Ataxia …

Robert Fekete MD

Movement Disorders

Updated 12.27.2023
Released 12.01.1999
Expires For CME 12.27.2026

Ataxia

Author: Robert Fekete MD

See Contributor Disclosures

Ataxia

In This Article

Quick Link

Introduction

Overview

The author discusses the concept of ataxia, identifies clinical features useful in evaluating patients with ataxia, and highlights the broad range of disorders that can present with ataxia as a prominent feature. He presents the differential diagnosis, treatment, and management of ataxic conditions, along with the latest information about the most recently discovered forms of hereditary ataxia.

Historical note and terminology

Ataxia is both a neurologic symptom and a sign of incoordination derived from the Greek verb tassein, meaning “to arrange” or “put in order.” Ataxic movements are poorly organized and usually relate to dysfunction of the cerebellum or its numerous connections with other brain regions (43). The Greek physician Herophilus recognized the cerebellum as a distinct brain division, but early studies of cerebellar anatomy and function were not performed until the 17th and 18th centuries (29). The first extensive clinical studies that defined cerebellar syndromes included World War I soldiers who received gunshot wounds to the head (56). Comparative studies between human and animal cerebelli helped define the function of the various cerebellar regions.

Many classification schemes have been developed for hereditary and degenerative disorders that share ataxia as a prominent presenting feature (134). Numerous new genes and their protein products have been identified since the early 2000s, and they should lead to a greater understanding of the pathophysiology and treatments for these diseases in the years ahead.

The term “olivopontocerebellar atrophy” is widely used without clear consensus on specific diagnostic or prognostic implications (10). Many cerebellar disorders were originally classified using clinical features, such as "olivopontocerebellar ataxias, types I to V," or pathological descriptions such as "spinopontine atrophy" or "cortical cerebellar degeneration" (74). These previous classification schemes built on clinical and pathological findings are being replaced by genetic classification based on identification of responsible gene mutations.

Although spasticity can be seen in several types of spinocerebellar ataxias (see Table 1), the term “spastic ataxia” is also occasionally used for the combination of spasticity and ataxia (23). The best known example of Charlevoix-Saguenay ataxia is inherited by autosomal recessive transmission due to sacsin gene (SACS/ARSACS) mutations (35). The first locus for autosomal dominant hereditary spastic ataxia (SAX1) has also been mapped (86). A case of atypical ARSACS in a Japanese patient with ataxia and polyneuropathy but no spasticity has been reported due to a novel compound mutation (p.Lys4326Glu and p.Leu1412Lysfs*16) in the SACS gene (01).

Clinical manifestations

Presentation and course

Ataxia is both a neurologic symptom and a sign seen only in association with movement or with an attempt to maintain position against a deflecting force such as gravity. Limb and gait ataxia are both common, but incoordination can also affect speech articulation, swallowing, vision, and truncal movements. Like all movement disorders, ataxia can be described in terms of its location, amplitude, frequency (severity), modifying factors, course over time, and associated neurologic and non-neurologic symptoms. The differential diagnosis of ataxia includes a large number of neurologic disorders, so efficient evaluation requires a careful history and a thorough physical and neurologic examination to place ataxia in its appropriate context. Various rating scales such as the Scale for Assessment and Rating of Ataxia (SARA), the Ataxia Functional Composite Scale (AFCS), and the International Cooperative Ataxia Rating Scale (ICARS) have been developed as sensitive instruments to assess ataxia-related disability reproducibly (05; 146).

Critical features that should be sought out in the patient’s history include age, gender, mode of onset (sudden, gradual, or chronic), lateral distribution (unilateral vs. bilateral), location (eyes, bulbar, limbs, or trunk), and progression (episodic, stable, or progressive). Specific symptoms that people with ataxia may develop include an unstable stance (much like when standing on a ship or boat), increased body sway, side-to-side truncal movements, blurred or bouncing vision (oscillopsia) due to abnormal eye movements, a need for back support when sitting, and widening of stance when standing or walking. The wide range of ataxic etiologies requires a full review of additional neurologic symptoms, including confusion, memory loss, headache, personality changes, seizures or convulsions, double vision, vision loss, weakness, numbness, tingling, itching, hiccups, seizures, hearing loss, tinnitus, voice changes, and word-finding difficulty. Complaints of dizziness should be carefully distinguished among lightheadedness or faintness, rotational vertigo ("room spinning"), rocking movements, and the sense of imbalance described above. The presence of any systemic illness should be noted, but especially diabetes mellitus, known malignancy, human immunodeficiency virus (HIV), cystic fibrosis, and biliary disease. Special inquiries should also be made for autoimmune diseases such as systemic lupus erythematosus, Sjögren syndrome, autoimmune hepatitis, Hashimoto thyroiditis, Graves disease, and celiac disease. Specific physical symptoms to inquire about include significant weight change, gastrointestinal symptoms, frequent infections, jaundice, and other skin changes. Previous trauma, known episodes of illness, prior or current use of medications (especially those that exert effects on the nervous system), and exposure to CNS toxins are all important considerations.

The age of onset can readily shorten a long list of causes. Ataxia of childhood onset is more likely to include congenital, infectious, or metabolic causes and posterior fossa tumors. Adult-onset ataxia during the 20s, 30s, and 40s is more frequently due to demyelinating disease such as multiple sclerosis or sporadic or hereditary ataxias. Ataxia in adults over the age of 50 may indicate ischemic or hemorrhagic stroke or posterior fossa or parietal lobe lesions, but sporadic or hereditary ataxias are also common.

An acute time course of hours to days is suggestive of vascular, traumatic, toxic, or metabolic causes of ataxia. Subacute ataxia presenting over weeks to months often indicates inflammatory, infectious, or paraneoplastic causes of gradual onset and progression. Chronic ataxia over months to years is most frequently genetic, paraneoplastic, or neurodegenerative, although there is often considerable overlap with subacute causes.

A comprehensive physical examination should specifically include orthostatic blood pressure measurements as evidence of autonomic dysfunction. Thyroid assessment should make note of pale or sallow appearance, puffiness or edema of the face, proptosis or lid lag of the eyes, hoarseness of voice, and brittle fingernails and hair in addition to palpable enlargement of the thyroid gland. Abnormalities of cardiac, musculoskeletal (including scoliosis, pes cavus, and hammertoes), and dermatologic examination should all be duly noted. Funduscopic examination should elicit specific evidence of pigmented retinopathy, macular degeneration, optic atrophy, retinal angiomata or telangiectasias, and cataracts. Formal ophthalmologic testing for Kayser-Fleischer rings is indicated in ataxic patients with undiagnosed liver disease, psychosis, tremor, dystonia, or dysphagia.

Neurologic examination should focus on several key features related to cerebellar and sensory dysfunction, including bulbar dysfunction, dysdiadochokinesia, dysmetria, excessive rebound, postural and kinetic limb tremor, rubral tremor, truncal titubation, nystagmus, impaired visual fixation, and gait disturbance.

Bulbar dysfunction includes both dysphagia (impaired coordination of swallowing) and dysarthria (impaired articulation of vocalized speech). Although the term "bulb" refers to the medulla oblongata, dysarthria and dysphagia are poorly localized in the brain, so numerous isolated lesions could result in these disturbances. Pronunciation of the phonemes "T" (primarily lingual), "P" (primarily labial), and "K" (primarily pharyngeal) can distinguish between these broad categories of dysarthria: ta-ta-ta, pa-pa-pa, and ka-ka-ka.

Dysdiadochokinesia refers to impaired coordination or breakdown of alternating movements. Rapid alternation is more likely to identify these breaking points than slower, careful execution of movements. Each upper limb can be tested individually by rapid repetitive pronation and supination of either hand. Each lower limb can be tested individually by rapid repetitive tapping of the heel and then the toes of either foot. Dysdiadochokinesia of articulation involves impaired alternation between distinct syllables even if syllables could individually be articulated effectively. For example, repetition of the phrase "Topeka, Topeka, Topeka" involves alternation between the different phonemes "T", “P,” and "K" described above. The phrase "scanning speech" is another way to describe the noticeable pauses between articulations of distinct syllables.

“Dysmetria” is a broadly used term indicating the inability to judge appropriate distance or measurement. Finger-nose-finger or finger-chin-finger maneuvers (with the eyes open) and finger-to-nose, finger-to-chin, and past-pointing maneuvers (with the eyes closed) are simple clinical assessments of limb overshoot or undershoot. Kinetic tremor involves rhythmic contraction of reciprocally innervated agonist and antagonist muscles noted with continuous movement of an affected body part. Kinetic tremor has a sinusoidal appearance and tends to increase in amplitude as the target is approached. Thus, some authors use the term “dysmetria” to imply inaccuracy (the movement ends off target due to measurement error), whereas kinetic tremor can imply imprecision (the process of movement demonstrates overshoot and undershoot). Rubral or midbrain tremor is a coarse, slow tremor seen at rest, with postural change or with limb movement in patients with disruption of connections to and from the red nucleus in the midbrain, including cerebellar connections.

Excessive rebound is tested by instructing a patient to extend the arms in front and not allowing the examiner to bear down force on the arms. If either or both arms disproportionately elevate in rebound, this "loss of check" implies hypermetria due to difficulty alternating from arm extensor activity to contraction of arm flexor muscles. Similarly, routine strength testing of elbow flexors in patients should involve placement of the examiner's other hand between the patient's arm and the patient's face to prevent excessive rebound resulting in punching the patient's own face.

Examination of eye coordination in cooperative patients includes observation of nystagmus, testing of impaired fixation, eliciting saccades, and identifying smooth pursuit abnormalities. The patient should be asked to fixate on the examiner's nose. Square-wave jerks are inappropriate horizontal saccades whereby the eye leaves the target and then a corrective saccade returns the eye to the target. Voluntary or volitional saccades involve alternating between the examiner's finger or pen on command (held at least 15 degrees laterally from the nose) and then back to the examiner's nose on command. These measurements of ocular dysmetria should be tested in all four cardinal directions. Hypermetric saccades describe overshoot of eye movements whereas hypometric saccades describe eye movements that fall short of the target. Saccadic intrusions that interrupt smooth pursuit movements can also be a nonspecific sign of brainstem or cerebellar disease. Some patients can also demonstrate apraxia of eye movements with difficulty initiating gaze toward one or more of the four cardinal directions on command ("look to the left...now the right").

Truncal titubation refers to sway of an unsupported sitting or standing trunk. Gait disturbance can include a widened stance to compensate for impaired balance, ataxic lurching toward one or both sides, and difficulty performing tandem gait (one foot placed in front of the other without assistance). The Fisher maneuver involves rapid tapping of the index finger to the interphalangeal joint of the ipsilateral thumb, and dysmetria indicates cerebellar pathology. The Romberg maneuver involves narrowing the stance such that one’s legs and feet are touching, if possible. Inability to perform this maneuver with the eyes open is suggestive of cerebellar disease. If balance is maintained successfully, then the maneuver may be "sharpened" by closing the eyes, thereby removing visual input. Subjective sensations of sway should be noted along with objective loss of balance, either of which suggests sensory ataxia from dorsal column or sensory nerve dysfunction. Extension of the arms with supinated hands during this maneuver can help identify "pronator drift" of the upper limb as subtle evidence of upper motor neuron weakness. Because Friedreich ataxia and ataxia with vitamin E deficiency involve degeneration of both the cerebellum and dorsal spinal cord, these disorders may still demonstrate the presence of Romberg sign. Associated neurologic signs and symptoms should be identified, including headache, dystonia, parkinsonism, spasticity, neuropathy, and autonomic dysfunction.

Limb hypotonia and pendular reflexes may be due to cerebellar lesions, particularly when one hemisphere is affected, leading to asymmetric ipsilateral findings. Focal cerebellar lesions can be difficult to separate from associated brainstem lesions and may present with headache, vomiting, blurry vision, double vision, vertigo, lightheadedness, hearing loss, tinnitus, or other cranial nerve abnormalities. Recognition of brainstem or other neurologic symptoms seen in association with ataxia or cerebellar symptoms is crucial due to the risk of acute brainstem compression or transtentorial herniation.

