Ataxias: Hereditary, Acquired, and Reversible Etiologies

Abstract

A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.

Ataxia refers to a specific constellation of symptoms and signs, characterized by a combination of the following features: lack of coordination in eye movements, speech fluency and voice volume, limb dexterity, and gait stability. These symptoms mainly arise from dysfunction of the cerebellum. Meanwhile, the cerebellum also depends on sensory input for its proper function; therefore, people with sensory dysfunction, especially proprioception loss seen in large fiber neuropathy, may also have ataxic symptoms (i.e., sensory ataxia). Given the diverse etiologies, the manifestation of ataxia symptoms varies in terms of disease chronicity or occurs in combination with nonataxia symptoms. Specifically, nonsensory and noncerebellar circuitry involved in these nonataxic symptoms, associated with dopaminergic and pyramidal dysfunction, adds to the diagnostic uncertainty and complexity. In this article, we provide the latest review and practical approaches to cerebellar ataxia for clinicians.

Ataxia Clinical Examination

The first step to approach patients with possible ataxia is to accurately identify the signs and symptoms of ataxia. As the cerebellum is important to the control of the precision of movement, the core clinical feature of ataxia is the variability of motor function.¹ For gait assessment, variability of step width, step length, and direction of the walking path are key features of gait ataxia. A wide-based gait, a common gait pattern described in ataxia patients, is compensatory to progressive gait instability and tends to emerge later in the disease course. Ataxic patients with a wide-based gait still retain the core feature of variability of gait as mentioned above. Of note, a wide-based gait is not specific to ataxia patients and can also be seen in patients with functional movement disorders, normal pressure hydrocephalus, and sensory neuropathy.^2–4 Variability of movement in other body regions is also observed in ataxia patients. Speech often manifests as variability of rhythm, volume, and tone control, and can further assist in the diagnosis of ataxia. There are interruptions of speech output due to overemphasized consonants and distorted, underemphasized vowels. Following the same principle, ataxic patients also have hand dexterity variability, manifesting as intention tremor with dysmetria on the finger–nose–finger test, dysdiadochokinesia in the fast alternating hand movement test, and overshooting or undershooting on the finger chase test. For leg movements, ataxia patients show variability in keeping the heel on track with the tibia shaft in the contralateral leg in the heel–knee–shin test. Finally, eye movements can present with a variety of abnormalities, such as square wave jerks (i.e., horizontal saccadic intrusions that interfere with the visual fixation on a target), hypermetric or hypometric saccades, and multidirectional, nonsuppressible nystagmus. These clinical features are commonly observed in patients with cerebellar ataxia. Of note, an individual with cerebellar ataxia is not expected to have all of the aforementioned signs. The majority of individuals with ataxia have gait difficulty as the initial presenting symptom. In a study investigating the initial symptoms of spinocerebellar ataxia (SCA), using the natural history of the Clinical Research Consortium for SCAs (CRCSCA) that studies SCA patients in North America, greater than 80% of SCA1, 2, 3, and 6 patients (SCA1: 92.3%, SCA2: 87.0%, SCA3: 87.5%, SCA6: 83.8%) had gait difficulty as their first symptom.⁵ In addition, speech and eye movement abnormalities at onset are not uncommon, which may be easily missed in the early stages. As the disease progresses, other ataxic symptoms and signs can become obvious, affecting all aspects of activities of daily living.^6,7

Experts have developed clinical rating scales to comprehensively capture ataxia symptoms, to quantify and compare the ataxia severity, and to longitudinally follow up patients with ataxia. The International Cooperative Ataxia Rating Scale (ICARS; total score = 100) measures specific core ataxic symptoms, and is divided into three compartments to measure postural and gait disturbances, kinetic functions for limb and speech, and oculomotor abnormalities.⁸ While ICARS is quite comprehensive, it may not be suitable for daily clinical practice due to the time needed for administration and its overlapping nature of certain items within the three compartmentalized measures.⁹ The Scale for the Assessment and Rating of Ataxia (SARA; total score = 40) and Brief Ataxia Rating Scale (BARS; total score = 30) were later developed. With high reliability and validity, SARA is now the most widely used rating score for cerebellar ataxia, which constitutes gait, finger–nose–finger, heel–knee–shin, and speech disturbance, sitting, stance, finger chase, and rapid alternating movements. In contrast to BARS, SARA does not measure oculomotor abnormalities. In addition to motor dysfunction, individuals with ataxia are also known to have a variety of cognitive and behavioral symptoms, such as executive dysfunction and depression; therefore, the Cerebellar Cognitive Affective Scale was developed to characterize and track the level of cognitive impairment in cerebellar ataxia.¹⁰ Impulsive and compulsive behaviors have been recently identified in patients with cerebellar ataxia and can also be highly disabling.^11–17 Most recently, the Patient-Reported Outcome Measure of Ataxia (PROMAtaxia) was developed, assessing physical capability, mental health, and activities of daily living from the patient’s perspective. These measures will be critical for future clinical trials to demonstrate clinical meaningfulness.¹⁸

Reversible Causes of Ataxia

After identifying ataxia signs and symptoms in a patient, the next step is to look for reversible causes, which often fall into nutritional and immune-mediated causes (►Fig. 1; ►Table 1). One important consideration is that such a “reversible” cause may also be a contributor to the accompanying nonataxia deficits and symptoms. Depending on the timing of treatment initiation, neurological deficits may be permanent despite correcting the underlying etiology of cerebellar ataxia.¹⁹

Fig. 1.

Characteristic structural MRI features of multiple system atrophy. The hot crossed bun sign in multiple system atrophy cerebellar type, a feature as a result of the olivopontocerebellar system degeneration (A), and T2 hyperintense external striatal signals, implying putaminal degeneration in multiple system atrophy parkinsonian type (B). MRI, magnetic resonance imaging.

Table 1.

