Assessment of Ataxia: The Right Clinical Information, Right Where It's Needed

Assessment of ataxia
The right clinical information, right where it's needed
Last updated: Jan 09, 2017

Table of Contents
Summary 3
Overview 5
Aetiology 5
Emergencies 17
Urgent considerations 17
Red flags 17
Diagnosis 19
Step-by-step diagnostic approach 19

Differential diagnosis overview 25
Differential diagnosis 28
Diagnostic guidelines 47
Online resources 49
References 50
Images 54
Disclaimer 62
Summary
◊ Ataxia is a neurological syndrome characterised by clumsy and unco-ordinated movement of the limbs, trunk,
and cranial muscles. It results from pathology in the cerebellum and its connections, or in the proprioceptive
sensory pathways. The list of causes of ataxia is extensive. Typically, ataxia is classified on the basis of whether
it is hereditary or acquired. Ataxia may also be classified by age of onset (childhood versus adulthood) or by
whether it is associated with other clinical features (e.g., seizures, dystonia, vision loss). Degenerative ataxia is
the term used to denote ataxia related to cerebellar atrophy of both genetic and unknown causation. Other
terms that have been used for this type of ataxia in a broad sense include spinocerebellar degenerations and
olivopontocerebellar atrophy, but these are becoming obsolete. [National Ataxia Foundation]
◊ Clinical signs :
Cerebellar ataxia produces a characteristic set of signs.[1] Gait is unsteady with tendency to falls, hand co-ordination
is impaired, and the patient may experience dysarthria or dysphagia. There may also be ocular symptoms related
to abnormal control of eye movements. Neurological examination shows dysmetria of limbs (inaccuracy of
targeted movements), as shown by abnormal finger-chase using patient fingers or toes. The patient may display
a kinetic tremor of limbs and an uncontrolled oscillation of limbs during relatively slow but targeted movements.
Early stance and gait problems include the inability to do a tandem stance or stand with feet together; stance
becomes broad-based and displays increased sway of the body. Tandem gait becomes impaired and, later, regular
gait can be frankly ataxic with a broad-based and lurching quality. Eye movements show gaze-evoked or other
types of nystagmus, abnormal pursuit of visually presented objects (jerky appearance due to intrusion of saccades
into pursuit), and inaccurate saccades when the person is asked to move the eyes quickly towards a target
(hypometric or hypermetric saccades). There is also a scanning type of dysarthria.
Sensory ataxia is characterised by lower-limb and upper-limb inco-ordination associated with lack of
proprioception. Clinical signs include impaired vibration sense, as well as impaired position and kinaesthetic
sense. Deep tendon reflexes are often absent, but eye movements and speech are not affected. In some patients,
sensory and cerebellar features can co-exist.
Patients with ataxia as a major feature often exhibit additional non-cerebellar neurological signs, either because
the lesion causing the ataxia extends beyond the cerebellum into neighbouring structures or because the
degenerative condition involves structures beyond the cerebellum.
◊ Epidemiology :
There are no precise data regarding the prevalence of ataxia of all causes.[2] [3] Epidemiological studies that
focus on hereditary types of ataxia have shown a prevalence of around 10 per 100,000 population, and idiopathic
ataxia probably outnumbers hereditary cases.[4] Because there are many causes of degenerative and inherited
ataxias, each individual type of ataxia is relatively rare. In the case of genetic forms of ataxia, there are clusters
of high incidence of specific types due to founder effects and ethnic and geographical variations in the prevalence
of many mutations.[5]
◊ Aetiology :
Ataxia may be acquired or genetic. The list of acquired causes is extensive and includes vascular, demyelinating,
neoplastic, autoimmune, toxic, degenerative, compressive, and infectious aetiologies. In many of these, ataxia
may be a major clinical finding or be overshadowed by other signs. Many acquired lesions can be easily identified
on imaging studies. However, imaging studies may reveal only cerebellar atrophy, a non-specific finding,
necessitating further diagnostic work-up.
Genetic ataxias may be further classified by their mode of inheritance, such as autosomal dominant, autosomal
recessive, or X-linked. In many of the commonly identified genetic ataxias, the clinical picture is dominated by
cerebellar signs. However, many inherited metabolic errors, especially in childhood, can have ataxia as a major
or minor feature. [Online Mendelian Inheritance in Man (OMIM)] In general, genetic forms of ataxia result in
cerebellar atrophy and atrophy of related structures, which can be seen on imaging studies.
◊ Pathogenesis :
The inherited ataxias have recently been the focus of increasing understanding of molecular mechanisms.[5]
[6] [7] [8] More than 40 distinct gene defects cause ataxia as a major feature, and recessive, dominant, X-linked,
and mitochondrial mutations have been identified. A wide range of primary pathogenic mechanisms have been
proposed, including oxidative stress, problems with respiratory chain function, cytoskeletal abnormalities, DNA
repair abnormalities, chaperone protein dysfunction, protein misfolding and aggregation, and channel dysfunction,
among others.
◊ Disorders resembling ataxia :

