, pontine micturition center, and periaqueductal gray. Damage to these autonomic nervous system-related nuclei can be observed in some SCAs patients.
4.1 Cardiac Autonomic Nervous Dysfunction
SCAs patients may have cardiac autonomic regulatory dysfunction, clinically manifesting as palpitations or even syncope. Heart rate variability analysis is a sensitive method for detecting cardiac autonomic dysfunction. Pradhan et al. found reduced heart rate variability in SCA1, 2, and 3 patients compared to healthy controls, and the prevalence of cardiac autonomic dysfunction varied among different SCA subtypes: 81.8% in SCA1, 66.7% in SCA2, and 60% in SCA3. Cardiac autonomic dysfunction can occur before motor symptoms, as noted by Montes-Brown et al., who observed cardiovascular autonomic dysfunction in more than half of the pre-symptomatic SCA2 patients.
4.2 Orthostatic Hypotension
Clinical research on blood pressure in SCAs patients is limited, possibly due to the non-prominent nature of cardiovascular autonomic dysfunction in SCAs patients. However, orthostatic hypotension can unexpectedly harm patients’ health, such as causing falls. Indelicato et al. found that cardiovascular autonomic function in SCAs patients is largely preserved, with no instances of orthostatic hypotension among all SCA2 patients. Similar results were validated in SCA2 patients in Latin America. One case report noted a SCA2 patient with significant orthostatic hypotension. It can be speculated that despite significant brainstem atrophy, orthostatic hypotension is not a primary clinical feature.
4.3 Urinary Symptoms
Urinary symptoms are common among SCAs patients, such as increased urinary frequency, nocturia, and urinary retention. Tateno et al. studied the lower urinary tract function in SCA6 patients and found that among 9 SCA6 patients, 3 exhibited urinary frequency, and 1 had overactive bladder, with 6 patients diagnosed with neurogenic changes via electromyography. This study also found no correlation between urinary symptoms and CAG repeat length, SARA scores, or disease duration. Lin et al. observed urinary difficulty, constipation, and sexual dysfunction in a SCA17 patient, whose bladder pressure suggested an uninhibited neurogenic bladder. Ito et al. found that, compared to multiple system atrophy patients, SCA6 patients had a lower frequency of overactive bladder and less post-void residual urine, aiding in the differentiation between SCA6 and multiple system atrophy, where overactive bladder or significant residual urine is common. Regarding the pathological mechanisms, Nishizawa et al. found in animal experiments that the cerebellum has an inhibitory effect on bladder function.
05 Peripheral Nervous System Dysfunction
SCAs patients often exhibit peripheral nerve damage, such as reduced vibratory sensation, diminished tendon reflexes, and abnormal nerve conduction. Electrophysiological examinations are highly sensitive, with changes paralleling pathology and often preceding clinical signs, providing relatively objective indicators for assessing the degree of spinal cord injury, treatment options, and efficacy evaluation. Linnemann et al. conducted multicenter nerve conduction studies on 162 genetically confirmed SCA1, SCA2, SCA3, and SCA6 patients, finding peripheral neuropathy in 82% of SCA1, 63% of SCA2, 55% of SCA3, and 22% of SCA6 patients, with most patients showing involvement of both sensory and motor fibers, and mixed axonal and demyelinating neuropathy being the most common. Schöls et al. had similar findings, also noting that age, disease duration, or severity of ataxia affects peripheral nerve involvement, with age being a more significant factor than CAG repeat length.
06 Olfactory Dysfunction
Olfactory dysfunction is common in various neurodegenerative diseases, and related studies have found that SCAs patients exhibit varying degrees of olfactory impairment, particularly noting the close relationship between the cerebellum and olfactory function. Savic’s functional imaging studies have shown activation of the cerebellum during olfactory stimulation. Fernandez-Ruiz et al. first confirmed that patients with cerebellar damage exhibit olfactory dysfunction, while also finding that the degree of olfactory impairment in SCA2 and SCA3 patients is not as severe as in Parkinson’s disease and Alzheimer’s disease patients.