Reversible and treatable causes of cerebellar ataxia, recommended tests, and treatment

Disorders/diseases	Test	Treatment and management
Alcohol-induced ataxia	History[a]	Alcohol cessation
Wernicke encephalopathy	Whole blood thiamine level, brain MRI[b]	High-dose IV or oral thiamine supplementation[c]
Vitamin B12 deficiency	Serum vitamin B12 level	Vitamin B12 supplementation
Vitamin E deficiency	Serum vitamin E level	Vitamin E supplementation
Steroid-responsive encephalopathy[d]	Serum anti-TPO and anti-TG antibodies	IVMP
Gluten ataxia	Anti-gliadin antibody	Gluten-free diet, IVMP, IVIG, or plasmapheresis
Multiple sclerosis	Brain MRI, spine MRI, oligoclonal band of CSF	Immune-modulating therapy
Sjogren syndrome	Anti-Ro (SS-A) and anti-La (SS-B) antibodies	Immune-modulating therapy
Paraneoplastic ataxia	See [Table 2]	IVMP, IVIG, or plasmapheresis; cancer curative treatment If possible
Anti-GAD	GAD antibody
Toxin-induced ataxia	History; brain MRI[f]	Lithium, amiodarone, metronidazole, cyclosporine, tacrolimus, and other chemotherapy agents[e]

Abbreviations: CSF, cerebrospinal fluid; GAD, glutamic acid decarboxylase; GluRd2, glucose receptor delta 2; IVMP, intravenous methylprednisolone; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; TG, thyroglobulin; TPO, thyroid peroxidase.

^a> 140 g or 50 ounces of wine per day for more than 10 years. Individual susceptibility and other contributors need to be considered.

^bThe purpose of MRI is for supporting the diagnosis; lack of classic findings does not serve as evidence of diagnostic exclusion.

^c500 mg every 8 hours for 3 days, followed by 250 mg every day for 5 days.

^dHashimoto encephalopathy is the alternative name.

^eLithium, amiodarone, metronidazole, cyclosporine, tacrolimus, and other chemotherapy agents.

^fBilateral dentate hyperintensity can sometimes be seen on MRI.

Alcohol-Induced Cerebellar Ataxia

Alcoholic cerebellar degeneration usually occurs with chronic heavy alcohol use. In this type of cerebellar ataxia, the pathology predominantly affects the anterior and superior vermis of the cerebellum, resulting in truncal ataxia and relatively mild appendicular ataxia. As opposed to acute alcohol intoxication that causes synaptic dysfunction in the cerebellum,²⁰ oxidative and endoplasmic reticulum stress on the cerebellar cortex has been proposed as the main mechanism of chronic ethanol toxicity,²¹ resulting in Purkinje cell degeneration.²² The amount and the duration of alcohol consumption needed to cause cerebellar degeneration remains inconclusive. It has been proposed that alcohol-induced cerebellar degeneration requires a large amount of daily alcohol drinking (>140 g or 50 ounces of wine per day, approximately 10 times of a standard drink) for more than 10 years.^23,24 A study found that this amount of alcohol is associated with cerebellar vermis atrophy identified by a computed tomography imaging study in 41 cases attributed to alcohol use.²³ On the other hand, a small amount of daily alcohol ingestion with 5 g for a similar length of time can also lead to ataxia.²⁵ The exact amount and the duration of alcohol use have not been consistently established; therefore, clinicians should always have high suspicion for alcohol-induced cerebellar ataxia. Another important consideration is the individual susceptibility to alcohol. Of note, alcohol can also contribute and perhaps aggravate other forms of cerebellar ataxia, such as gluten ataxia.²⁶ Multifactorial causes should also be considered. Alcohol abstinence has been the major intervention; however, improvement of truncal ataxia after cessation of alcohol is not uniform.^22,27 Alcohol-induced cerebellar ataxia is associated with Wernicke encephalopathy, which we will discuss in the below section. Of note, excessive alcohol consumption can cause alcoholic polyneuropathy, involving sensory, motor, and autonomic systems. Large and small sensory fiber function abnormality, including paresthesia and loss of vibratory sensation, is seen in a symmetric and distally predominant distribution, further contributing to gait ataxia.^28,29

Nutritional Deficiency Cerebellar Ataxia

Frequently associated with alcohol overuse, Wernicke encephalopathy due to thiamine deficiency can be found in people with alcohol abuse or other causes of malnutrition, such as cancer, pregnancy, or gastric bypass surgery.³⁰ While the classic triad for Wernicke encephalopathy is gait ataxia, ophthalmoplegia, and encephalopathy, the caveat for diagnosis is that with incomplete presentations of the triad, varying degrees of oculomotor dysfunction and atypical manifestations such as a stroke mimic have been frequently reported.^31–33 Similarly, while Wernicke encephalopathy typically affects midline structures such as thalamus, mammillary bodies, and periaqueductal gray matter, in addition to the cerebellar hemisphere and superior anterior vermis,^30,34 a wide range of radiographic findings have been reported, including stroke-like cortical T2 hyperintensity or the absence of an overt imaging abnormality.^33,35,36 Given that ataxia associated with thiamine deficiency is treatable, patients with ataxia and risk factors for nutritional deficiency should be treated empirically with high-dose intravenous thiamine to avoid devastating brain hemorrhage,³⁷ preferably after sending a test of whole blood thiamine level.³⁰ Analternative is to measure the activity of erythrocyte thiamine transketolase, as thiamine is the cofactor for the transketolase.^38,39 However, in clinical practice, sending an erythrocyte thiamine transketolase activity test can be nontimely as it is usually not immediately available and the precision is considered low, partly due to the instability of the transketolase.⁴⁰ A standardized protocol was also recently proposed to solve the issues of lack in consensus on the cut-off value.³⁸ Of note, even with treatment, about half of patients with Wernicke encephalopathy will have an incomplete recovery with residual ataxia, and 25% will evolve into Wernicke–Korsakoff syndrome, often requiring care in long-term facilities.⁴¹

Vitamin E deficiency-related cerebellar ataxia will be discussed in the hereditary ataxia section below, since it is caused by genetic defects in the vitamin E metabolism pathway. Sensory ataxia with high steppage gait, peripheral neuropathy, and hyperreflexia are classic signs of subacute combined degeneration resulting from vitamin B12 deficiency. Other causes, such as nitrous oxide toxicity as well as metformin use, should also be screened.⁴² Serum vitamin B12 and E levels should be determined in patients with cerebellar ataxia.^43–45

Immune-Mediated Ataxia

Cerebellar ataxia is a well-established common symptom in multiple sclerosis (MS).⁴⁶ Depending on the demyelinating lesion sites, cerebellar ataxia can be truncal and/or appendicular, and can manifest as acute or chronic. In progressive MS, the prevalence of cerebellar ataxia is as high as 80%.⁴⁶ Extensive cerebellar involvement, along with white matter hyperintensities in the middle and superior cerebellar peduncles, are commonly identified on brain magnetic resonance imaging (MRI),^47,48 Moreover, cerebellar gray matter cortical volume loss and demyelination extending from the white matter may be a distinctive pathological hallmark of MS.⁴⁹ Cerebellar involvement in MS is often associated with cognitive deficits, especially in the posterior–inferior lobes responsible for nonmotor functions.⁵⁰ A recent study showed that greater superior and middle cerebellar peduncle volume is associated with better motor and cognitive function, further highlighting the importance of the cerebellar status on overall functioning in MS.⁵¹