Many types of gait problem can superficially resemble ataxia. Examples include gait abnormalities from bilateral
frontal lobe lesions (i.e., frontal ataxia or Brun ataxia) and occasionally dystonic gait. Gait disorders from muscle
disease, neuropathies, and spinal cord problems can usually be easily differentiated by clinical examination.
Gait difficulties from lesions of the vestibular apparatus also need to be differentiated from cerebellar ataxia.
The co-ordination problem in the limbs is in the nature of "past pointing" rather than true dysmetria, and eye
movement problems are often confined to nystagmus in the primary position. Dysarthria is not a feature of
vestibular disease, but nausea and oscillopsia can be a feature of vestibular lesions.
The presence of speech and oculomotor signs related to cerebellar pathology can clearly differentiate cerebellar
ataxia from other types of inco-ordination.
Assessment of ataxia Overview
Aetiology
Ataxia can be caused by an array of conditions. The aetiology of ataxia may be broadly categorised as acquired and
inherited.
OVERVIEW
Acquired causes
Toxic
• Alcoholic cerebellar degeneration is probably the most frequent form of acquired ataxia. It mainly results in a midline
(vermian) cerebellar degeneration leading to prominent gait ataxia in the absence of major upper limb, speech, or
oculomotor problems, although all of these can be seen in some people.
• Many medications can result in ataxia, including anticonvulsants (such as phenytoin, carbamazepine, vigabatrin,
gabapentin, and phenobarbital, as well as some of the newer agents[9]), fluorouracil, cytarabine, intrathecal
methotrexate, lithium, amiodarone, cyclosporine, bismuth salts, and epothilones.
• Mercury toxicity and toluene exposure have been reported to cause ataxia.
Vascular and hypoxic
• Acute ataxia can result from both ischaemic and haemorrhagic stroke in the cerebellum or cerebellar pathways.
• A more sub-acute ataxia can occur with vascular malformations in the cerebellum (e.g., von Hippel-Lindau syndrome).
• A stable ataxic syndrome can be a sequel to recovery from major hypoxia or heat stroke as well as previous ischaemic
or haemorrhagic strokes.
Infectious/para-infectious
• In children, acute ataxia can occur in the setting of a viral infection such as chickenpox or after immunisation (i.e.,
acute cerebellitis and acute cerebellar ataxia of childhood).[10] [11] The cerebellum can also be affected in more
diffuse encephalomyelitis, which is often thought to be an autoimmune problem triggered by an antecedent
infection.
• Rapid onset of ataxia with headache can be caused by a cerebellar abscess, which can be a complication of middle
ear infections.
• HIV infection has been associated with a form of progressive ataxia that becomes debilitating over several months;
many cases of HIV dementia may exhibit ataxia at onset.[12]
• Prion protein disease can have a predominantly ataxic presentation. Although there is an ataxic variant of
Creutzfeldt-Jakob disease (CJD), an ataxic presentation may be more frequent with familial prion disease
(Gerstmann-Straussler syndrome), as well as with variant CJD related to contaminated meat.[13]
• Whipple's disease may have ataxia as a neurological complication.[14]
Neoplastic/compressive
• Tumours associated with ataxia include medulloblastomas, astrocytomas, ependymomas, haemangioblastomas,

meningiomas, and cerebellopontine angle schwannomas.
• Primary tumours in the posterior fossa seem to be more common in children. Cerebellar gliomas and ependymomas
can present with ataxia in addition to symptoms of raised intracranial pressure. Pontine gliomas in children usually
manifest multiple cranial nerve palsies with ataxia and other signs.
• In adults, both metastatic and primary tumours in the cerebellum and its vicinity (such as posterior fossa
meningiomas) and meningeal carcinomatosis can have an ataxic presentation.
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• Non-neoplastic causes of cerebellar compression include skeletal abnormalities at the craniovertebral junction,
such as basilar invagination and Arnold-Chiari malformation.
Autoimmune
OVERVIEW
• Ataxia can be a feature of multiple sclerosis when lesions occur in the cerebellum or brain stem. Often, signs related
to other structures such as the optic nerve, spinal cord, and cerebral hemispheres can be found.
• Paraneoplastic cerebellar degenerations are usually related to immune dysfunction triggered by an underlying
visceral cancer such as those of the lung, ovary, or breast. In most of these cases, the ataxia precedes the diagnosis
of cancer, which may require careful assessment to detect.
• Opsoclonus-myoclonus-ataxia (OMA) is a syndrome characterised by ataxia, involuntary multivectorial eye