The family history should be reviewed extensively as many patients have undiagnosed blood relatives. Relatives from at least three generations should be evaluated whenever possible. Specific questions should be asked regarding the possibility of consanguinity. Because certain hereditary ataxias have been more commonly described in certain ethnic groups, discussion of ancestry can be useful if one’s heritage is known. Genetic penetrance and variability in clinical manifestation of these diseases among family members can also make it difficult to suspect a similar pathophysiologic process. The existence of a similarly affected parent suggests a dominantly inherited disease, whereas multiple affected siblings without an affected parent would be more typical of a recessively inherited disorder. The presence of multiple affected males in a family related through clinically unaffected or minimally affected females is the hallmark of X-linked inheritance. These disorders can include fragile X-tremor ataxia syndrome (FXTAS) and adrenoleukodystrophy. Family history inquiries should also include questions about autoimmune disease because these disorders may cluster due to underlying immune-mediated dysfunction. Many patients are not familiar with examples of autoimmune disease, so specific disorders such as lupus, Hashimoto thyroiditis, Graves disease, rheumatoid arthritis, Sjögren syndrome, or other specific conditions should be mentioned by name when appropriate. Paraneoplastic ataxia, as well as nonneoplastic autoimmune ataxia, may be a consequence of antiglutamic acid decarboxylase and anti-contactin-associated protein 2 (CASPR2) antibodies (09; 65). Metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in two patients with paraneoplastic ataxia was reported by Ruiz-Garcia and colleagues (114). One of these cases had full resolution with intravenous methylprednisolone and immunoglobulin. Table 1 provides an outline of hereditary ataxias.

Although sporadic versions of most degenerative ataxias exist, the absence of a family history does not entirely exclude the possibility of hereditary disease. As is commonly seen in genetic disorders, some patients are unaware of their true birth status (adoption or nonpaternity may not have been explained), a parent may have died young prior to developing symptoms, or an affected parent may simply be unaware or in denial of symptoms. Recessive disorders typically appear de novo; a hereditary disorder is not often suspected until a second family member develops a similar disease. Even sporadic cases of ataxia do not exclude the possibility of autosomal dominant inheritance. A child of asymptomatic parents may also develop symptoms before the parents due to the phenomenon of genetic anticipation. If the family history is positive, examination of several affected family members can allow the clinician to develop a "family phenotype," which is often broader than the phenotype of a particular individual at a single point in time.

Table 1. Key Clinical Aspects of the Dominant Ataxias

	U.S. frequency	Age of onset (years)	Duration	Distinguishing features
SCA-1	5%-10%	30-40	10-20 years	neuropathy, pyramidal signs
SCA-2	15%	20-40	5-30 years	slow saccades, paucity of gaze-evoked nystagmus and dysmetric saccades, neuropathy, dementia
SCA-3	15%-25%	30-40	10-15 years	pyramidal signs, parkinsonism, muscle atrophy, neuropathy, saccadic intrusions
SCA-4/31	rare	30-50	normal lifespan	sensory axonal neuropathy (pure ataxia in one family)
SCA-5	rare	variable	several decades	early onset, pure cerebellar, slow course
SCA-6	15%	variable	several decades	pure cerebellar ataxia, sometimes episodic, mild neuropathy, prominent nystagmus with downbeat nystagmus induced by head shaking
SCA-7	5%	20-40	1-40 years	pigmentary retinopathy, blindness, hearing loss
SCA-8	2%-5%	20-40	normal lifespan	dysarthria, mild neuropathy, pyramidal signs, late-onset spasticity
SCA-9	--	--	--	--
SCA-10	rare	36	9 years	seizures
SCA-11	rare	20-30	normal lifespan	pure cerebellar, hyperreflexia, slow course
SCA-12	rare	20-30	?	tremor, hyperreflexia, dementia late in course
SCA-13	rare	childhood	normal lifespan	mental retardation, pyramidal signs
SCA-14	rare	10-40	?	axial myoclonus, cognitive decline (pure ataxia in some families)
SCA-15	rare	10-50	?	pure cerebellar ataxia, one report of hydrocephalus
SCA-16	--	20-66	?	head tremor
SCA-17	rare	10-70	?	tremor, parkinsonism, dystonia, chorea, atypical absence and generalized seizures, dysphagia, early dementia, mutism
SCA-18	rare	10-20	normal lifespan	neuropathy, muscle atrophy, sensory loss followed by cerebellar ataxia
SCA-19	?	20-45	probably normal lifespan	mild ataxia, cognitive impairment, myoclonus, postural tremor
SCA-20	rare	19-64	?	palatal tremor, dysphonia, dentate calcification
SCA-21	?	6-30	probably normal lifespan	hyporeflexia, cognitive impairment, rigidity, postural tremor
SCA-22	?	10-46	probably normal lifespan	pure cerebellar, hyporeflexia, slow progression
SCA-23	?	43-56	probably normal lifespan	sensory loss, pyramidal signs, hyporeflexia
SCA-24	?	20-30	probably normal lifespan	pyramidal, myoclonus, horizontal macrosaccadic oscillations, possibly autosomal recessive
SCA-25	?	1-39	?	sensory neuropathy, severe cerebellar atrophy
SCA-26	?	26-60	?	pure cerebellar
SCA-27A	probably rare	20-40	probably normal lifespan	tremor, dyskinesia, psychosis, different FGF14 mutation from SCA-27B
SCA-27B	most common late onset ataxia	50-60	probably normal life span	pure cerebellar, usually with omnidirectional downbeat nystagmus, sensory deficits (55%), dysautonomia (28%)
SCA-28	3% of all SCA patients	12-36	?	ophthalmoparesis, hyperreflexia, nystagmus, late-onset ptosis
SCA-29	rare	?	?	tremor, myoclonus
SCA-30	rare	mid to late life	slow	dysarthria, hypermetric saccades, brisk leg reflexes
SCA-31	Rare but 3rd most common ADCA in Japan	59	Slow	Cerebellar syndrome, but 51% of Saucier and colleagues’ case series have deafness, sensory loss, and dysautonomia (116)
SCA-35	rare	40-48	5-31 years	dysarthria prominent, may have cervical dystonia
SCA-36	rare, but most frequent in Galicia, Spain	adult onset	slow	hearing loss, ataxic gait more prominent than limb ataxia, dysarthria, slow saccades, tongue fasciculations
Dentato-rubropallidoluysian atrophy (DRPLA)	rare in U.S. (20% in Japan)	0-70	10-20 years	chorea, seizures, dementia, myoclonus
Episodic ataxia-1	rare	2-15	several decades	myokymia, exercise-induced attacks lasting seconds to minutes
Episodic ataxia-2	rare	3-50	several decades	nystagmus, vertigo, late-onset ataxia, attacks lasting minutes to hours
Episodic ataxia-3	1 family	1-42	?	vertigo, tinnitus, attacks last minutes to hours
Episodic ataxia-4	rare	?	?	nystagmus, vertigo, late-onset ataxia
Episodic ataxia-5	1 family	3-40		nystagmus, vertigo, late-onset ataxia, attacks lasting minutes to hours
Episodic ataxia-6	1 family	6	?	seizures, migraine, alternating hemiplegia
Episodic ataxia-7	1 family	1-20	?	dysarthria, fatigue, attacks lasting hours to days
Episodic ataxia with paroxysmal choreoathetosis	rare	2-15	?	limb dystonia, paresthesias, headache, spastic paraplegia
Gerstmann-Sträussler-Scheinker syndrome (GSS)	rare	38-70 years	?	truncal ataxia, areflexia, lower extremity sensory loss, dementia
Ataxia-telangiectasia like disorder (ATLD)	rare	4	?	later onset and milder than ataxia telangiectasia, typically normal total serum immunoglobulin levels, no telangiectasia
Ataxia due to Coenzyme-Q10 deficiency	rare	early childhood or late onset	?	lipid accumulation on muscle biopsy, dystonia, migraine, tremor, and spasticity
ARSACS (Charlevoix-Saguenay)	rare, associated with Quebec	early childhood, late onset form possible	slow	pyramidal tract signs and peripheral neuropathy
HSP7	2-6/100,000	typically 3rd or 4th decade	slow	spastic ataxia with dysarthria, nystagmus
Adult onset Alexander disease	rare	onset at 12-71 years	slow	spastic ataxia, palatal tremor; on imaging, white matter changes, medulla and upper spinal cord atrophy without cerebellar atrophy
Paroxysmal kinesigenic dyskinesia	rare	21 year old	Probably normal	Episodic ataxia due to C.649dupC pRRT2 mutation

Spinocerebellar ataxia types 1, 2, and 3 are the most common of the complicated ataxias (those with prominent neurologic symptoms in addition to ataxia). Slowed saccadic eye movements are a hallmark of spinocerebellar ataxia type 2 (139). Spinocerebellar ataxia type 3, also known as Machado-Joseph disease, presents the widest range of symptoms with earlier-onset patients showing prominent spasticity along with ataxia, and patients with older ages of onset sometimes showing prominent parkinsonian features (31). Several review articles characterize the clinical, genetic, and pathologic features of the most common forms of spinocerebellar ataxia (75; 94; 110; 72; 44). SCA3 manifests square-wave jerks and ocular flutter on fixation. Saccadic intrusions appear to be most suggestive for SCA3. Downbeat nystagmus induced by head shaking maneuver is associated with SCA6. SCA2 has a paucity of gaze-evoked nystagmus and dysmetric saccades (68). “Bulging eyes” have been reported more frequently in SCA3 as opposed to SCA1, SCA2, SCA6, and SCA7 (90).

Some hereditary ataxias present with pure cerebellar ataxia, including spinocerebellar ataxia types 4, 5, 6, 10, 11, 14, 15, 16, 22, and 26. Spinocerebellar ataxia type 6 may present with much milder or later onset, sometimes with episodic ataxia at onset or prominent vestibular symptoms and nystagmus as an early finding. Unlike spinocerebellar ataxia types 1, 2, or 3, individuals with spinocerebellar ataxia type 6 tend to lack pyramidal, extrapyramidal, or bulbar symptoms, although a mild neuropathy may be observed (59). Axonal sensory polyneuropathy is also a feature noted in one family with spinocerebellar ataxia type 4. Spinocerebellar ataxia type 7 is associated with retinal degeneration and tends to follow an earlier, more rapidly progressive course than some of the other dominant ataxias.

Mild incoordination and cerebellar atrophy are present in SCA1 and SCA2 carriers prior to the development of the full clinical ataxia phenotype. In addition, gaze-evoked nystagmus is present in pre-symptomatic SCA3 carriers. Pre-symptomatic SCA2 carriers show brainstem atrophy whereas brainstem volume remains normal in SCA6 carriers (61). Based on an analysis of 462 patients with SCA1, SCA2, SCA3, or SCA6 and a median observation time of 49 months, the annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0·07) in patients with SCA2, 1.56 (0·08) in patients with SCA3, and 0.80 (0·09) in patients with SCA6. Older age at inclusion and longer repeat expansions were associated with more rapid progression of the SARA score (60).

Friedreich ataxia is the most common autosomal recessive ataxia and should be considered in sporadic individuals without family history or with only a family history seen in distant relatives. Patients typically present with limb and gait ataxia, absent reflexes due to sensory axonal neuropathy, and pyramidal signs, although spasticity and a variety of other neurologic signs have been described since the discovery of the causative gene (109).

Ataxia and other findings in Friedreich ataxia

These are two members of a family with Friedreich ataxia and dystonia. Note the ataxia, marked scoliosis (much improved with Harrington rods), high-arched feet, and dystonic writer's cramp. (Contributed by Dr. Joseph Jankovic.)...

The age of onset is most commonly before adolescence, but some patients may have preserved reflexes and present even in their 20s or 30s. It is important to consider this diagnosis in patients with an atypical presentation. Friedreich ataxia involves multiple organ systems and increases the risk for diabetes mellitus, hearing or visual loss, progressive scoliosis, and cardiomyopathy ultimately leading to fatal congestive heart failure. In addition to progressive ataxia, patients may exhibit a variety of hyperkinetic movement disorders, such as kinetic tremor, dystonia, and chorea (58). Friedreich ataxia should be carefully distinguished from ataxia with oculomotor apraxia in which most children and young adults also display evidence of initial choreoathetosis, hypoalbuminemia, and abnormal lipid profiles (88).

Several physical examination findings can often be valuable in suggesting different possible disorders. The absence of these findings, however, does not exclude these disorders completely. Scoliosis is a key feature of Friedreich ataxia, ataxia with oculomotor apraxia types I and II, and Marinesco-Sjögren syndrome. Hearing loss can be found in Friedreich ataxia, Refsum disease, mitochondrial recessive ataxia syndrome, and infantile onset spinocerebellar ataxia syndrome. Cataracts may be seen in cerebrotendinous xanthomatosis and Marinesco-Sjögren syndrome. Retinitis pigmentosa is more characteristic of ataxia with vitamin E deficiency, Refsum syndrome, and abetalipoproteinemia. Optic atrophy is seen in ataxia with oculomotor apraxia (type I only) and infantile-onset spinocerebellar ataxia syndrome. Evidence of hypogonadism can be found in infantile-onset spinocerebellar ataxia syndrome and Marinesco-Sjögren syndrome. CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is in the differential diagnosis but is less likely given 1 in 1 million incidence. A key feature is ataxic encephalopathy in children after a febrile illness. This disorder is caused by ATP1A3 mutation that is different from the mutation causing alternating hemiplegia of childhood or DYT12/rapid onset dystonia parkinsonism (24; 87).