Ataxia associated with primary Sjogren syndrome (pSS) presents as a sensory ataxia due to a sensory neuronopathy affecting large sensory fibers.⁵² Cerebellar ataxia in pSS, although rare, can occasionally occur—both acute and chronic cerebellar ataxia have been reported.^53–55 Therefore, we still recommend testing the antinuclear antibody with reflex testing, together with tests of other autoimmune disorders such as gluten ataxia and Hashimoto encephalopathy (details addressed below), as part of the initial workup for cerebellar ataxia. Of note, a greater incidence of multiple system atrophy (MSA) has been observed in a large cohort of pSS patients, and a higher prevalence of pSS in MSA has been reported, advancing the hypothesis that systemic autoimmune disorders can contribute to neurodegenerative diseases.⁵⁶

Gluten ataxia refers to an immune-mediated cerebellar ataxia resulting from heightened gluten sensitivity,^57,58 which can present as acute, subacute, or chronic ataxia.⁵⁹ Anti-transglutaminase 6 antibody appears to be most specific to gluten ataxia; however, this test has not been commercially available. Therefore, the commercially available anti-gliadin antibody test should be considered to aid in the diagnosis of gluten ataxia.⁶⁰ A gluten-free diet is the first-line intervention for gluten ataxia, and immunotherapy with intravenous immunoglobulin (IVIG) has been proposed as well.⁶¹

Steroid-responsive encephalopathy associated with antithyroid antibodies (SREAT), or Hashimoto encephalopathy, is another type of immune-mediated ataxia with heterogeneous clinical manifestations, including dementia, epilepsy, myoclonus, and ataxia.⁶² The cerebellar ataxia in SREAT can present at the onset or late in the disease course.^63,64 Of note, patients with SREAT do not need to have clinical or laboratory hyper- or hypothyroidism; a euthyroid status does not rule out SREAT. Serum anti-thyroperoxidase (anti-TPO) antibodies are the standard tests for SREAT; however, the cut-off values for confirmatory diagnosis and the need for testing these antibodies in cerebrospinal fluid (CSF) remain unclear.⁶⁵ Some studies have proposed testing for antibodies against the N-terminus of α-enolase, considered to be more specific for SREAT, but this has not been widely adopted in clinical practice.⁶⁶ Intravenous steroids are the standard treatment for SREAT,⁶⁷ and the success of IVIG has been reported as well.⁶⁸ Another rare form of immune-mediated ataxia is caused by anti-GluRd2 antibody, which produces tremor along with cerebellar ataxia.^69,70 Testing the anti-GluRd2 is feasible, but not widely available. Resolution of anti-GluRd2 ataxia after steroid administration was reported.⁶⁹

Paraneoplastic cerebellar degeneration (PCD) should be considered in a patient with the subacute onset of ataxia with a rapidly progressive course. Purkinje cells attacked by onconeural antibodies from a heightened immune response to proteins expressed by tumor cells is the main mechanism.⁷¹ Several paraneoplastic onconeural antibodies have been identified, including Purkinje cytoplasmic antibody type 1 (PCA-1), also known as anti-Yo, or anticerebellar degeneration-related antigen 2 (CDR2), strongly associated with ovarian and breast cancers and one of the most well-known causes of PCD.^72,73 Anti-Hu (ANNA-1) with small cell lung cancer and testicular cancer, Purkinje cytoplasmic antibody type 2 (PCA-2) with small cell lung cancer, and Purkinje cytoplasmic antibody type tr (PCA-Tr), also known as anti-Tr or anti-Delta/Notch-like epidermal growth factor-related (DNER) with Hodgkin lymphoma are also common forms of PCD.^71,74 Anti-DNER-associated PCD has been recently identified. The long-term outcomes of paraneoplastic syndrome with anti-DNER antibodies were further characterized in a cohort of 28 patients: 96.4% had cerebellar ataxia and became moderately to severely disabled, of whom 50% improved and 32.1% only had slight or absent disability after 26-month follow-up.⁷⁵ Younger age, less reduced cerebellar gray matter volume, and milder clinical symptoms are all associated with favorable outcomes (i.e., modified Rankin Scale score 2).⁷⁵ The full list of PCD onconeural antibodies and the respective underlying malignancies are listed in ►Table 2.

Table 2.

The onconeuronal antibodies related to paraneoplastic cerebellar degeneration and its underlying malignancy^252,253

Antibody	Alternative name	Commonly reported tumor/malignancy
ANNA-1	Anti-Hu	Small cell lung cancer, prostate cancer, testicular seminoma
ANNA-2	Anti-Ri	Small cell lung cancer, breast cancer, ovarian cancer
ANNA-3		Small cell lung cancer
PCA-1	Anti-Yo	Breast cancer, ovarian cancer
PCA-2		Small cell lung cancer, breast cancer, ovarian cancer
PCA-Tr	Anti-DNER	Hodgkin lymphoma
mGluR1		Hodgkin lymphoma
CRMP-5	Anti-CV2	Small cell lung cancer, thymoma
Amphiphysin		Small cell lung cancer, breast cancer
DPPX		B cell lymphoma, mantle cell lymphoma, B cell lymphocytic leukemia
NMDA		Ovarian teratoma (malignant and nonmalignant), small cell lung cancer
LGI-1		Lung (squamous cell), thyroid, breast, kidney
CASPR2		Thymoma

Abbreviations: ANNA, antineuronal nuclear antibody; CASPRI2, contactin-associated protein-like 2; CRMP, collapsin response-mediator protein; CV, clathrin-coated vesicles; DNER, delta/notch like epidermal growth factor-related; DPPX, dipeptidyl-peptidase-like protein-6; LGI-1, leucine-rich glioma-inactivated 1; mGluR1, metabotropic glutamate receptor 1; NMDA, N-methyl-D-aspartate; PCA, Purkinje cytoplasmic antibody.