It is essential to note that olfactory function is linked to cognitive function. Vázquez-Pérez et al. tested the olfactory function of 53 SCA2 patients and 53 healthy controls, finding that the SCA2 group had significantly lower olfactory scores than the healthy controls, with a significant correlation between olfactory scores and Mini-Mental State Examination (MMSE) scores (P=0.03). During olfactory testing, the recognition and discrimination of odors require the involvement of the central nervous system and are considered cognitive tasks. Although the prevalence and severity of cognitive impairment vary widely among different SCA subtypes, clinical research data indicate that SCAs patients generally exhibit some degree of cognitive impairment, which often affects the results of olfactory tests. Animal experiments have also shown that olfactory functional activity plays a crucial role in the expression of neurons in the piriform cortex of adult guinea pigs. These findings may provide new insights into understanding the pathogenesis of SCAs.
07 Other Non-Motor Symptoms
Other non-motor symptoms in SCAs patients include hearing impairment, visual impairment, and skin lesions, among others.
7.1 Hearing Impairment
Auditory impairment is a clinical feature that distinguishes SCA36 from other SCAs. Pure tone average (PTA) was calculated based on audiograms and brainstem auditory evoked potentials. SCA36 patients exhibited significantly lower PTA than healthy controls and other ataxia groups, with Ikeda et al. finding a significant positive correlation between PTA and the severity of ataxia in SCA36 patients.
7.2 Visual Impairment
Retinal macular degeneration and visual impairment are typical clinical features of SCA7, with research indicating a correlation between visual impairment and CAG repeat length. When CAG repeat length is between 50-55, it represents the classic type of SCA7, characterized by simultaneous visual impairment and ataxia. These symptoms begin during adolescence and last for 20-40 years. Abnormal results in color vision tests and electroretinograms may suggest early disease progression. In contrast, when CAG repeat length is between 36-43, visual symptoms appear later, primarily manifesting as dysarthria and ataxia, with few or no retinal abnormalities at this stage; visual impairment often becomes more pronounced after age 60, with patients’ lifespans generally unaffected, as the oldest patients have lived up to 95 years. When CAG repeat length is between 18-35, patients typically exhibit no visual impairment symptoms.
7.3 Skin Lesions
Erythrokeratodermia variabilis (EKV) is one of the clinical features of SCA34, characterized by well-defined erythema and excessive keratinization of the skin. Mutations in the connexin genes GJB3 and GJB4 are the primary causes of EKV, though their correlation with SCA34 genes remains unclear. The incidence of skin lesions is notably high among French-Canadian SCA34 families (14 out of 19 mutation carriers, or 73.7%). However, the occurrence of such skin lesions shows regional differences, as Ozaki et al. reported no skin lesions like EKV among two Japanese families with SCA34.
08 Outlook
Through the continuous understanding of non-motor symptoms in SCAs, there is an increased and comprehensive awareness of SCAs, which also raises higher demands for the treatment of SCAs patients. Advances in biological and genetic technologies provide reliable means for pre-symptomatic diagnosis and prenatal counseling for SCAs patients. Non-motor symptoms can appear at various stages of SCAs patients’ disease progression and are significant factors in reducing the quality of life for patients, profoundly impacting both patients and their caregivers. Clinically recognizing and addressing these non-motor symptoms is crucial for improving patients’ quality of life; however, further elucidation of the pathogenesis of non-motor symptoms in SCAs is still needed.
Chinese Clinical Neuroscience, February 2023, Vol. 31, No. 1
Authors: Liu Yiwen, Zhou Hao, Zhang Liangjie (Graduate School of Anhui University of Chinese Medicine), Han Yongsheng (Anhui Provincial Hospital of Traditional Chinese and Western Medicine [Third Affiliated Hospital of Anhui University of Chinese Medicine], Neurology Research Institute of Anhui University of Chinese Medicine)
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