Other common genetic ataxias can be recognized by distinctive clinical features. Episodic ataxia, as the name suggests, is characterized by attacks of incoordination often related to exercise or stress and usually beginning before 20 years of age. These disorders are most commonly the result of autosomal dominant channelopathies caused by mutations in two genes, KCNA1 and CACNA1A (63). Co-occurrence of episodic ataxia type 2 and SCA6 phenotype has been described in a single family tree due to same p.D302N CACNA1A mutation (105). A case of episodic ataxia in a 21-year-old woman due to C.649dupC PRRT2 mutation was reported (78). PRRT2 is typically associated with paroxysmal kinesigenic dyskinesia. Ataxia telangiectasia is a disorder of DNA repair with autosomal recessive inheritance. Additional systemic symptoms include telangiectasias of the skin or conjunctivae, immune deficiency with recurrent infections, and increased incidence of hematologic malignancies. Although dentatorubropallidoluysian atrophy (DRPLA) is uncommon in the United States, a large African-American family located in North Carolina has a similar condition known as “Haw River syndrome.” DRPLA is more commonly seen in those of Japanese descent and affects multiple systems resulting in possible cognitive decline, seizures, myoclonus, and chorea. Seizures can be seen in patients with episodic ataxia type 6 and spinocerebellar ataxia types 10 and 17 (85).

In one study of 1500 patients with ataxia assessed over 20 years in the Sheffield Ataxia Centre, UK, 20% reported family history of ataxia (52). In the cases of sporadic ataxia, 25% were “gluten ataxia” and genetic cause was identified in 156 (13%) of sporadic cases. Other causes included alcohol abuse (12%) and cerebellar variant of multiple system atrophy (11%). Using next-generation screening, genetic mutation or variant was found in 32% of 146 patients tested; the commonest ataxia identified was episodic ataxia type 2 (EA2). A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%), and mitochondrial disease (10%). The overall diagnostic yield was 63%.

Detailed descriptions of selected disorders

Spinocerebellar ataxia type 15 (SCA15). SCA15 is associated with ITPR1 gene variants. It is known as a classic pure ataxia, but there is a single case report of a hydrocephalus phenotype that improved with ventriculoperitoneal shunting (131).

Spinocerebellar ataxia type 19 (SCA19). SCA19 has been found to be caused by a potassium channel mutation (30). More specifically, mutations involve the KCND3 gene coding for Kv4.3, which is a voltage-gated potassium channel highly expressed in the cerebellum. SCA19 is associated with mild ataxia, cognitive impairment, myoclonus, and postural tremor.

Spinocerebellar ataxia type 21 (SCA21). Spinocerebellar ataxia type 21 is an early onset ataxia associated with cognitive impairment. It has been associated with the TMEM240 transmembrane protein (25).

GAA-FGF14 ataxia/spinocerebellar ataxia 27B (SCA27B). FGF14 gene GAA repeat expansions in the first intron have been in found in six persons with late onset autosomal dominant cerebellar ataxia, and this repeat expansion was confirmed in a larger case control series (102). It produces a pure cerebellar ataxia syndrome, with afferent sensory deficits reported in 55% of patients and dysautonomia in 28% (142). Omnidirectional downbeat nystagmus is commonly seen in SCA27B and is likely due to disruption of the vestibulo-ocular reflex at the cerebellar cortex (124). There was partial improvement in downbeat nystagmus after treatment with 4-aminopyridine (142).

Spinocerebellar ataxia type 35 (SCA35). Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal dominant progressive ataxia with onset in the fourth decade of life. It was first reported in two Chinese families who had mutations in the TGM6 transglutaminase gene (141). Clinical features include onset in the fourth decade of life, disease duration of up to 31 years, prominent cerebellar dysarthria, upper motor neuron findings, cervical dystonia, early gait disturbance, and late upper extremity ataxia.

Spinocerebellar ataxia type 36 (SCA36). SCA36 is an autosomal dominant, adult onset progressive ataxia found to be caused by GGCCTG repeat expansion. It is also called Costa da Morte ataxia based on a coastal area of Galicia, Spain, where it is the most common type of genetic spinocerebellar ataxia (42). Cases were also reported from western Japan, but it is otherwise rare worldwide. The repeat expansion occurs in the NOP56 gene, whose product is a component of the 60S ribosomal subunit.

Ataxia-telangiectasia-like disorder (ATLD). ATLD has been identified to be due to MRE11 mutation. The MRE11 protein forms a part of the MRE11/RAD50/NBS1 (MRN) complex, which is involved in repairing damage from ionizing radiation (129). In contrast to ataxia telangiectasia, these patients have no telangiectasias, they have normal total serum immunoglobulin levels and normal serum alpha-fetoprotein, and they are less sensitive to damage from ionizing radiation. Onset in the first reported cases was at age 3 to 4 years with mildly ataxic gait, dysarthria during teenage years, and vertical nystagmus as well as saccadic pursuit (55).

Gerstmann-Sträussler-Scheinker syndrome (GSS). GSS is an autosomal dominant prion disease that may cause progressive ataxia. GSS caused by the Pro102Leu mutation in the PRNP gene (GSS102) manifests prominent truncal ataxia, absent reflexes, and lower extremity sensory loss as well as dementia in late stages (04). MRI findings include diffuse cerebral atrophy as well as hyperintense cortical diffusion-weighted imaging lesions consistent with prion disease.

Episodic ataxia type 1 (EA1). EA1 is an autosomal dominant disorder with brief attacks of ataxia that last seconds to minutes as well as myokymia between episodes. Sensation of imbalance preceding the attack has been reported (63). Mutations of the KCNA1 potassium channel gene, analogous to the Shaker potassium channel in drosophila, are responsible for the disease. Acetazolamide and avoidance of stress and caffeine may be useful in controlling disease manifestations (22).

Episodic ataxia type 2 (EA2). Brain-specific P/Q-type Ca2+ channel alpha 1-subunit gene, CACNL1A4, mutations causing episodic ataxia type 2 and familial hemiplegic migraine were first reported in 1996 by Ophoff and colleagues (98). Familial hemiplegic migraine involves migraine with aura that includes hemiparesis and possible cerebellar atrophy, whereas episodic ataxia type 2 consists of cerebellar atrophy and attacks of ataxia lasting over an hour with near normal neurologic function except for nystagmus between attacks. Episodic ataxia type 2 was previously called acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (138). Choi and colleagues identified SLC1A3 mutation as another genetic cause of an EA2 phenotype (19).

Episodic ataxia type 2 due to CACNA1A was reported in a Taiwanese family with an older age of onset (third and fourth decade of life) and family history absent for migraines (79). The particular mutation was c.4537G/T, p.1437R/L in exon 27 of the CACNA1A gene. The ataxia responded well to acetazolamide. Intron 19 c.3093A/G mutation leads to aberrant splicing and was found in a woman with classic acetazolamide responsive EA2 phenotype. Her father had the same mutation but was acetazolamide unresponsive (128).

Spinocerebellar ataxia type 6 (SCA6), which may have an episodic phenotype, is caused by CAG repeats in the CACNA1A gene (151).

Ataxia due to coenzyme Q10 deficiency. Horvath and colleagues describe multiple cases of ataxia secondary to mutation in CABC1/ADCK3, which codes for a kinase that modulates Coenzyme Q10 synthesis (57). These patients may have lipid accumulation on muscle biopsy, but they do not have not ragged red fibers. A childhood-onset variant of ataxia as well as milder late onset variant is possible. Spasticity, epilepsy, and exercise intolerance are present to varying degrees. Chang and colleagues recommend ubiquinone titrated from 10 mg/kg/day to 15 mg/kg/day as a 6-month treatment trial (16).

SARS-CoV-2-related acute cerebellar ataxia and myoclonus (ACAM). Individual case reports of SARS-CoV-2-related acute cerebellar ataxia and myoclonus (ACAM) have been reported (48). These cases have an excellent clinical response to intravenous steroids followed by oral steroids, immunoglobulins, or both. Opsoclonus may or may not be present.

Other rare ataxias. Cerebrotendinous xanthomatosis is a disorder of CYP27A1 gene product function, which is sterol 27 hydroxylase. Mutations lead to abnormal brain cholesterol deposits while serum cholesterol level remains normal. Treatment with chenodeoxycholic acid replacement therapy is possible (03). Childhood cataracts and Achilles tendon xanthoma can be diagnostic clues (121).

Abetalipoproteinemia, secondary to microsomal triglyceride transfer protein mutation, can be treated with alpha-tocopherol.

Sensory axonal neuropathy with dysarthria and ophthalmoplegia (SANDO), with onset between 20 and 60 years of age, is caused by POLG mutation and may lead to ataxia with dysarthria, ophthalmoplegia, and myoclonus.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) due to FA2H mutation is in the family of neurodegeneration with brain iron accumulation disorders and may have an ataxic phenotype in addition to dystonia and spasticity.

Mutation in the JNK pathway (CCDC88C) has been found to cause an autosomal dominant form of ataxia (132). A new autosomal dominant spinocerebellar ataxia with linkage to hematologic cytopenias has also been found (17).

The CANVAS syndrome consists of cerebellar ataxia, neuropathy, and vestibular areflexia. Dysautonomia has been reported in 83% of a group of 26 patients with CANVAS (145). Biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) has been identified as a cause of this syndrome. Cough, vestibular dysfunction, cerebellar involvement, and sensory neuropathy are diagnostic clues for this disorder (20). Persistent cough was seen in three out of five patients from different families, and cough preceded ataxia and neuropathy in two of them as reported by Cakar and colleagues (14).

Aconitase (ACO2) mutation has been found to cause juvenile cerebellar ataxia without retinal involvement, whereas infantile ataxia and retinal degeneration occur with a more severe phenotype (126; 08).

CWF19L1 mutation has been associated with autosomal recessive cerebellar ataxia and atrophy (96). ANO10 mutation can cause adult onset cerebellar ataxia with atrophy, coenzyme Q10 deficiency in muscle with and without ptosis, nystagmus, and spasticity with possible mild clinical improvement with coenzyme Q10 supplementation (07).

Autosomal recessive spinocerebellar ataxia 20 (SCAR20) was found to be due to mutations in the SNX14 gene and includes hearing loss, cognitive disturbance, and progressive coarsening of facial features (125).

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract) is a rare autosomal recessive disorder caused by ABHD12 mutations (130).

Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) phenotype also includes dementia, polyneuropathy, and dysautonomia. This disorder was found to be due to DNMT1 gene mutations (140).

Point mutation in noncoding RNA, RNU12, has been identified as a cause of early-onset cerebellar ataxia. This gene codes for a small nuclear RNA (snRNA), which is a spliceosome component (33).

ATP8A2 mutations may cause recessively inherited ataxia in addition to the better-known syndrome of encephalopathy, intellectual disability, severe hypotonia, chorea, and optic atrophy (49).

RNA polymerase POLR1C mutations can cause young onset ataxia and leukodystrophy with myopia, diffuse hypomyelination, and thalamic and dentate T2 MRI hypointensities serving as diagnostic clues (53).

Young onset ataxia, deafness, and progressive spasticity have been described with KCNJ10 mutations. This gene encodes Kir4.1 potassium channel and is involved in epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome) (89).

VPS13 gene, whose mutations have been identified in chorea-acanthocytosis and rapidly progressive early onset Parkinson disease, can also be involved in spastic ataxia (32).

Mitochondrial cerebellar ataxia, renal failure, neuropathy, and encephalopathy (MCARNE). This is a mitochondrial disorder from the same missense mutation (mitochondrial NADH dehydrogenase 5 [MT-ND5] Asp393Asn) that can also cause mitochondrial encephalopathy and lactic acidosis with stroke like episodes (MELAS). A case report of a 60-year-old male with this mutation presenting as peripheral neuropathy, renal failure requiring transplantation, memory loss, construction apraxia, and severe cerebellar degeneration leading to ataxic dysarthria and appendicular as well as gait ataxia was published by Ng and colleagues (95).

Paraneoplastic ataxia due to anti-Yo antibody (anti-Purkinje cytoplasmic antibody 1/PCA-1). This is the most common cause of paraneoplastic cerebellar degeneration. Dysarthria, ataxia, and vertigo with progressive course are seen clinically. The typical presentation is a female more than 60 years old with presence of gynecological cancer such as breast, uterine, or ovarian cancer. It is rarely reported on lung cancers and in men (54). A single case due to cholangiocarcinoma has been reported (83).