The glutamic acid decarboxylase (GAD) autoantibody is known to be associated with type 1 diabetes and movement disorders, especially cerebellar ataxia and stiff-person syndrome.⁷⁶ Other neurological manifestations, including seizures, cognitive decline, and behavioral disturbance, seen in limbic encephalitis can also occur.^77,78 The prevalence of anti-GAD in the general population remains unclear, which raises several questions, including the possibility of overdiagnosis of stiff-person syndrome in the context of mildly elevated GAD seropositivity. The association between anti-GAD antibodies and cerebellar ataxia was first reported in 2000,⁷⁹ and a titer higher than 2,000 IU/mL (normal reference range: <5.0 IU/mL) is considered convincing for the diagnosis of anti-GAD ataxia.^80–82 Broadly speaking, GAD autoimmunity can be considered a paraneoplastic syndrome. The reports of cancer prevalence in GAD seropositivity cases vary from 4 to 26%, yet seem to be higher in cases of cerebellar ataxia and limbic encephalitis than stiff-person syndrome. In ataxia, nonsmall cell lung cancer and pancreatic neuroendocrine tumor are the most commonly associated malignancies, while in stiff-person syndrome, thymoma, kidney, and colorectal cancer predominates.^83–88 Assessing for malignancy in GAD-positive cases is thus recommended, and IVIG and intravenous methylprednisolone are treatments of choice.^89–91

A recent history of infection prior to the ataxia onset can be informative. Several viruses, including varicella-zoster, herpes simplex type 1, mumps, measles, rubella, Epstein–Barr, coxsackie, and rotavirus are known to cause acute cerebellitis.⁹² Postinfectious acute cerebellar ataxia is the most common neurological complication of varicella infection in the pediatric population,⁹³ accounting for approximately 10% of cases of varicella infection requiring hospitalization in one retrospective study.⁹⁴ Since the coronavirus disease (COVID) pandemic began, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been identified as the newly emerging virus for postinfectious cerebellar ataxia in adults and children.^95–99 Of note, although white matter signal changes in the corpus callosum, middle cerebellar peduncle, and cerebellar hemispheric were reported,^95,99,100 some cases had a normal appearing cerebellum on brain MRI.^96–98 Acute COVID infection can worsen any already existing ataxia symptoms, and some patients may be left with increased dizziness and ataxia symptoms long after the infection. Subacute cerebellar ataxia after SARS-CoV-2 infection has also been reported, with ataxia symptoms emerging after the resolution of COVID respiratory symptoms.⁹⁹

Drug-Induced Ataxia

A wide range of drugs can cause cerebellar ataxia. Drug-induced cerebellar ataxia typically presents with an acute to subacute onset, from days to weeks from drug initiation. While complete recovery is expected after discontinuation of such drugs, some, especially lithium, are associated with chronic cerebellar ataxia, suggesting irreversible damage.¹⁰¹ The common offending agents associated with cerebellar ataxia are: (1) amiodarone, commonly used for atrial fibrillation, cerebellar ataxia, and bilateral vestibulopathy are typical symptoms for amiodarone-induced ataxia^102,103; (2) cyclosporine and tacrolimus, used in the kidney and liver transplant population; in addition to cerebellar ataxia, these drugs can also cause tremor, paresthesias, or even seizures, encephalopathy, and cognitive dysfunction^104–107; (3) metronidazole, an antibiotic for anaerobic coverage, can cause bilateral dentate hyperintensity on T2 FLAIR as the classic imaging finding, which can be reversible after drug discontinuation^108,109; (4) irinotecan and cytarabine, chemotherapy agents used to treat colorectal cancer^110,111 and acutemyeloid leukemia, respectively; high doses of either medication can result in irreversible cerebellar atrophy and persistent ataxia followed by an acute phase¹⁰¹; postmortem examination reveals cerebellar Purkinje cell loss despite normal imaging, suggesting toxicity to Purkinje cells¹¹²; (5) lithium, a mood stabilizer; lithium-induced cerebellar ataxia should be particularly considered in the setting of impaired renal function, active infection, and dehydration. Lithium may still induce cerebellar ataxia, despite being in a “therapeutic range.”¹¹³ Thus, the diagnosis of lithium-induced ataxia should be based on clinical symptoms, such as nausea, vomiting, tremor, and myoclonus associated with ataxia, as well as the temporal relationship between the drug initiation and symptom development. Hemodialysis should be considered in acute lithium intoxication,¹¹⁴ and long-term cerebellar ataxia, despite drug discontinuation, occurs in 1% of the lithium users¹⁰¹; and (6) antiseizure medications, especially lamotrigine and oxcarbazepine, which have the highest likelihood of causing cerebellar ataxia.¹⁰¹ Phenytoin and valproate can both cause acute and chronic cerebellar ataxia, despite serum levels being within the therapeutic range. Coexistence of sensory ataxia due to folate deficiency can occur in long-term phenytoin users, given that phenytoin inhibits folate conjugase activity in human jejunum and also inhibits folate polyglutamate.¹¹⁵ In patients with cerebellar ataxia, these medications should be discontinued or at least adjusted for dose reduction. Even in patients with a clear diagnosis of degenerative or genetic causes of ataxia, these medications are likely to contribute to the symptoms.

Degenerative Causes of Ataxia

Multiple System Atrophy

MSA is one of the diseases commonly referred to as an atypical parkinsonism, or Parkinson-plus syndrome, and parkinsonian symptoms are among the core features of MSA. However, some MSA patients may have predominant cerebellar ataxia with relatively subtle parkinsonian signs. As reflective of its nomenclature, MSA affects several brain regions, constituting four major systems: autonomic, dopaminergic, cerebellar, and pyramidal systems. Based on the motor symptoms, MSA can be further categorized into MSA-parkinsonian (MSA-P) or MSA-cerebellar (MSA-C) subtypes. Pyramidal symptoms and signs, such as hyperreflexia, are an often neglected but useful clinical pearls to assist diagnosis. Pyramidal signs are more common in MSA-P patients¹¹⁶ and can be associated with pathology in the motor cortex.¹¹⁷ As opposed to Lewy bodies consisting of aggregates of neuronal α-synuclein in Parkinson disease (PD), in MSA, α-synuclein deposits are primarily found in the glial cells, called glial cytoplasmic inclusions, as the hallmark of MSA pathology. MSA patients also have common signs associated with synucleinopathy: (1) rapid eye movement behavioral disorder (RBD), (2) hyposmia, and (3) constipation. Anterocollis is frequently seen in MSA cases and remains very difficult to treat despite botulinum toxin injection.¹¹⁸ With high diagnostic predictive value, laryngeal stridor is an important feature of MSA and can be an adverse prognostic factor for survival.¹¹⁹ Patients may need continuous positive airway pressure and eventually tracheostomy in the later stages of the disease.¹¹⁹ Classic yet not pathognomonic brain MRI findings for MSA are (1) “hot crossed bun” sign (►Fig. 1A) along with reduced pontocerebellar volume in MSA-C and (2) external striatal linear T2 hyperintensity in MSA-P (►Fig. 1B).