Opsoclonus-myoclonus-ataxia syndrome (OMAS) associated with SARS-CoV-2. There are individual case reports of ataxia as well as opsoclonus-myoclonus-ataxia reported secondary to SARS-CoV-2. In the report by Urrea-Mendoza and colleagues, there was a substantial improvement of myoclonus and ataxia and resolution of opsoclonus at day 24 after diagnosis of SARS-CoV-2 and treatment with methylprednisolone 40 mg daily (133). Przytuła and colleagues report two cases of ataxia myoclonus and reviewed 14 other published cases (106). Twelve of these cases were treated with intravenous immunoglobulin, steroids, or both, and significant clinical improvement was reported within 1 to 8 weeks.

Prognosis and complications

The prognosis of ataxia depends on the underlying diagnosis. Severe unilateral or bilateral cerebellar ataxia, by itself, is not life-threatening, although the tight space in which the cerebellum is contained does not accommodate much swelling or edema. Therefore, acute lesions of the cerebellum accompanied by edema or space-occupying lesions can be life-threatening and require immediate neurosurgical attention. Among hereditary causes of ataxias, the prognosis depends on the specific genetic diagnosis, the associated symptoms in the particular individual, and to an extent, the age of disease onset.

In general, spinocerebellar ataxia types 1, 2, and 3 are conditions that progress over 5 to 20 years with progressive disability related to gait and bulbar dysfunction. In the late stages, the consequences of immobility and dysphagia include weight loss, pneumonia, urinary tract infections, venous thromboemboli, sepsis, and eventually death. Spinocerebellar ataxia type 6 and other pure cerebellar ataxias are associated with milder, prolonged courses and may not shorten the lifespan. Spinocerebellar ataxia type 7 tends to have a more malignant course, often leading to blindness and death within a decade. The prognosis for patients with dominant ataxia without a mutation in one of the known genes can only be based on the family phenotype and may not be accurate. Some patients with dominant ataxias appear to develop a mild dementia although this has not been well-studied. Little information is presently available regarding associated prognosis of the rarer, newly discovered forms of spinocerebellar ataxia.

The course of sporadic olivopontocerebellar atrophies is similar to that of the hereditary olivopontocerebellar atrophies or multiple system atrophy in that they show slow progression over several years leading to a chair-bound or bed-bound state.

The prognosis of Friedreich ataxia is that of a slowly progressive spinal cord disease. Most patients are wheelchair bound within 10 years of onset but are able to live for decades after that time with appropriate assistance. Bowel and bladder control are often impaired as the disease progresses, and dysarthria becomes more prominent making communication more difficult. Although cognitive disturbance was once thought to be atypical in Friedreich ataxia, greater understanding of the cerebellar role in cognition has led to further research in this area. One study showed evidence of decreased motor and mental reaction times, letter fluency deficits, impairment in acquiring and consolidating verbal information, and visuospatial abnormalities compared with controls (143).

Clinical vignette

A 35-year-old man presented with a history of episodic dizziness, unsteadiness, and loss of coordination that started at 13 years of age. These symptoms lasted from 30 minutes to several hours. He denied any provoking factors that caused his symptoms. Episodes of dizziness and incoordination increased in frequency, and he experienced almost daily episodes at 30 years of age. He also noticed his words slurring during the episodes. He reported poor balance when he did not experience his typical spells. The remainder of his past medical history was unremarkable, and he denied alcohol abuse.

Family history was significant for similar problems experienced by his brother and son. The patient reported that his son’s first episode was provoked by a strenuous physical activity at 8 years of age, and 2 years later, he began to have almost daily attacks of dizziness and unsteadiness that lasted for several hours. His brother had similar age of onset, but his paroxysmal ataxia episodes were less severe and less frequent.

Interictal neurologic examination of the proband demonstrated saccadic pursuit, hypermetric saccades, and mild midline ataxia. His MRI demonstrated moderate atrophy of the superior cerebellar vermis with sparing of other parts of the cerebellum.

Episodic ataxia type 2 (brain MRI)

Midline sagittal MRI of a patient with 20-year history of episodic ataxia type 2 demonstrating atrophy of the superior cerebellar vermis. (Contributed by Dr. Peter Hedera.)

DNA testing for spinocerebellar ataxia type 6 was with normal number of CAG repeats in both alleles.

The patient was started on acetazolamide without any clinical change. Later, he was switched to another carbonic anhydrase inhibitor dichlorphenamide, and he reported significant improvement of his symptoms.

Biological basis

Etiology and pathogenesis

More than 780 hereditary conditions where ataxia can be a symptom are listed in the Online Mendelian Inheritance in Man. These disorders can be divided into common dominant and recessive conditions, less common and ill-defined dominant and recessive syndromes, metabolic disorders, mitochondrial disorders, disorders of DNA repair, structural disorders of the cerebellum, ataxia associated with abnormality of the sensory systems (blindness, deafness, or peripheral neuropathy syndromes), and ataxia associated with certain mental retardation syndromes. Table 2 presents the key genetic features of the dominantly inherited ataxias (127; 113).

A wide variety of lesions can also affect the cerebellum, including vascular, infectious, inflammatory, demyelinating, degenerative, toxic/metabolic, and neoplastic, among others.

Table 2. Genetic Aspects of the Dominantly Inherited Ataxias

Disorder	Chromosome	Gene	Protein	Mutation	Available Testing
SCA-1	6p23	SCA1	ataxin-1	CAG expansion	Yes
SCA-2	12q24.1	SCA2	ataxin-2	CAG expansion	Yes
SCA-3	14q21	SCA3	ataxin-3	CAG expansion	Yes
SCA-4/31	16q22.1	?	?	TGGAA pentanucleotide repeat insertion	No
SCA-5	11q13	SPTBN2	β-III Spectrin	inframe deletions and missense mutations (Leu253Pro)	Yes
SCA-6	19p13.1-p13.2	CACNA1A	α-I voltage-dependent calcium channel protein	CAG expansion	Yes
SCA-7	3p14-p21.1	SCA7	ataxin-7	CAG expansion	Yes
SCA-8	13q21	SCA8	--	CUG expansion of 3' mRNA with incomplete penetrance	Yes
SCA-9	reserved	--	--	--	--
SCA-10	22q13	ATXN10	ataxin-10	ATTCT expansion in intron 9	Yes
SCA-11	15q14-q21.3	TTBK2	tau tubulin kinase 2	stop frameshift insertion or deletion mutations	No
SCA-12	5q31-q33	PPP2R2B	protein phosphatase2, regulatory subunit B	CAG expansion	Yes
SCA-13	19q13.3-q13.4	KCNC3		missense mutations (Phe448Leu and Arg420His)	Yes
SCA-14	19q13.4	PRKCG	protein kinase C-γ	numerous missense mutations	Yes
SCA-15/16/29	3p25-26, 3p26.2	ITPR1	inositol 1,4,5-triphosphate receptor, type 1	Heterozygous deletion of 5’ regions; can extend into neighboring SUMF1 gene	No
SCA-17	6q27	TBP	TATA-box binding protein	CAG expansion	Yes
SCA-18	7q31-q32	?	?	?	No
SCA-19	1p21-q21	KCND3	Voltage gate K+ channel	T352P, M373I, S290N	No
SCA-20	11	?	?	?	No
SCA-21	7p15.1-p21	TMEM240	Transmemb-rane protein	c.509C>T, c.239C>T,c.346C>T, and others	No
SCA-22	1p21-q23	?	?	?	No
SCA-23	20p12.2-p13	?	?	?	No
SCA-24	1p36	?	?	?	No
SCA-25	2p15-p21	?	?	?	No
SCA-26	19p13	?	?	?	No
SCA-27	13q34	FGF14	fibroblast growth factor 14	point mutations (F145S)	No
SCA-28	18p11.21	AFG3L2	ATPase family gene 3-like 2	?	No
SCA-29	3p26	?	?	probable variant of SCA-15	No
SCA-30	4q34.3-q35.1	ODZ3 (candidate gene)	Tenascin M3	?	No
SCA-35	20p13–12.2	TGM6	Transglutaminase-6	Missense L517W and D327G	No
SCA-36	20p	NOP56	Nucleolar protein	GGCCTG repeat expansion	No
SCA-37	1p32.2	DAB1 (119)	?	ATTTC(n) insertion	No
SCA-38	6p12	ELOVL5 (26)	?	missense G230V and L72V	No
SCA-40	14q32.11-q32.12	CCDC88C	JNK signaling (132)	R464H	No
SCA-41	4q27	TRPC3 (40)	?	Heterozygous missense mutation	No
SCA-42	17q21.33	CACNA1G (69)	Voltage gated calcium channel, alpha1 G subunit	c.5144G>A; R1715H	No
Dentato-rubropallido-luysian atrophy (DRPLA)	12p13.31	DRPLA	atrophin-1	CAG expansion	Yes
Episodic ataxia-1	12p13	KCNA1	voltage-gated potassium channel protein	missense point mutations	No
Episodic ataxia-2	19p13.1-p13.2	CACNA1A	voltage-dependent calcium channel protein, α1 subunit	point mutations or small deletions (CAG expansion in two families)	No
Episodic ataxia-3	1q42	?	?	?	No
Episodic ataxia-4	?	PATX	?	?	No
Episodic ataxia-5	2q22-q23	CACNB4β4	voltage-dependent calcium channel protein, β4 subunit	?	No
Episodic ataxia-6	5p11-12	SLC1A3	glial high affinity glutamate transporter protein	?	No
Episodic ataxia-7	19q13	?	?	?	No
Episodic ataxia with paroxysmal choreo-athetosis	1p	DYT9	?	?	No
Gerstmann-Sträussler-Scheinker syndrome (GSS)	20(p12-pter)	PRNP	prion protein	Pro102Leu	No
Ataxia-telangiectasia-like disorder (ATLD)	11q21	MRE11	part of the MRN repair complex	?	No
Ataxia due to Coenzyme Q10 deficiency	1q42.13	CABC1/ADCK3	kinase that modulates synthesis of CoQ10	multiple mutations	No
ARSACS (Charlevoix-Saguenay)	13q12	SACS	?	6594delT, 5254C>T	6594delT testing available via 23andme
HSP7	16q24.3	SPG7	paraplegin required for m-AAA protease/ribosomal assembly	multiple	Yes
Adult-onset Alexander disease	17q21	GFAP	function poorly understood	multiple	Yes
Cerebro-tendinous xantho-matosis (CTX)	2q33	CYP271A	sterol oxidase	multiple	Yes
CAPOS syndrome	19q13.2	ATP1A3	Na+/K+ ATPase α3	c.2452G > A (p.(Glu818Lys))	Yes via Invitae

Ataxia is most often due to dysfunction of the cerebellum or its inflow or outflow tracts. Acute lesions of the cerebellum are often severe but may improve gradually with a relatively good prognosis. Chronic degeneration of the cerebellum usually leads to gradual, persistent decline. Vestibulocerebellar lesions tend to result in impaired equilibrium and ataxic gait. Spinocerebellar lesions involve the vermis and tend to cause truncal ataxia and ataxic gait with minimal limb involvement. Neocerebellar lesions involve the cerebellar hemispheres and tend to result in severe limb ataxia. Less commonly, motor or sensory lesions can lead to a similar-appearing ataxic movement disorder (47; 46). Infectious, vascular, structural, and other causes of ataxia produce neurologic symptoms by mechanical disruption of the cerebellum or its numerous connecting pathways.

The dominant ataxias, spinocerebellar ataxia types 1, 2, 3, 6, 7, 12, and 17 and dentatorubropallidoluysian atrophy (DRPLA) share a common type of genetic mutation unique to neurodegenerative disorders called a cytosine-adenine-guanine repeat expansion. Within each of the responsible genes is a segment containing the trinucleotide cytosine-adenine-guanine (CAG), which encodes for the amino acid glutamine. The responsible mutation for each disorder is an increase in the number of CAG repeats leading to the production of normal amounts of an enlarged protein containing an excessive number of glutamine moieties. CAG repeat expansion does not appear to disrupt the translation of the gene or synthesis of the protein. The RAS-MAPK-MSK1 pathway has been implicated in modulating expression of ATXN1 protein in SCA1 (101). Diminished Nemo-like kinase (NLK) expression in SCA1 knock-in mice markedly improves phenotype, suggesting that NLK may play an important role in SCA1 pathogenesis (66).

Pathologically, synaptic loss is most severe in the olives in spinocerebellar ataxia type 1 and in the cerebellum and brainstem in spinocerebellar ataxia type 2; synaptic loss is much more variable in location and extent in spinocerebellar ataxia type 3 (36; 73). Work with transgenic mouse models of spinocerebellar ataxia type 1 has shown that the abnormal ataxin-1 protein is cleaved and forms inclusion bodies within the nucleus of the Purkinje cells that are destined to die. Preventing cleavage of the abnormal protein or its translocation into the nucleus of the cell appears to slow the expected course of the disease, whereas inhibiting the formation of inclusion bodies actually promotes the disease process (70). Analysis of spinocerebellar ataxia type 1 transgenic mice showed evidence of downregulation of several genes expressed by Purkinje cells, and it appears that several of these genes play a role in calcium regulation (80). Phosphorylation of ataxin-1 at serine 776 has been suggested as an important mechanism necessary for the development of degeneration in transgenic mice (34).

The pathogenesis of spinocerebellar ataxias that are not due to expanded CAG repeat remains unclear. Spinocerebellar ataxia type 10 is associated with an expanded adenine-thymine-thymine-cytosine-thymine (ATTCT) pentanucleotide repeat in intron 9 of the SCA10 gene (85). This is one of the largest expansions in the human genome, and evidence points to the role of expanded ATTCT tracts in unwinding DNA leading to instability (81). Point mutations in fibroblast growth factor 14 and protein kinase C gamma have been found in ataxia families without anticipation (18; 135). The identification of TGGAA pentanucleotide repeats on chromosome 16p22 in a large number of Japanese patients with spinocerebellar ataxia seems to be a more plausible pathogenetic mechanism than a single mutation in an untranslated region of the puratrophin-1 gene (PLEKHG4) (115).

Intronic expansion is also a feature of Friedreich ataxia caused by expanded guanine-adenine-adenine (GAA) repeat within the first exon of the frataxin gene (15). Rarely, some patients are found to be compound heterozygotes with a GAA triplet repeat expansion in one allele and a point mutation in the second allele of frataxin. Frataxin is localized to mitochondria and plays a role in the transport of iron out of the mitochondria, so it is thought that Friedreich ataxia may be a result of disrupted iron homeostasis. This theory is supported by analysis of frataxin-deficient mice as these animals exhibited time-dependent intramitochondrial iron accumulation and neurodegeneration (107). The number of GAA repeats is not as predictive as age of onset, with the latter more likely due to the combined result of several genetic and environmental factors (77).

De novo mutations in MORC2 have been described to cause early onset cerebellar atrophy together with spinal muscular atrophy like neuropathy and diaphragmatic paralysis. The test for this disorder is not available commercially (149). Regarding recessive ataxia, mutations in SLC52A2 gene for the riboflavin transporter have been linked to spinocerebellar ataxia with blindness and deafness type 2 (06).

Epidemiology

The epidemiology of ataxia is difficult to generalize because it is dependent on the epidemiology of a large array of many disorders that result in ataxia. The epidemiology of the hereditary and sporadic degenerative ataxias is somewhat better studied (117). As a group, the ataxias have an overall prevalence of about 5 in every 100,000 individuals. Friedreich ataxia is the most common hereditary ataxia, most commonly having onset at less than 25 years of age, but occasionally presenting later. Friedreich ataxia is more common in individuals of French-Canadian or Acadian descent. This type of “founder effect” is described as the presence of an otherwise uncommon inherited disease gene in a progenitor of a physically or culturally isolated population, which then increases in frequency within that isolated population over succeeding generations (45; 99). In the United States, spinocerebellar ataxia type 2 and type 3 appear to be more common than spinocerebellar ataxia type 1, but it is unclear how common other types of spinocerebellar ataxias will prove to be. Most autosomal dominant ataxias begin during adult years, but due to the dynamic nature of the gene mutations responsible for these diseases, childhood onset of any of these syndromes is possible. Based on an extensive review of published data, the prevalence of childhood ataxia in Europe was estimated to be 26 out of 100,000 children and likely reflects a minimum prevalence worldwide (92).

The currently known dominant ataxia genes appear to account for between 25% and 75% of dominant ataxia families, depending on the population studied (38; 64; 91; 93; 100). A study of apparently sporadic cases of ataxia identified a known type of ataxia in 19% of affected subjects; Friedreich ataxia was the most common, followed by spinocerebellar ataxia type 6 and type 8 (118).

Epidemiologic studies focusing on sporadic cases of olivopontocerebellar atrophy found no association with head trauma, smoking, alcohol use, rural living, or well water. Affected individuals had less medication usage and a lower frequency of hypertension than unaffected individuals (71).

Differential diagnosis

The differential diagnosis of ataxia includes a large number of conditions. These are divided by category below; this list is not exclusive but is intended to highlight the more common conditions. The list of genetic conditions, alone, in which ataxia may be a symptom numbers more than 780.

Vascular
	• Ischemic stroke (arterial or venous) • Intracranial hemorrhage • Subdural or subarachnoid hemorrhage • Postcardiac arrest • Cavernous malformations
Trauma
	• Injury to the bilateral posterior parietal cortex (Balint syndrome), cerebellum, spinal cord, or peripheral nerves • Postconcussive syndrome • Dementia pugilistica
Developmental and Structural
	• Dandy-Walker malformation • Chiari malformation • Cerebellar hypoplasia syndromes (11) - Vermian aplasia - Joubert syndrome • Kallmann syndrome • Megalencephaly • High altitude cerebral edema • Normal pressure hydrocephalus
Neoplastic/paraneoplastic
	• Astrocytoma • Glioma • Oligodendroglioma • Dermoid or epidermoid tumors • Medulloblastoma • Meningioma • Colloid cyst of the third ventricle • Ependymoma • Schwannoma • Metastatic tumors • Von Hippel-Lindau syndrome (cerebellar hemangioblastoma) • Paraneoplastic syndromes of ataxia, neuropathy, and opsoclonus-myoclonus
Infectious
	• Viral: Epstein-Barr virus, varicella zoster, herpes, human immunodeficiency virus, hepatitis, subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, rabies (pathologic though typically not clinical involvement of the cerebellum) • Rickettsial: Rocky Mountain spotted fever, Lyme disease • Bacterial: brucellosis, malaria, sleeping sickness, cryptococcal infection, tuberculosis, tabes dorsalis (syphilis), listeriosis, abscess of any type
Inflammatory
	• Postinfectious viral cerebellitis in children • Miller-Fisher variant of acute inflammatory demyelinating polyneuropathy • Systemic lupus erythematosus • Multiple sclerosis or acute demyelinating encephalomyelitis • Celiac disease-associated ataxia related to antigliadin antibodies • Anti-GAD antibody and anti-CASPR2 autoimmune ataxia
Metabolic
	• Leukodystrophies (eg, metachromatic leukodystrophy, adrenoleukodystrophy, Alexander disease, Krabbe disease, Pelizaeus-Merzbacher disease) • Urea cycle disorders (eg, ornithine transcarbamylase deficiency, maple syrup urine disease, argininosuccinase deficiency) • Nutritional disorders (eg, ataxia with vitamin E deficiency, vitamin B1 (thiamine) deficiency, vitamin B6 toxicity (pyridoxine-induced neuropathy), vitamin B12 (cyanocobalamin) deficiency, copper deficiency, folate deficiency • Mitochondrial disorders (eg, mitochondrial encephalomyopathy with ragged red fibers, progressive external ophthalmoplegia, Leber optic atrophy, Kearns-Sayre syndrome, Leigh disease, pyruvate carboxylase deficiency) • Mucopolysaccharide storage diseases (eg, mannosidosis, sialidosis, GM1 gangliosidoses, GM2 gangliosidoses) • Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) • Hepatolenticular degeneration (Wilson disease) • Heredopathia atactica polyneuritiformis (Refsum disease) • Biotinidase deficiency
Toxic- or drug-related
	• Medications (eg, phenytoin, carbamazepine, oxcarbazepine, lamotrigine, valproic acid, vigabatrin, gabapentin, pregabalin, tiagabine, cyclosporine, methotrexate, topiramate, amiodarone, cisplatin, lithium, barbiturates, fluorouracil, cytarabine, zolpidem, nitrous oxide) • Recreational drugs (ketamine, dextromethorphan, phencyclidine, inhalation of chlorocarbon solvents or paint thinner) • Alcohol: acute and chronic use • Systemic metabolic disturbance (eg, hepatic dysfunction, hypothyroidism, hyperventilation, hypoxic/ischemic sequelae, and hyperthermia) • Other toxic exposures (eg, lead, mercury, thallium, carbon monoxide, ciguatera, and eucalyptus oil poisoning)
Hereditary and sporadic ataxias (Table 1; Table 2)
	• Friedreich ataxia • Ataxia telangiectasia • Episodic ataxias • Autosomal dominant adult-onset ataxia (spinocerebellar ataxia, SCAN) • Dentatorubropallidoluysian atrophy (DRPLA) • Nonclassified hereditary ataxias • Sporadic olivopontocerebellar atrophy • Sporadic pure cerebellar atrophy
As a symptom of other neurologic disorders
	• Acute neuropathies (Guillain-Barré syndrome) • Migraine • Prion disorders (eg, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, kuru) • Cerebral amyloid angiopathy • Myoclonic epilepsy syndromes (progressive myoclonic epilepsy, Unverricht-Lundborg syndrome, ceroid lipofuscinosis) • Myopathies (eg, congenital fiber type disproportion, fingerprint body myopathy) • Static encephalopathy/cerebral palsy/hypoxic-ischemic encephalopathy • Dystonia (cervical dystonia, craniocervical dystonia, idiopathic torsion dystonia) • Spastic paraplegias • Other movement disorders (multiple system atrophy, advanced Parkinson disease, Huntington disease, neuroacanthocytosis)
As part of other genetic syndromes
	• Fragile X syndrome (premutation carriers) • Oral-facial-digital syndromes • Cockayne syndrome • Down syndrome • Fabry disease • Rett syndrome • Prader-Willi syndrome

Diagnostic workup

Careful attention to history, examination, and use of brain MRI can significantly shorten the long list of diagnostic possibilities in a patient with ataxia (104). Of the most commonly acquired causes of ataxia, tumors, structural and developmental anomalies, and multiple sclerosis all have characteristic MRI findings. Vascular lesions and traumatic injury frequently warrant further imaging with magnetic resonance angiography (MRA). Most of the hereditary or sporadic degenerative ataxias show atrophy of the cerebellum and sometimes the pons and olives corresponding with the clinical characterization of a pure cerebellar disorder or a more complex, multisystem degenerative disorder. Leukodystrophies usually show striking white matter abnormalities. Select patients may also be identified with MRI of the spinal cord. For example, the cerebellum usually appears normal in patients with Friedreich ataxia, but the cervical spinal cord may reveal atrophy. Alcohol-related chronic ataxia typically shows prominent atrophy of the cerebellar vermis out of proportion to any atrophy of the cerebellar hemispheres.

The history and physical examination should help substantially in the diagnosis of stroke syndromes, trauma-related or posttraumatic ataxia, ataxia related to other movement disorders or neurologic disorders, and ataxia related to certain syndromes. A history of exposure to toxins or metabolic stresses is important to consider. Unfortunately, no test is available that can clearly diagnose alcohol-related cerebellar degeneration (136). Patients with a history of heavy alcohol use in the distant past or modest ongoing use require that the physician look for other indicators of alcohol-related systemic or neurologic effects and consider other diagnoses before concluding that the problem is exclusively alcohol-related, especially given that alcohol use can lead to other potentially treatable nutritional deficiencies.

Spinocerebellar ataxia type 6 (brain MRI)

Midline sagittal brain MRI of a patient with spinocerebellar ataxia type 6 demonstrating cerebellar atrophy without pontine or medullary atrophy. (Contributed by Dr. Michael Oh.)

If MRI does not show diagnostic abnormalities, laboratory studies may be obtained to look for evidence of suspected conditions. A reasonable laboratory battery should include a complete blood count; electrolytes; serum vitamin B12 and vitamin E levels; levels of any known or suspected toxins (ie, phenytoin, carbon monoxide, or alcohol); a urine toxicologic screen, including drugs and heavy metals; liver function tests, including albumin level; a venous ammonia level; serum electrophoresis with immunofixation; and thyroid studies. In the proper context, a screen for antibodies associated with paraneoplastic cerebellar disturbance might be considered (122). Gluten sensitivity with high titers of antigliadin antibodies has been suggested as a cause of ataxia, even in patients without typical gastrointestinal symptoms seen in celiac sprue (144). Antigliadin antibodies have been documented in 41% of patients with sporadic ataxia (50). However, antigliadin antibodies can be found in a high proportion of patients with familial ataxia, and reports of improvement of neurologic symptoms after gluten-free diet are conflicting (21). Tissue transglutaminase levels are thought to be a more sensitive and specific diagnostic indicator of celiac sprue and have been shown to correlate with ataxic findings (51). Investigation into other treatable causes of ataxia in appropriate patients might include serum vitamin B1 or erythrocyte transketolase levels, a fasting lipid profile, red blood cell folate, serum pyruvate and lactate levels, creatine kinase, serum iron studies, antinuclear antibody and anti-SSA/SSB antibodies, plasma/urinary amino acid screen, HIV antibody test, ceruloplasmin, 24-hour urinary copper, and a paraneoplastic antibody panel. Abetalipoproteinemia may be detected via low serum levels of low-density lipoprotein, apolipoprotein, and triglycerides, with treatment focusing on dietary modification and treatment of associated vitamin deficiencies (108). Serum cholestanol and urinary bile alcohol levels are abnormal in cerebrotendinous xanthomatosis, which is treatable with oral deoxycholic acid (108).