Currently, the diagnosis of MSA is based on clinical features and neuroimaging findings. To optimize the diagnostic accuracy, especially in the early phase,¹²⁰ the International Parkinson and Movement Disorders Society (MDS) released recommended criteria in 2022.¹²¹ Compared with the second consensus established in 2008,¹²² the overarching revision of the present criteria proposed a category to define “possible prodromal MSA,” including people with at least one of the following core clinical features: RBD diagnosed via polysomnography, neurogenic orthostatic hypotension within 10 minutes of standing or head-up tilt, and urogenital failure. Either subtle parkinsonism or subtle cerebellar ataxia signs need to be identified in addition to the core features to fulfill this category. Another improvement in the new criteria is the delineation of objective measures for autonomic dysfunction with clearly defined cut-off values: the neurogenic orthostatic hypotension is re-defined as the drop of systolic blood pressure of 20 mm Hg and diastolic blood pressure of 10 mm Hg, with “within 3 minutes” for the “clinically established” MSA and “within 10 minutes” for the “clinically probable” MSA. Of note, “possible prodromal” MSA is a newly created category to further the research for current unmet needs in MSA, not meant for clinical practice, and a neurogenic orthostatic hypotension that happens within 10 minutes is listed as one of the four core clinical features in possible prodromal MSA. The agedefined cut-off of 60 years has been proposed for the definition of early erectile dysfunction, and the incomplete urinary voiding volume is defined as postvoiding residual volume >100 mL, further highlighting the use of bladder ultrasound to assist the diagnosis. Of note, to increase diagnostic specificity, while cognitive impairment and behavioral disturbance can be expected in MSA, the criteria proposed exclude early emergence of dementia and visual hallucinations, defined as within 3 years of disease onset.¹²¹ This revision intends to minimize the possibility of diagnosing cognitive disorders with parkinsonism, especially dementia with Lewy bodies as MSA.¹²³ Last but not least, an unexplained Babinski sign is listed as a supportive motor feature based on the involvement of the pyramidal system.¹¹⁶

Challenges remain in differentiating MSA versus PD in the context of parkinsonism with neurogenic orthostatic hypotension. Laboratory tests such as scintigraphy with 123I-metaiodobenzylguanidine enable the quantification of post-ganglionic sympathetic cardiac innervation to differentiate MSA versus PD,¹²⁴ but clinical application has so far been limited because it is not widely performed in clinical settings. Recently, using skin biopsies to quantify phosphorylated α-synuclein in intraepidermal nerve fibers has shown potential utility for differentiating MSA versus PD, despite biopsy sites varying across studies.^125,126 The phosphorylated α-synuclein deposits in MSA were primarily found in epidermal somatic fibers, while in PD with orthostatic hypotension, the deposits were found in the autonomic fibers innervating the sweat glands, pilomotor, and vasomotor structures.¹²⁵ A recent novel CSF assay demonstrated the ability to differentiate conformational strains of α-synuclein in MSA versus PD, which holds promise for future diagnostic precision.¹²⁷ Treatment of MSA should focus on specific symptoms and is outside of the scope of this review. Orthostatic hypotension can be treated with fludrocortisone, midodrine, droxidopa, and atomoxetine.^128–131 Although associated with an overall poorer response than in PD, levodopa remains first-line treatment, and a total daily dose of up to 900 to 1,000 mg is recommended before considering levodopa ineffectiveness.¹³²

While assessing people with suspected MSA-C, it is of importance to keep two genetic disorders which are MSA-C mimickers, the replication factor C subunit 1 (RFC1)-related spectrum disorders and Fragile X-associated tremor ataxia syndrome (FXTAS), in mind. Given its diverse presentation and frequent autonomic system involvement, testing RFC1 in suspected MSA-C cases with relatively atypical presentation can further reveal the etiology. These atypical features include slow progression and life expectancy longer than 9 years, coexisting pronounced sensory and vestibular dysfunction, and mild autonomic dysfunction.¹³³ Sullivan et al studied 207 patients with possible and probable MSA and found 3 cases with RFC1 expansion.¹³⁴ Similarly, autonomic dysfunction is frequently seen in FXTAS.¹³⁵ The European MSA Study Group found 4 out of 426 MSA-C cases carrying FMR1 premutation and recommended that for cases with slow disease progression and tremor predominant feature, the FXTAS needs to be considered.¹³⁶ The details of RFC1 ataxia and FXTAS will be further discussed in the “Genetic Causes for Ataxia” section.

Progressive Supranuclear Palsy—Cerebellar Ataxia Subtype

Although cerebellar ataxia was intentionally placed in the exclusion condition in both NINDC-SPSP¹³⁷ and MDS progressive supranuclear palsy (PSP) criteria to increase the diagnostic specificity for PSP, the MDS-PSP Study Group acknowledged the presence of cerebellar ataxia in rare PSP cases (i.e., PSP-C).¹³⁸ Dentate nucleus degeneration was found in PSP via neuroimaging and neuropathological studies with or without cerebellar ataxia.^139,140 The compromise of cerebellar function was supported by an electrophysiological study using transcranial magnetic stimulation to assess the dentato-thalamo-cortical pathway.¹⁴¹ Varying genetic and environmental influences have been hypothesized given the higher prevalence of PSP-C higher in Asia, especially in Japan, than in Western countries.^142–144 Ando et al proposed the diagnostic criteria for PSP-C based on increasing recognition of cerebellar ataxia in PSP cases.¹⁴⁵ The criteria highlight the importance of early truncal ataxia, limb ataxia, and falls (i.e., all within 2 years of symptoms onset). The key feature, supranuclear gaze palsy, is also listed in the criteria. The criteria will help researchers to further investigate and delineate the features of PSP-C.

Creutzfeldt–Jakob Disease

Cerebellar ataxia is one of the four core clinical features for Creutzfeldt–Jakob disease (CJD).¹⁴⁶ CJD is a prion disease, and patients with prion disease most commonly have limb ataxia as well as gait disturbance (either ataxic or apraxic gait) in the earliest stage of the disease.¹⁴⁷ Ataxia can present as an isolated, early feature before the cognitive symptoms manifest in CJD.^148–150 Rapidly progressive aphasia to akinetic mutism and cortical blindness are common cognitive deficits,¹⁴⁶ and other higher cortical dysfunction, such as apraxia or auditory agnosia, can also occur.^149,151 The diagnosis of CJD has dramatically improved because of the recent development of CSF RT-QuIC analysis (sensitivity 92%, specificity 100% at UK National CJD Research and Surveillance Unit).^146,152,153 It is important to consider CJD in the differential diagnosis when encountering patients with cerebellar ataxia, especially for those with a rapidly progressive disease course in combination with myoclonus and dementia.