When initial laboratory studies do not yield a specific or obviously treatable diagnosis in a patient with chronic ataxia, the possibility of a primary degenerative condition becomes more likely. Careful consideration of the family history is important at this juncture, and detailed characterization of the neurologic condition may help direct the diagnostic process. Neuropsychometric testing may disclose and characterize dementia, neurophysiologic studies can document the presence and nature of an associated neuropathy, and spinal cord imaging or evoked potential studies may reveal evidence of spinal cord atrophy or dysfunction. Male patients with cognitive decline and ataxia may be premutation carriers for fragile X syndrome (55 to 200 CGG repeats) (62). These patients frequently develop additional neurologic problems, including parkinsonism, postural tremor, and polyneuropathy. Positive family history of a grandchild with mental retardation is commonly present, and one or more female family members may have a history of premature ovarian failure. Increased signal on T2-weighted MRI in the area of the middle cerebellar peduncles has been suggested as a specific radiological marker for this condition.

For the patient with a positive family history of ataxia with a dominant inheritance pattern, analysis of the testable dominant ataxia genes should be considered. Most laboratories offer a panel of gene tests, but because the clinical features of the dominant ataxias overlap, it may not be possible to exclude or select a particular genetic diagnosis reliably based on the clinical examination and adjunctive testing alone.

The role of genetic testing in a patient with apparently sporadic degenerative ataxia remains uncertain. Studies typically show a low yield of positive results when patients are tested for dominant ataxia genes compared to a higher rate of positive results when testing for the frataxin gene (118). Although general approaches to treatment do not depend on a specific diagnosis, the genetic counseling of the patient and family are markedly altered by the diagnosis of a specific dominant or recessive genetic condition. Another potential benefit is the possibility of participating in clinical research trials that require a specific diagnosis prior to inclusion. Patients and involved family members should be made aware that some insurance companies or other third-party payers might not routinely cover the cost of all ataxic gene tests; however, obtaining prior authorization before ordering the studies in question likely reduces, but does not guarantee, the chances of denied coverage.

Management

Treatments for most hereditary forms of ataxia are not readily available. Ataxia with vitamin E deficiency may respond to pharmacologic doses of vitamin E. Ataxia as a result of Wernicke encephalopathy usually improves with replacement of deficient thiamine (vitamin B1), although several months of recovery are often needed, and improvement in ataxia sometimes trails improved ophthalmoparesis. Sensory ataxia due to vitamin B12 deficiency often improves after replacement with vitamin B12 although resolution of the underlying neuropathy or associated cognitive deficits is often incomplete. A small study found that recombinant human erythropoietin injections three times a week increased frataxin levels, significantly improved ataxia on standard rating scales, and lowered oxidative stress levels, but four of the eight patients required phlebotomy due to elevated hematocrit, so further studies will be needed to evaluate benefit and the extent of blood monitoring (12).

Many of the symptoms associated with some forms of ataxia, such as spasticity, parkinsonism, sleep disturbance, muscle cramping, or depression, are amenable to drug therapy and are, therefore, important to recognize.

Management of ataxia includes identification and treatment of any condition underlying the specific symptom of ataxia. For degenerative ataxias, the next step is reaching a conclusion as to whether the condition is hereditary or sporadic and, if possible, identifying a specific genetic cause. Patients with a multisystemic disorder (eg, Friedreich ataxia and ataxia telangiectasia) should be referred to additional specialists when indicated, such as a cardiologist, endocrinologist, or clinical immunologist. Genetic counseling should begin early after the diagnosis of any hereditary ataxia. After the appropriate diagnosis is made, ongoing expectant management is important. Referrals to occupational therapy and physical therapy can help patients adapt to increasing disability. A social worker can be helpful as questions of permanent disability, home safety, or the need for long-term care placement arise. Family education about prognostic details and reviewing likely changes before they occur can help minimize unexpected surprises. Referral to appropriate support organizations, such as the National Ataxia Foundation, can be useful to patients and families with hereditary or sporadic ataxia. Pharmacologic management of related symptoms (ie, spasticity or sleep disturbance) can also improve quality of life. Establishing advanced care directives will help patients with progressive degenerative ataxia address uncertainty about whether their care would continue according to their wishes should they become unable to communicate effectively.

Deep brain stimulation has been studied in various patients with spinocerebellar ataxia with modest improvement on underlying tremor but no tangible benefit on ataxia observed (103; 123; 41). Bilateral deep brain stimulation of the ventralis intermedius nuclei has been investigated in a patient with fragile X tremor-ataxia syndrome with improvement noted in tremor but no significant change in ataxia (37). The use of deep brain stimulation in patients with ataxia remains investigational and is NOT an approved therapy by the Food and Drug Administration.

Alternative therapies such as herbal remedies, magnet therapy, acupuncture, and biofeedback are not known to improve ataxia. Many medications that act on the central nervous system, including anticonvulsants, can worsen ataxia. Some patients with parkinsonism or dystonia associated with spinocerebellar ataxia type 2 notice visible improvement after treatment with therapeutic doses of levodopa (84). A few anecdotal cases of improvement of ataxia symptoms following treatment with buspirone or N-acetylcysteine have been reported (82). Surgical treatments (transplantation of cerebellar allografts) have shown temporary benefits in an animal model but have not been studied in humans (67). Idebenone, a short-chain analogue of coenzyme Q10 is an effective free radical scavenger and has been used in Friedreich ataxia (39). First results of clinical trials demonstrated significant improvement of the cardiac function in these patients; however, there was no effect on a relentless progression of neurologic symptoms (13). Children can frequently tolerate higher doses of idebenone than originally studied, so further trials might be possible. One randomized trial showed evidence of a dose-dependent trend toward improvement of ataxia at higher doses of idebenone; however, no significant improvement was found (28; 27). There was no significant improvement of Friedreich ataxia on memantine (120). Refsum disease can be treated with plasma exchange, and cerebrotendinous xanthomatosis can be treated with oral deoxycholic acid (108). Alpha tocotrienol quinone is being investigated in Friedreich ataxia. This compound did not meet the primary end point in the placebo-controlled 6-month phase based on raw scores but disease progression at 24 months was improved compared to historical norms (150).

A novel approach for finding new treatments stems from targeting genetic networks that modulate expression of disease-causing genes. Park and colleagues found that suppressing the RAS-MAPK-MSK1 signaling pathway will reduce ATXN1 levels in SCA1 (101).

The transcriptome is an important therapeutic target. Yang and colleagues designed a molecule that binds to RNA AUUCU repeats present in SCA10 patient-derived fibroblast cells, leading to near wild-type level reduction in activation of caspase 3 (147).

Etravirine, a non-nucleoside reverse transcriptase inhibitor, has been shown to increase frataxin messenger RNA translation and normalize frataxin levels in cell culture models (02). Anti-ATXN3 microRNA can suppress the expression of ATXN-3 and reduce accumulation of mutant Ataxin-3 in a mouse model (111). CRISPR gene editing of the FMR1 gene has been attempted in induced pluripotent stem cells in fragile X-associated tremor/ataxia syndrome (148). Profound ethical questions need to be resolved before considering human genome editing as a treatment strategy.

Special considerations

Pregnancy

None of the forms of ataxia have any direct effects on pregnancy. It is possible that an underlying condition responsible for ataxia can also independently affect pregnancy. Individuals with impairment of cardiac function, respiration, blood pressure regulation, or bowel, bladder, or sexual function as part of an ataxia syndrome may have difficulty during labor. Premature ovarian failure as a cause for infertility can often be seen in families with fragile X tremor-ataxia syndrome. Similarly, patients with vitamin E deficiency are often infertile. The vast majority of causes of ataxia do not have direct effects on fertility. Newborns with congenital malformations involving hypoplasia of the cerebellum and brainstem such as Joubert syndrome may be at risk for neonatal apnea due to disordered regulation of respiration, and neonatology consultations may be appropriate in these patients.

Anesthesia

Ataxia is not known to have any effects on anesthesia. Some patients who receive nitrous oxide anesthesia develop subacute combined degeneration due to occult B12 deficiency. Neuropathic pain medications or other centrally acting medications used postoperatively could worsen ataxia, especially gait ataxia, so falling precautions should be introduced in appropriate patients. It is possible that an underlying metabolic disorder that causes ataxia could also have deleterious effects on the metabolism of anesthetic agents. One case report documented a patient with apparently altered electrophysiologic and autonomic responses to propofol that were not clinically significant (76). Congenital forms of ataxia, such as Joubert syndrome, that are associated with brainstem and other anatomical abnormalities may complicate the successful performance of an epidural block; the use of caffeine has been suggested to alleviate episodes of apnea in infants with this disorder (137). A patient with nonhereditary cerebellar degeneration has been described as successfully receiving neuromuscular blockade using vecuronium (97). Another case report described successful use of an epidural in a patient with spinocerebellar ataxia without acute or long-term neurologic deficits (112).

Media

References

01: Aida I, Ozawa T, Fujinaka H, Goto K, Ohta K, Nakajima T. Autosomal recessive spastic ataxia of Charlevoix-Saguenay without spasticity. Intern Med 2021;60(24):3963-7. PMID 34121011
02: Alfedi G, Luffarelli R, Condo I, et al. Drug repositioning screening identifies etravirine as a potential therapeutic for Friedreich's ataxia. Mov Disord 2019;34(3):323-34. PMID 30624801
03: Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med 2012;366(7):636-46. PMID 22335741
04: Arata H, Takashima H, Hirano R, et al. Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu). Neurology 2006;66(11):1672-8. PMID 16769939
05: Assadi M, Leone P, Veloski JJ, Schwartzman RJ, Janson CG, Campellone JV. Validating an Ataxia Functional Composite Scale in spinocerebellar ataxia. J Neurol Sci 2008;268(1-2):136-9. PMID 18191149
06: Babanejad M, Adeli OA, Nikzat N, et al. SLC52A2 mutations cause SCABD2 phenotype: a second report. Int J Pediatr Otorhinolaryngol 2018;104:195-9. PMID 29287867
07: Barca E, Balreira A, Boczonadi V, et al. ANO10 mutations cause ataxia and coenzyme Q10 deficiency (P2.109). Neurology 2015a;84(14):Supplement P2.109.
08: Barca E, Neil H, Naini A, De Vivo D, DiMauro S. Early-onset cerebellar ataxia due to novel mutation in ACO2 (P2.224). Neurology 2015b;84(14):Supplement P2.224.
09: Becker EBE, Zuliani L, Pettingill R, et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J Neurol Neurosurg Psychiatry 2012;83(4):437-40. PMID 22338029
10: Berciano J, Boesch S, Perez-Ramos JM, Wenning GK. Olivopontocerebellar atrophy: toward a better nosological definition. Mov Disord 2006;21:1607-13. PMID 16874757
11: Bertini E, Campos-Castello J. Congenital ataxias of genetic origin with structural abnormalities of the cerebellum. Rev Neurol 1999;28:63-8. PMID 10101768
12: Boesch S, Sturm B, Hering S, et al. Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial. Mov Disord 2008;23:1940-4. PMID 18759345
13: Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring. Neurology 2003;60:1679-81. PMID 12771265
14: Cakar A, Sahin E, Tezel S, et al. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (canvas): an important cause of late-onset ataxia with unique clinical features. Acta Neurol Belg 2022;122(4):939-45. PMID 34101140
15: Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271:1423-7. PMID 8596916
16: Chang A, Ruiz-Lopez M, Slow E, Tamopolsky M, Lang AE, Munhoz RP. ADCK3-related coenzyme Q10 deficiency: a potentially treatable genetic disease. Mov Disord Clin Pract 2018;5(6):635-9. PMID 30637285
17: Chen DH, Below P, Sul Y, et al. A novel spinocerebellar ataxia with hematologic cytopenias: linkage analysis and exome sequencing identifies a candidate gene (P6.058). Neurology 2014;82(10):Supplement P6.058.
18: Chen DH, Brkanac Z, Verlinde CL, et al. Missense mutation in the regulatory domain of PKC-gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 2003;72:839-49. PMID 12644968
19: Choi KD, Jen JC, Choi SY, et al. Late-onset episodic ataxia associated with SLC1A3 mutation. J Hum Genet 2017;62(3):443-6. PMID 27829685
20: Cortese A, Tozza S, Yau WY, et al. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain 2020;143(2):480-90. PMID 32040566
21: Cross AH, Golumbek PT. Neurologic manifestation of celiac disease: proven, or just a gut feeling. Neurology 2003;60:1566-8. PMID 25247899
22: D’Adamo MC, Hanna MG, Di Giovanni G, Pessia M. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. Source: GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle, 2010.
23: de Bot ST, Willemsen MA, Vermeer S, Kremer HP, van de Warrenburg BP. Reviewing the genetic causes of spastic-ataxias. Neurology 2012;79(14):1507-14. PMID 23033504
24: Demos MK, van Karnebeek CD, Ross CJ, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 2014;9:15. PMID 24468074
25: Deplanque J, Devos D, Huin V, et al. TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment. Brain 2014;137(10):2657-63. PMID 25070513
26: Di Gregorio E, Borroni B, Giorgio E, et al. ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet 2014;95(2):209-17. PMID 25065913
27: Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol 2007b;6:878-86. PMID 17826341
28: Di Prospero NA, Sumner CJ, Penzak SR, Ravina B, Fischbeck KH, Taylor JP. Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia. Arch Neurol 2007a;64:803-8. PMID 17562928
29: Dow RS, Moruzzi G. The physiology and pathology of the cerebellum. Minneapolis MN: University of Minnesota Press, 1958.
30: Duarri A, Jezierska J, Fokkens M, et al. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol 2012;72(6):870-80. PMID 23280838
31: Durr A, Stevanin G, Cancel G, et al. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 1996;39:490-9. PMID 8619527
32: Dziurdzik SK, Bean BD, Davey M, Conibear E. A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13. Hum Mol Genet 2020;29(4):635-48. PMID 31943017
33: Elsaid MF, Chalhoub N, Ben-Omran T, et al. Mutation in noncoding RNA, RNU12 causes early-onset cerebellar ataxia. Ann Neurol 2017;81(1):68-78. PMID 27863452
34: Emamian ES, Kaytor MD, Duvick LA, et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 2003;38:375-87. PMID 12741986
35: Engert JC, Berube P, Mercier J, et al. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nature Genet 2000;24:120-5. PMID 10655055
36: Estrada R, Galarraga J, Orozco G, et al. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol (Berl) 1999;97:306-10. PMID 10090679
37: Ferrara JM, Adam OR, Ondo WG. Treatment of fragile X associated tremor/ataxia syndrome with deep brain stimulation. Mov Disord 2009;24:149-51. PMID 18951504
38: Filla A, De Michele G, Santoro L, et al. Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. J Neurol 1999;246:467-71. PMID 10431773
39: Filla A, Moss AJ. Idebenone for treatment of Friedreich's ataxia. Neurology 2003;60:1569-70. PMID 12771240
40: Fogel BL, Hanson SM, Becker EB. Do mutations in the murine ataxia gene TRPC3 cause cerebellar ataxia in humans? Mov Disord 2015;30(2):284-6. PMID 25477146
41: Freund HJ, Barnikol UB, Nolte D, et al. Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor-an unusual clinical benefit. Mov Disord 2007;22:732-5. PMID 17265523
42: García-Murias M, Quintáns B, Arias M, et al. ‘Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization. Brain 2012;135(Pt 5):1423-35. PMID 22492559
43: Gilman S, Bloedel JR, Lechtenberg R. Disorders of the cerebellum. Philadelphia: FA Davis Co, 1981.
44: Globas C, du Montcel ST, Baliko L, et al. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Mov Disord 2008;23:2232-8. PMID 18759344
45: Goldfarb LG, Chumakov MP, Petrov PA, et al. Olivopontocerebellar atrophy in a large Iakut kinship in eastern Siberia. Neurology 1989;39:1527-30. PMID 2812335
46: Gordon N. Ataxia of parietal lobe origin. Dev Med Child Neurol 1999;41:353-5. PMID 10378764
47: Gorman MJ, Dafer R, Levine SR. Ataxia hemiparesis: critical appraisal of a lacunar syndrome. Stroke 1998;29:2549-55. PMID 9836766
48: Guerra AF, Martinelli I, Rispoli V, et al. Ataxia-myoclonus syndrome in patients with SARS-CoV-2 infection. Can J Neurol Sci 2022;49(6):824-5. PMID 34645540
49: Guissart C, Harrison AN, Benkirane M, et al. ATP8A2-related disorders as recessive cerebellar ataxia. J Neurol 2020;267(1):203-13. PMID 31612321
50: Hadjivassiliou M, Grunewald RA, Sharack B, et al. Gluten ataxia in perspective: epidemiology, genetic susceptibility, and clinical characteristics. Brain 2003;126:685-91. PMID 12566288
51: Hadjivassiliou M, Maki M, Sanders DS, et al. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 2006;66(3):373-7. PMID 16476935
52: Hadjivassiliou M, Martindale J, Shanmugarajah P, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry 2017;88(4):301-9. PMID 27965395
53: Han JY, Kim SY, Cheon JE, Choi M, Lee JS, Chae JH. A familial case of childhood ataxia with leukodystrophy due to novel POLR1C mutations. J Clin Neurol 2020;16(2):338-40. PMID 32319256
54: Hasadsri L, Lee J, Wang BH, Yekkirala L, Wang M. Anti-Yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung. Case Rep Neurol Med 2013;2013:725936. PMID 24167748
55: Hernandez D, McConville CM, Stacey M, et al. A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23. J Med Genet 1993;30:135-40. PMID 8445618
56: Holmes G. The cerebellum of man. Brain 1939;62:1-30.
57: Horvath R, Czermin B, Gulati S, et al. Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry 2012;83(2):174-8. PMID 22036850
58: Hou JG, Jankovic J. Movement disorders in Friedreich’s ataxia. J Neurol Sci 2003;206:59-64. PMID 12480086
59: Ishikawa K, Watanabe M, Yoshizawa K, et al. Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6). J Neurol Neurosurg Psychiatry 1999;67:86-9. PMID 10369828
60: Jacobi H, du Montcel ST, Bauer P, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol 2015;14(11):1101-8. PMID 26377379
61: Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013;12(7):650-8. PMID 23707147
62: Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72:869-78. PMID 12638084
63: Jen JC, Graves TD, Hess EJ, et al. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 2007;130:2484-93. PMID 17575281
64: Jin DK, Oh MR, Song SM, et al. Frequency of spinocerebellar ataxias types 1,2,3,6,7, and dentatorubropallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia. J Neurol 1999;246:207-10. PMID 10323319
65: Joubert B, Honnorat J. Nonparaneoplastic autoimmune cerebellar ataxias. Curr Opin Neurol 2019;32(3):484-92. PMID 30694927
66: Ju H, Kokubu H, Todd TW, et al. Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1. J Neurosci 2013;33(22):9328-36. PMID 23719801
67: Kaemmerer WF, Low WC. Cerebellar allografts survive and transiently alleviate ataxia in a transgenic model of SCA Type 1. Exp Neurol 1999;158:301-11. PMID 10415138
68: Kim JS, Cho JW, Kim JS, et al. Ocular motor characteristics of different subtypes of spinocerebellar ataxia: Distinguishing features. Mov Disord 2013;28(9):1271-7. PMID 23609488
69: Kimura M, Yabe I, Hama Y, et al. SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia. J Hum Genet 2017;62(9):857-9. PMID 28490766
70: Klement IA, Zoghbi HY, Orr HT. Pathogenesis of polyglutamine-induced disease: a model for SCA1. Mol Genet Metab 1999;66:172-8. PMID 10066385
71: Klockgether T, Burk K, Wullner V, et al. Risk factors for idiopathic cerebellar ataxia of late onset. J Neurol Sci 1998;160:171-4. PMID 9849801
72: Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum 2005;4:62-73. PMID 15895563
73: Koeppen AH, Dickson AC, Lamarche JB, et al. Synapses in the hereditary ataxias. J Neuropathol Exp Neurol 1999;58:748-64. PMID 10411345
74: Konigsmark BW, Weiner LP. The olivopontocerebellar atrophies: a review. Medicine 1970;49:227-41. PMID 4910986
75: Koshy BT, Zoghbi HY. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol 1997;7:927-43. PMID 9217976
76: Kuroda M, Fukura H, Soruki N, et al. Vecuronium dose requirement and pupillary response in a patient with olivopontocerebellar atrophy (OPCA). Can J Anaesth 1998;45:979-84. PMID 9836034
77: La Pean A, Jeffries N, Grow C, et al. Predictors of progression in patients with Friedreich ataxia. Mov Disord 2008;23:2026-32. PMID 18759347
78: Legris N, Chassin O, Nasser G, Riant F, Tournier-Lasserve E, Denier C. Acute-onset ataxia and transient cerebellar diffusion restriction associated with a PRRT2 mutation. J Stroke Cerebrovasc Dis 2019;28(2):e3-4. PMID 30501978
79: Lin WY, Huang CL, Lia SC, Yeh TH, Lu CS. Identification of a novel CACNA1A mutation in a Taiwanese family with episodic ataxia. From: MDS 17th International Congress of Parkinson's Disease and Movement Disorders. Mov Disord 2013;28 Suppl 1:709.
80: Lin X, Antalffy B, Kang D, et al. Polyglutamine expansion down-regulates specific neuronal genes before pathological changes in SCA1. Nature Neurosci 2000;3:157-63. PMID 10649571
81: Liu G, Bissler JJ, Sinden RR, et al. Unstable spinocerebellar ataxia type 10 (ATTCT(AGAAT) repeats are associated with aberrant replication at the ATX10 locus and replication origin-dependent expansion at an ectopic site in human cells. Mol Cell Biol 2007;27(22):7828-38. PMID 17846122
82: Lou JS, Goldfarb L, McShane L, et al. Use of buspirone for treatment of cerebellar ataxia: an open label study. Arch Neurol 1995;52:982-8. PMID 7575226
83: Lou Y, Xu SH, Zhang SR. Anti-Yo antibody-positive paraneoplastic cerebellar degeneration in a patient with possible cholangiocarcinoma: a case report and review of the literature. World J Clin Cases 2021;9(17):4423-32. PMID 34141810
84: Lu CS, Wu Chou YH, Yen TC, et al. Dopa-responsive parkinsonism phenotype of spinocerebellar ataxia type 2. Mov Disord 2002;17(5):1046-51. PMID 12360557
85: Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet 2000;26:191-4. PMID 11017075
86: Meijer IA, Hand CK, Grewal KK, et al. A locus for autosomal dominant hereditary spastic ataxia, SAX1, maps to chromosome 12p13. Am J Hum Genet 2002;70:763-9. PMID 11774073
87: Methling B, Köhler C, Thiels C, Lücke T. CAPOS-syndrome: a rare differential diagnosis to Friedreich’s ataxia. Neuropediatrics 2017;48(S 01):S1-45.
88: Moreira MC, Barbot C, Tachi N, et al. The gene mutated in ataxia-oculomotor apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nature Genet 2001;29:189-93. PMID 11586300
89: Morin M, Forst AL, Perez-Torre P, et al. Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype. Neurogenetics 2020;21(2):135-43. PMID 32062759
90: Moro A, Munhoz RP, Arruda WO, Raskin S, Teive HA. Clinical relevance of "bulging eyes" for the differential diagnosis of spinocerebellar ataxias. Arq Neuropsiquiatr 2013;71(7):428-30. PMID 23857626
91: Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1999;51:1666-71. PMID 9855520
92: Musselman KE, Stoyanov CT, Marasigan R, et al. Prevalence of ataxia in children: a systematic review. Neurology 2014;82(1):80-9. PMID 24285620
93: Nagaoka U, Suzuki Y, Kawanami T, et al. Regional differences in genetic subgroup frequency in hereditary cerebellar ataxia, and a morphometrical study of brain MR images in SCA1, MJD, and SCA6. J Neurol Sci 1999;164:187-94. PMID 10402032
94: Nance MA. Clinical aspects of the CAG repeat diseases. Brain Pathol 1997;7:881-900. PMID 9217974
95: Ng PS, Pinto MV, Neff JL, et al. Mitochondrial cerebellar ataxia, renal failure, neuropathy, and encephalopathy (MCARNE). Neurol Genet 2019;5(2):e314. PMID 31041396
96: Nguyen M, Boesten I, Hellebrekers D, et al. Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy. Eur J Hum Genet 2016;24(4):619-22. PMID 26197978
97: Oikawa M, Nitahara K, Shono S, et al. Vecuronium in a patient with late cerebellar cortical atrophy. J Clin Anesth 2006;18(2):145-7. PMID 16563336
98: Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543-52. PMID 8898206
99: Orozco G, Estrada R, Perry TL, et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: clinical, neuropathological, and biochemical findings. J Neurol Sci 1989;93:37-50. PMID 2809629
100: Pareyson D, Gelerra C, Castellotti B, et al. Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type 1: SCA1 and SCA2 are the most common genotypes. J Neurol 1999;246:389-93. PMID 10399872
101: Park J, Al-Ramahi I, Tan Q, et al. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 2013;498(7454):325-31. PMID 23719381
102: Pellerin D. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med 2023;388(2):128-41. PMID 37224214
103: Pirker W, Back C, Gerschlager W, et al. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord 2003;18:222-5. PMID 12539221
104: Plaitakis A, Katoh S, Huang YP. Clinical and radiologic features of cerebellar degeneration. In: Plaitakis A, editors. Cerebellar Degenerations: Clinical Neurobiology. Boston: Kluwer Academic Publishers, 1992:305-65.
105: Pradotto L, Mencarelli M, Bigoni M, Milesi A, Di Blasio A, Mauro A. Episodic ataxia and SCA6 within the same family due to the D302N CACNA1A gene mutation. J Neurol Sci 2016;371:81-4. PMID 27871455
106: Przytuła F, Błądek S, Sławek J. Two COVID-19-related video-accompanied cases of severe ataxia-myoclonus syndrome. Neurol Neurochir Pol 2021;55(3):310-3. PMID 34096013
107: Puccio H, Simon D, Cossee M, et al. Mouse models of Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nature Genet 2001;27:181-6. PMID 11175786
108: Ramirez-Zamora A, Zeigler W, Desai N, Biller J. Treatable causes of cerebellar ataxia. Mov Dis 2015;30(5):614-23. PMID 25757427
109: Ribai P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol 2007;64:558-64. PMID 17420319
110: Robitaille Y, Lopes-Cendes I, Becher M, et al. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 1997;7(3):901-26. PMID 9217975
111: Rodríguez-Lebrón E, Costa Mdo C, Luna-Cancalon K, et al. Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Mol Ther 2013;21(10):1909-18. PMID 23820820
112: Rofaeel A, Balki M, Carvalho JC. Case report: successful labour epidural analgesia in a patient with spinocerebellar ataxia. Can J Anaesth 2007;54(6):467-70. PMID 17541076
113: Rossi M, Perez-Loret S, Doldan L, et al. Autosomal dominant cerebellar ataxias: a systematic review of clinical features. Eur J Neurol 2014;21(4):607-15. PMID 24765663
114: Ruiz-Garcia R, Martinez-Hernandez E, Joubert B, et al. Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2. Neurol Neuroimmunol Neuroinflamm 2020;7(2). PMID 31826987
115: Sakai H, Yoshida K, Shimizu Y, Morita H, Ikeda S, Matsumoto N. Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan. Neurogenetics 2010;11(4):409-15. PMID 20424877
116: Saucier J, Al-Qadi M, Ben Amor M, Ishikawa K, Chamard-Witkowski L. Spinocerebellar ataxia type 31: a clinical and radiological literature review. J Neurol Sci 2023;444:120527. PMID 36563608
117: Schoenberg BS. Epidemiology of the inherited ataxias. Adv Neurol 1978;21:15-32. PMID 367115
118: Schols L, Szymanski S, Peters S, et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet 2000;107:132-7. PMID 11030410
119: Seixas AI, Loureiro JR, Costa C, et al. A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia. Am J Hum Genet 2017;101(1):87-103. PMID 28686858
120: Seritan AL, Nguyen DV, Mu Y, et al. Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2014;75(3):264-71. PMID 24345444
121: Shaji B, Srikumar B, Ramachandran D. A preventable ataxia: cerebrotendinous xanthomatosis. Ann Indian Acad Neurol 2019;22(4):493-6.
122: Shams'ili S, Grefkens J, De Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003;126:1409-8. PMID 12764061
123: Shimojima Y, Hashimoto T, Kaneko K, et al. Thalamic stimulation for disabling tremor in a patient with spinocerebellar degeneration. Stereotact Funct Neurosurg 2005;83:131-4. PMID 16155369
124: Shirai S, Mizushima K, Fujiwara K, et al. Case series: downbeat nystagmus in SCA27B. J Neurol Sci 2023;454:120849. PMID 37907039
125: Shukla A, Upadhyai P, Shah J, Neethukrishna K, Bielas S, Girisha KM. Autosomal recessive spinocerebellar ataxia 20: report of a new patient and review of literature. Eur J Med Genet 2017;60(2):118-23. PMID 27913285
126: Spiegel R, Pines O, Ta-Shma A, et al. Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet 2012;90(3):518-23. PMID 22405087
127: Subramony SH, Filla A. Autosomal dominant spinocerebellar ataxias ad infinitum. Neurology 2001;56:287-9. PMID 11171890
128: Tate C, Siddiqui M, Haq I. A novel familial mutation in the CACNA1A gene associated with an episodic ataxia type 2 phenotype (S47.005). Neurology 2014;82(10):S47.005.
129: Taylor AM, Groom A, Byrd PJ. Ataxia-telangiectasia-like disorder (ATLD): its clinical presentation and molecular basis. DNA Repair 2004;3:1219-25. PMID 15279810
130: Tingaud-Sequeira A, Raldúa D, Lavie J, et al. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. Neurobiol Dis 2017;98:36-51. PMID 27890673
131: Tipton PW, Guthrie K, Strongosky A, Reimer R, Wszolek ZK. Spinocerebellar ataxia 15: a phenotypic review and expansion. Neurol Neurochir Pol 2017;51(1):86-91. PMID 27908616
132: Tsoi H, Yu AC, Chen ZS, et al. A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia. J Med Genet 2014;51(9):590-5. PMID 25062847
133: Urrea-Mendoza E, Okafor K, Ravindran S, Absher J, Chaubal V, Revilla F. Opsoclonus-myoclonus-ataxia syndrome (OMAS) associated with SARS-CoV-2 infection: post-infectious neurological complication with benign prognosis. Tremor Other Hyperkinet Mov (N Y) 2021;11:7. PMID 33614199
134: van de Warrenburg BP, van Gaalen J, Boesch S, et al. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol 2014;21(4):552-62. PMID 24418350
135: van Swieten JC, Brusse E, de Graaf BM, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet 2003;72(1):191-9. PMID 12489043
136: Victor M, Adams RD, Mancall EL. A restricted form of cerebellar cortical degeneration occurring in alcoholic patients. Arch Neurol 1959;1:579-88.
137: Vodopich DJ, Gordon GJ. Anesthetic management in Joubert syndrome. Paediatr Anaesth 2004;14(10):871-3. PMID 15385018
138: von Brederlow B, Hahn AF, Koopman WJ, Ebers GC, Bulman DE. Mapping the gene for acetazolamide responsive hereditary paroxysmal cerebellar ataxia to chromosome 19p. Hum Mol Genet 1995;4(2):279-84. PMID 7757080
139: Wadia N, Pang J, Desai J, et al. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees: the significance of slow saccades in diagnosis. Brain 1998;121:2341-55. PMID 9874485
140: Walker LA, Bourque P, Smith AM, Warman Chardon J. Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) associated with progressive cognitive and behavioral deterioration. Neuropsychology 2017;31(3):292-303. PMID 27869457
141: Wang JL, Yang X, Xia K, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 2010;133(Pt 12):3510-8. PMID 21106500
142: Wilke C, Pellerin D, Mengel D, et al. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain 2023;146(10):4144-57. PMID 37165652
143: Wollmann T, Barroso J, Monton F, et al. Neuropsychological test performance of patients with Friedreich's ataxia. J Clin Exp Neuropsychol 2002;24(5):677-86. PMID 12187450
144: Wong D, Dwinnel M, Schulzer M, Nimmo M, Leavitt BR, Spacey SD. Ataxia and the role of antigliadin antibodies. Can J Neurol Sci 2007;34:193-6. PMID 17598597
145: Wu TY, Taylor JM, Kilfoyle DH, et al. Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia ‘CANVAS’ syndrome. Brain 2014;137(Pt 10):2649-56. PMID 25070514
146: Yabe I, Matsushima M, Soma H, et al. Usefulness of the scale for assessment and rating of ataxia (SARA). J Neurol Sci 2008;266:164-6. PMID 17950753
147: Yang WY, Gao R, Southern M, Sarkar PS, Disney MD. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10. Nat Commun 2016;7:11647. PMID 27248057
148: Yrigollen CM, Davidson BL. CRISPR to the rescue: advances in gene editing for the FMR1 gene. Brain Sci 2019;9(1). PMID 30669625
149: Zanni G, Nardella M, Barresi S, et al. De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia, axonal polyneuropathy and nocturnal hypoventilation. Brain 2017;140(6):e34. PMID 28402445
150: Zesiewicz T, Perlman S, Sullivan K, et al. EPI-743 (alpha-tocotrienol quinone) demonstrates long-term improvement in neurological function and disease progression in Friedreich’s ataxia. Neurology 2017;88(16 Supplement):S17.005.
151: Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha1A-voltage-dependent calcium channel. Nat Genet 1997;15:62-9. PMID 8988170