Idiopathic Late-Onset Cerebellar Ataxia

After extensive investigation (►Fig. 2), if a specific etiology is still unable to be identified, most such cases will be classified as idiopathic late-onset cerebellar ataxia (ILOCA).^154,155 ILOCA should be taken as a form of degenerative ataxia with slow progression instead of a diagnostic waste bin, since the prognosis is distinct from MSA.¹⁵⁶ Some experts also call ILOCA a sporadic adult-onset ataxia of unknown etiology.¹⁵⁷ ILOCA is late-onset cerebellar ataxia without parkinsonism or autonomic features, and ILOCA patients have a longer life expectancy and slower progression than MSA patients.^158,159 Cerebellar atrophy without involvement of other intracranial structures is the standard neuroimaging finding in ILOCA.^158,159

Fig. 2.

The recommended diagnostic algorithm for cerebellar ataxia. CANVAS, cerebellar ataxia, neuropathy, vestibular areflexia syndrome; CJD, Creutzfeldt–Jakob disease; FXTAS, fragile X tremor and ataxia associated syndrome; ILOCA, idiopathic late-onset cerebellar ataxia; MSA, multiple system atrophy.

The gene FGF14 that encodes fibroblast growth factor 14 first gained its attention in a Dutch family with 14 affected relatives who presented with cerebellar ataxia due to alteration of the coding sequence,¹⁶⁰ which was later named SCA type 27 (SCA27).¹⁶¹ Recently, the intronic GAA repeat expansion in FGF14, a different type of mutation, was also identified as the cause of cerebellar ataxia revealed from an Australian cohort, named SCA50.¹⁶² Interestingly, the intronic FGF14 GAA repeat expansion was found in patients who were previously diagnosed with ILOCA, including 61% in French Canadian, 18% in German, 15% in Australian, and 10% in Indian cohorts from a multicentered study.¹⁶³ These findings overall highlight that novel genetic mutations can account for a significant portion of sporadic late-onset ataxia cases.

Miscellaneous

Here we aim to highlight several conditions to be considered when assessing acquired causes of cerebellar ataxia. Essential tremor (ET) patients can have subtle ataxia signs, such as difficulty in tandem gait, recently proposed as having “ET-plus.” These ataxic signs are rather mild (e.g., difficulty with tandem gait, but with no truncal sway on normal ambulation) or subclinical (i.e., detected only in laboratory gait analysis).^164,165 Whether ET-plus represents separate disease entities or different stages of disease progression remains controversial.^166,167 In pathological analysis, ETs with and without difficulty in tandem gait are not different in terms of cerebellar pathology.¹⁶⁸ While the majority of the gait impairment in ET is rather subtle, a small subset of ET cases can eventually develop pronounced gait ataxia.¹⁶⁹ In this population, investigating other ataxia causes will be necessary.¹⁷⁰ Overall, how tremor and ataxia derive from a dysfunctional cerebellum and how these two symptoms interact in the context of cerebellar degeneration remain of high interest in the field.^171,172

When sensorineural hearing loss is seen in cerebellar ataxia, superficial siderosis (SS) should be on the differential diagnoses. As a rare neurological disorder, SS can be idiopathic, iatrogenic, or from a variety of vascular factors such as subarachnoid hemorrhage or arteriovenous malformation. It is usually slowly progressive and can result in dementia. MRI is a necessary diagnostic tool to display rim hemosiderin deposition in the subpial space of the brain and spinal cord on gradient recalled echo or susceptibility-weighted images. Deferiprone is the chelation therapy in addition to surgical repair of bleeding sources.^173–175 An ATP1A3-related disorder, the cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome should be a top consideration in pediatric patients with a dominant family history of relapsing ataxia and hearing loss.^176–178 Cerebellar ataxia can also be a postradiotherapy complication. This was described in lung cancer patients who received whole brain radiation therapy^179,180 whose FDG-PET (fluorodeoxyglucose-positron emission tomography) showed profound hypometabolism of the cerebellum while structural MRI did not reveal any remarkable abnormality.¹⁸⁰

Ataxia is also associated with developmental structural abnormalities. The most common disorder in this category is Chiari malformation. Chiari malformation type 1 is a condition associated with cerebellar atrophy and adult-onset ataxia.¹⁸¹ The compressive effect of the downward shifted brain tissues on the vasculature or inferior olivary nucleus has been proposed as the cause of cerebellar degeneration Surgical decompression of the posterior fossa is the standard treatment. Chiari malformation type 2 is accompanied by spinal bifida and myelomeningocele. The ataxia seen in Chari type 2 typically starts from infancy, together with other symptoms such as headache from hydrocephalus. Chiari malformation type 3 is extremely rare and usually life-threatening in infancy.

Genetic Causes for Ataxia

Genetic Approaches for Cerebellar Ataxias

Genetic mutations are common causes of ataxia, and should be considered in patients with young onset of ataxia symptoms and when there is one or more affected family members with ataxia, peripheral neuropathy, or parkinsonism. One should also keep in mind that a lack of family history of ataxia does not preclude the possibility of genetic ataxias. Specifically, autosomal recessive cerebellar ataxias (ARCAs) or autosomal dominant cerebellar ataxias (ADCAs) of de novo mutations or expanded repeats are inherited from parents who are carriers or intermediate repeat expansions.¹⁸²

The first step to the approach for genetic ataxias is to test for genetic mutations associated with repeat expansions. Interestingly, the most common causes of ADCA, ARCA, and X-linked cerebellar ataxias are all due to pathological expansions of naturally occurring repeats in the respective genes.^1,7 These repeat expansions either exist in the coding region that leads to toxic gain of function of the abnormal protein being produced or in the noncoding region that causes epigenetic changes resulting in abnormal RNA expression. These expanded repeats are not readily detectable by whole exome or whole genome sequencing technologies. Therefore, unless the patient’s clinical presentation points to a specific genetic form of cerebellar ataxia, a panel of repeat expansion mutations should be considered first. If the repeat expansion-related causes of cerebellar ataxias are excluded, whole exome sequencing or whole genome sequencing should be the next step, which is effective in detecting sequence alterations. Other considerations include structural genomic mutations such as large deletions, inversions, duplications, and translocations, which may not be readily captured by whole exome sequencing. In these cases, chromosomal microarray analysis thus can be implemented. Finally, mitochondrial DNA mutations may not be captured in blood, and muscle biopsy thus is warranted.

Autosomal Dominant Cerebellar Ataxias

Most ADCAs are designated as SCAs, except for dentatorubral-pallidoluysian atrophy (DRPLA). SCAs are often adult-onset, progressive neurodegenerative disorders affecting the cerebellum and its afferent and efferent pathways. SCAs are numbered in the order of discovery, and the number of described SCAs has recently reached 49.¹⁸³ SCAs are rare disorders, and the estimated prevalence of SCAs is 1.0 to 5.6 in 100,000.^184–186 Among all subtypes of SCAs, SCA1, SCA2, SCA3, SCA6, SCA7, and SCA8 are most common in the United States and Europe, while the prevalence of SCA subtypes can vary widely in different geographic regions throughout the world,¹⁸⁷ reflecting founder effects.

CAG repeat expansions, which encode poly-glutamine peptide (PolyQ), are the most common genetic mutations for SCAs. This group includes SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and DRPLA.^188–190 In these CAG repeat expansion disorders, the age of onset is inversely correlated with the size of repeat expansions.¹⁸⁶ SCA8 is caused by the CTG repeat expansion in the 3′-untranslated region of the ATXN8OS gene and is one of the few SCAs with incomplete penetrance. SCA10, SCA12, SCA31, SCA36, and SCA37 are also caused by repeat expansions. Other types of genetic mutations of SCAs are point mutations (SCA13), deletions (SCA15/16), translocations (SCA27), and duplications (SCA20).^191,192

The term “anticipation” means progressively earlier onset of the disease in successive generations with increasing severity of the disease within a family, which correlates with intergenerational increase of the number of CAG repeats in PolyQ SCAs.¹⁹³ Anticipation is especially prominent in SCA7 patients, leading to infantile or pediatric onset with complex neurological symptoms, including impaired vision.¹⁹⁴

The most common initial clinical presentation for SCAs is gait difficulty, while some patients can have speech or hand dexterity problems as the first symptoms.¹⁹⁵ Cerebellar ataxia is the key clinical symptom in all SCAs, but each SCA can have its unique, additional features (►Table 3). SCA1 patients have early dysarthria and dysphagia.¹⁹⁶ SCA2 patients usually have slow saccades, hyporeflexia, truncal titubation, and postural and rest tremor.^171,172 SCA3 patients often have dystonia, depression, restless leg syndrome, and levodopa-responsive parkinsonism.^197,198 SCA6 patients are classically considered “pure ataxia” without extra-cerebellar symptoms, and SCA7 patients invariably have vision loss due to macular degeneration. SCA17 patients have complex symptoms, including dementia, chorea, and dystonia. Sometimes SCA patients can initially present with extra-cerebellar symptoms, such as parkinsonism, before developing cerebellar ataxia^199–201; therefore, a detailed family history of ataxia is helpful to raise clinical suspicion of an SCA.

Table 3.

Predominant clinical features and characteristics in cerebellar ataxia of autosomal dominant inheritance

Type	Gene	Predominant or characteristic clinical features	Note
SCA1	ATXN1	Pyramidal signs	Onset: 3rd or 4th decade
SCA2	ATXN2	Early ophthalmoparesis and slow saccade; pronounced truncal sway and proximal limb tremor	Onset: 4th decade; life span is shortened: between 10 and 15 years after onset.
SCA3	ATXN3	Extrapyramidal signs/parkinsonism; restless leg syndrome	Onset: highly variable between 2nd to 5th decade.
SCA6	CACNA1A	Pure cerebellar ataxia; may be very late onset without family history	Onset: 4th to 5th decade; mentation is generally not affected.
SCA7	ATXN7	Vision loss, especially early in adolescent onset	Due to macular pigmentary retinal degeneration
SCA8	ATXN8 and ATXN8OS	Pyramidal and extrapyramidal signs; slowly progressive
SCA10	ATXN10	Epilepsy/recurrent generalized or complex partial seizures
SCA12	PPP2R2B	Early tremor followed by dementia
SCA17	TBP	Early dementia and neuropsychiatric symptoms (<50 years old); combined with chorea and dystonia	Cognitive and behavioral symptoms can be the initial manifestation
SCA23	PDYN	Sensory loss in distal limbs
SCA26	EEF2	Pure cerebellar ataxia
SCA28	AFG3L2	Early ophthalmoparesis, eyelid ptosis
SCA34	ELOVL4	Papulosquamous erythematous skin lesions
SCA38	ELOVL5	Pure cerebellar ataxia
SCA40	CCDC88	Pyramidal signs
SCA46	PLD3	Lower limb sensory ataxia in addition to cerebellar ataxia
SCA47	PUM1	Early intellectual disability, epilepsy
DRPLA	ATN1	Dementia, chorea, seizures

Abbreviations: GI, gastrointestinal; SCA, spinocerebellar ataxia.

The natural history of SCAs has been well studied, both in Europe and in the United States, with defined rates of progression. Among the four most common types of SCAs, SCA1 progresses the fastest, followed by SCA2 and SCA3. SCA6 progresses the slowest.^202–204 Not only can pathological CAG repeat length determine the rate of disease progression, but ethnic background and educational levels appear to play important roles.^205,206

Besides SCAs, primary episodic ataxias are another group of ADCAs, leading to recurring ataxic episodes with some patients developing progressive ataxia. The core symptoms are recurrent, brief episode of dizziness and gait unsteadiness, accompanied by other associated features (listed below). Episodic ataxias are mostly caused by mutations in genes that encode ion channels, including KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4,²⁰⁷ resulting in neuronal firing abnormalities in the cerebellum.²⁰⁸ Missense mutations in KCNA1 have been identified in episodic ataxia type 1 (EA1) which causes the dysfunction of potassium channels. Symptoms onset is usually in early childhood or adolescence (<20 years old). The attacks of gait unsteadiness and dizziness can be precipitated by sudden movements or emotional stress and can be up to multiple times a day. The interictal myokymia is another core feature of EA1, which can be confirmed by electromyography.²⁰⁹ EA2 is the most common type of primary episodic ataxia and the responsible gene is CACNA1A, affecting the P/Q-type calcium channel function.²¹⁰ Affected individuals, in addition to recurrent ataxia, can have the following characteristic feature: familial hemiplegic migraine and interictal gaze-evoked or/and down-beating nystagmus.²¹¹ Similar to EA1, the onset of EA2 usually started from childhood or adolescence, but cases with late adulthood onset (>60 years old) were reported.²¹² Of note, lack of a family history did not exclude the possibility of EA diagnosis,²¹³ and the associated migraine does not need to be hemiplegic.²¹⁴ Clinicians can consider carbamazepine, valproic acid, and acetazolamide in EA1, as well as 4-aminopyridine and acetazolamide in EA2 to decrease the frequency and severity of the spells.^215,216