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
See Profile

Former Authors

Martha A Nance MD (original author), Peter Hedera MD, and Muhammad M Nashatizadeh MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, >2:1
Heredity: heredity may be a factor
Population groups selectively affected: none preferentially affected
Occupation groups selectively affected: none preferentially affected

ICD & OMIM codes

ICD-9: Progressive ataxia: 094.0

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome: 277.87

Alcohol-related ataxia: 303.9

Degenerative cerebral ataxia: 331.89

Spinocerebellar disease: 334

Friedreich ataxia: 334.0

Hereditary spastic paraplegia: 334.1

Primary cerebellar degeneration: 334.2

Other cerebellar ataxia: 334.3

Cerebellar ataxia in diseases classified elsewhere: 334.4

Ataxia telangiectasia syndrome: 334.8

Spinocerebellar disease, unspecified: 334.9

Cerebellar hemorrhage: 431

Ataxia, late effect of cerebrovascular disease: 438.84

Agenesis of the cerebellum: 742.2

Gait ataxia: 781.2

Lack of coordination: 781.3

Cerebellar contusion with open wound: 851.5

Cerebellar laceration with open wound: 851.7
ICD-10: Progressive ataxia: A52.1

Alcohol-related ataxia: F10.2

Hereditary ataxia: G11

Congenital nonprogressive ataxia: G11.0

Early-onset cerebellar ataxia: G11.1

Late-onset cerebellar ataxia: G11.2

Ataxia telangiectasia: G11.3

Hereditary spastic paraplegia: G11.4

Other hereditary ataxias: G11.8

Hereditary ataxia, unspecified: G11.9

Alcoholic cerebellar degeneration: G31.2

Brain ataxia: G31.88

Neuropathy in association with hereditary ataxia: G60.2

Agenesis of the cerebellum: Q04.3

Gait ataxia: R26.0

Other and unspecified lack of coordination: R27.8

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Ataxia

Associated Disorders

Acute cerebellar ataxia in children
Autosomal dominant hereditary ataxias
Celiac disease (Neurologic complications of celiac disease)
Cerebellar astrocytoma
Chiari malformation
- Fragile X-associated tremor/ataxia syndrome
- Hereditary spastic paraplegia
- Medulloblastoma
- Nondominant hereditary ataxias
- Nonparaneoplastic autoimmune cerebellar diseases
- Paraneoplastic cerebellar degeneration
- Pontocerebellar hypoplasias
- Sensory neuropathies associated with anti-GD1b ganglioside antibodies
- Spinocerebellar ataxias
- Structural lesions of the cerebellum
- Wilson disease
- Many other specific disorders

Differential Diagnosis

May be confused with cerebellar ataxias:
Acquired sensory neuronopathies
Bilateral vestibulopathy
Ataxias associated with blindness
Ataxias associated with deafness
- Ataxias associated with peripheral neuropathies
- Ataxias associated with spinal cord disorders
- Disequilibrium
- Essential tremor (Tremors)
- Vestibular disorders

Also Relevant

Acute cerebellar ataxia in children
Alcohol abuse and its neurologic complications
Cerebellar infarction and cerebellar hemorrhage
Dysarthria
Functional movement disorders
- Gait disorders
- Imaging of movement disorders
- Movement disorders associated with autoimmune encephalitis
- Movement disorders in childhood
- Neurogenetics and genetic and genomic testing
- Outpatient rehabilitation of chronic neurologic conditions
- Principles of rehabilitation of patients with neurologic disorders
- Rating scales of movement disorders
- Sleep and cerebral degenerative disorders
- Vitamin E in neurologic disorders

Ataxia …

Ataxia

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Key Clinical Aspects of the Dominant Ataxias

Detailed descriptions of selected disorders

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. Genetic Aspects of the Dominantly Inherited Ataxias

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

Ataxia

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Key Clinical Aspects of the Dominant Ataxias

Detailed descriptions of selected disorders

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. Genetic Aspects of the Dominantly Inherited Ataxias

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

This is an article preview.
Start a Free Account
to access the full version.