Autosomal Recessive Cerebellar Ataxias

ARCAs are often early onset, with symptoms starting at childhood, adolescence, or early adulthood and frequently accompanied by other neurological and systemic manifestations.^217–219 Peripheral neuropathy is the most common comorbid neurological sign in ARCAs. An algorithm has been recently developed when considering the diagnosis of ARCAs.²²⁰ Different from SCAs, the nomenclature of ARCAs is not assigned with numbers. Instead, each ARCA has its own unique name. Because of the complex nomenclature of ARCAs, a new set of nomenclature was recently proposed.²²¹

The most common of the ARCAs is Friedreich’s ataxia (FA), which is characterized by vibratory sensation loss, hyporeflexia, scoliosis, pes cavus, diabetes, and cardiomyopathy.^222,223 The majority of FA patients have two alleles of large GAA repeat expansions in intron 1 of the FXN gene, whereas some patients have a compound heterozygous mutation, with a GAA expansion in one allele of the FXN gene and a point mutation in the other. The age of symptom onset is inversely correlated with the shorter expanded allele of FXN gene.²²⁴ These genetic mutations cause insufficient production of frataxin, a key protein for mitochondrial iron homeostasis.^225,226 The consequences of mitochondrial dysfunction eventually lead to neurodegeneration in the dorsal root ganglia and cerebellar dentate nuclei, along with cardiomyopathy.^227–229 The age of onset of FA often falls between 10 and 16 years of age, but FA can also present in adulthood.²³⁰ The natural history of FA has been well studied, with biomarker identification and vibrant therapeutic programs being developed.^223,231

Another unique ARCA with a distinctive clinical presentation is cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, the genetic mutation of CANVAS has been identified, which is the homozygous biallelic intronic AAGGG repeat expansion in the RFC1 gene.²³² Not only is this genetic mutation associated with CANVAS, it is also associated with chronic cough and sensory neuropathy with or without cerebellar ataxia, which are considered part of the broader spectrum of RFC1-related disorders.^233,234 Since cerebellar ataxia in CANVAS often develops in older age, the symptoms can mimic MSA-C.^134,234

POLG ataxia is ARCA caused by the mutation in the DNA polymerase subunit g-1 (POLG) gene, causing cerebellar ataxia and neuropathy. The most common presentation of POLG ataxia is SANDO syndrome, characterized by sensory ataxia neuropathy, dysarthria, and ophthalmoplegia. Patients with POLG ataxia often develop myoclonus and seizures. Since POLG mutations cause mitochondrial dysfunction, muscle biopsy in these patients shows mitochondrial proliferation.^235,236

Three ARCAs are commonly associated with oculomotor apraxia: ataxia telangiectasia (A-T), ataxia with oculomotor apraxia type 1, 2, and 4 (AOA1, AOA2, and AOA4). A-T is caused by mutation in ATM gene, which encodes a protein important for DNA repair. A-T patients have early onset ataxia, choreoathetosis, telangiectasia, myoclonus, and dystonia. In addition, sensitivity to ionizing radiation, immune compromise with recurrent infection, and an increase in the incidence of hematological malignancies are hallmarks of A-T.²³⁷ We discussed that cerebellar ataxia can be a complication of postradiation therapy in the above section. Of note, A-T patients are prone to have heightened radiosensitivity to ionized radiation, including gamma- and X-rays.²³⁸ Byrd et al reported a newly identified milder form of A-T case who developed a serious, unexpected adverse tissue reaction to radiation despite absence of preceding neurological symptoms.²³⁹ For A-T patients who are in need of radiation therapy, alternative therapies or radiation dose reduction should be considered to minimize injury.²⁴⁰ AOA1 and AOA2 share many clinical presentations with A-T, but there is a lack of telangiectasia and systemic features. AOA1, AOA2, and AOA4 are caused by the mutations in the APTX gene, the SETX gene, and the PNKP gene, respectively.^241,242 In addition to cerebellar ataxia, AOA1 patients exhibit dysarthria and mild intention tremor,²⁴³ AOA2 patients have axonal sensorimotor neuropathy,²⁴⁴ and AOA4 patients have combined dystonia, chorea, and seizures.^241,242 Nie-mann–Pick type C (NPC) is another ARCA with ataxia that gradually develops after late infantile stage.²⁴⁵ Vertical saccade paresis is a very characteristic feature of NPC, which can serve as an important diagnostic clue in the context of cerebellar ataxia.^245,246

Another group of ARCAs less often recognized is those associated with myoclonus and epilepsy,²⁴⁷ which are categorized as myoclonic epilepsy syndromes. These patients often have childhood-onset neurological symptoms and have predominant symptoms of ataxia, myoclonus, epilepsy, dementia, or a combination of these symptoms.

X-Linked Cerebellar Ataxia

FXTAS is the most common X-linked ataxia.²⁴⁸ FXTAS is caused by CGG triplets in the premutation range (55–200 CGG repeats) in the FMR1 gene. Note that a “full” mutation with CGG repeats above 200 is associated with Fragile X syndrome, one of the most common causes of inherited intellectual disability and autistic spectrum disorders. FXTAS, a late-onset ataxic disorder, often has additional features of tremor, including postural, action, rest, and intention tremor in the hands. Parkinsonism and cognitive impairments are common in FXTAS.²⁴⁹ Women with pre-mutations of FMR1 can also develop FXTAS but may show Fragile X-associated primary ovarian insufficiency.²⁴⁹ MRI brain of FXTAS patients often shows characteristically T2 hyperintensities in the middle cerebellar peduncles or corpus callosum.^250,251

Mitochondrial Cerebellar Ataxias

Cerebellar ataxia can be the result of mitochondrial DNA mutations, which will have characteristic maternal inheritance. Common disorders in this category are Kearns–Sayre syndrome, myoclonus epilepsy with ragged-red fibers, and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Epilepsy is very common, and myopathy, dementia, and myoclonus often occur in these disorders. Muscle biopsy is needed to assess mitochondrial cerebellar ataxia because mitochondrial defects are more likely to be detected in the nondividing cells such as in muscle.

Conclusion

This review covers the common diagnostic approach and considerations for cerebellar ataxias. The current and emerging therapies for cerebellar ataxia are another important topic and were recently reviewed.⁷ With a step-by-step approach, clinicians should be able to first recognize ataxia phenomenology, followed by identification of reversible and genetic investigations to pin down potential etiologies. As more genetic causes of ataxia have been identified, future precision medicine therapies may be on the horizon for certain cerebellar ataxias.