movements, and muscle twitches. In children, OMA may be triggered by an underlying neuroblastoma. In adults,
OMA is associated with paraneoplastic, infectious (e.g. West Nile virus), or post-infectious aetiologies.
• More recently, an immune basis for isolated ataxia has been proposed, involving antibodies to gliadin (coeliac
disease) and antibodies to glutamic acid decarboxylase (GAD).[15] [16]
Endocrine
• Hypothyroidism and hypoparathyroidism may present with ataxia.
Nutritional
• Deficiencies of vitamin B1 and vitamin B12 may result in ataxia, the former from cerebellar vermis pathology and
the latter from posterior column dysfunction.
• Ataxia related to vitamin B1 deficiency is often part of Wernicke-Korsakoff syndrome in alcoholic people and other
patients who have severe nutritional deficiency.
• Severe vitamin E deficiency, as occurs in fat malabsorption or certain genetic syndromes, may result in ataxia.[17]
Sensory neuropathies
• Pure sensory neuropathies that primarily affect large myelinated fibres in the peripheral nerves cause sensory
ataxia because of loss of proprioceptive sensation.[18]
• These patients exhibit gait and limb inco-ordination with no involvement of eye movements or bulbar co-ordination,
but the gait problems can be similar to those in cerebellar ataxia.
• Causes include paraneoplastic neuropathy, certain toxins (e.g., platinum drugs, large doses of vitamin B6), Sjogren's
syndrome, and neuropathy related to monoclonal gammopathy. Some cases are idiopathic.
• An acute form of neuropathy resulting in ataxia is the Miller-Fisher variant of Guillain-Barre syndrome, which causes
ataxia, ophthalmoplegia, and areflexia evolving over a few days. A similar clinical picture can be caused by brain
stem encephalitis (Bickerstaff's encephalitis).
Inherited causes
Inherited ataxias usually have a chronic evolution, measured in many years. Autosomal-recessive, autosomal-dominant,
and X-linked genetic defects, and defects involving mitochondrial genes, can result in ataxia as a major clinical symptom.
Recent years have seen an explosion of knowledge regarding various gene mutations associated with ataxia.
In autosomal-recessive ataxias, parents (who carry single mutated alleles) are not symptomatic, but their offspring, who
may inherit a mutated allele from each of the parents, have symptomatic disease. Thus, the disease may affect many
siblings but can appear just in a single child if the sibship is of small size.[18] [19] [20]
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Autosomal-dominant ataxias occur when only one allele is mutated and is transmitted from generation to generation,
with each offspring of an affected person having a 50% risk. By convention, progressive autosomal-dominant ataxias are
labelled spinocerebellar ataxia (SCA), followed by a number to denote a particular gene locus. In addition, there are
autosomal-dominant ataxias with episodic symptoms (episodic ataxias).
OVERVIEW
X-linked ataxias primarily affect men but are passed on through women. An unusual type of X-linked ataxia is called
fragile-X tremor-ataxia syndrome (FXTAS).
Mitochondrial DNA mutations, either sporadic or maternally inherited, can result in ataxia.
Inherited causes: autosomal recessive

Friedreich's ataxia
• Most common autosomal-recessive ataxia and also the most common inherited ataxia presenting in people aged
5 to 20 years.
• Gene mutation is an expanded trinucleotide repeat (GAA repeat) in the first intron of the frataxin gene on
chromosome 9. The mutation seems confined to Indo-European populations.[6]
• Pathogenesis seems to involve the deficiency of frataxin, a protein that functions in the mitochondrial handling of
iron.
• Associated with a variable clinical phenotype. Clinical features include ataxia, peripheral neuropathy, corticospinal
tract signs, kyphoscoliosis, diabetes, hearing loss, and restless leg syndrome.[21]
• Hypertrophic cardiomyopathy is a cardinal feature; therefore, all patients with Friedreich's ataxia should be screened
for cardiomyopathy with an ECG and echocardiogram.[22] Death often occurs before age 40 years in the classical
group, but variant patients can have a long life, especially if cardiomyopathy is not present.
Ataxia telangiectasia
• The most common cause of inherited ataxia presenting at <5 years of age.
• Results from point mutations, insertions, and deletions in the ATM gene on chromosome 11. The gene product of
ATM seems to be involved in double-strand DNA break repair.[20] [23]
• Clinical features include ataxia, oculocutaneous telangectasias, and immunodeficiency with recurrent sinopulmonary
infections.
• Children have increased radiation sensitivity and develop malignancies (usually lymphoreticular) during childhood.
• Those who survive to adulthood also have increased risk of solid tumours.
• Alpha-fetoprotein levels are high.
Ataxia with oculomotor apraxia 1 (AOA 1)
• A rare form of autosomal-recessive ataxia.
• The causative mutations involve the aprataxin gene, possibly involved in single-strand DNA break repair.[20] [24]
• Clinical features include ataxia, peripheral neuropathy, and oculomotor apraxia.
• Patients exhibit hypoalbuminaemia and hypercholesterolaemia.
• The second most common form of autosomal-recessive ataxia in some areas such as Portugal, and perhaps the
most common in Japan.
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• Mutations involve the senataxin gene, again associated with single-strand DNA break repair and RNA processing.[20]
[25] [26]
• Clinical features are similar to those seen in AOA 1.

OVERVIEW
Ataxia with vitamin E deficiency (AVED)
• Many cases have been described from the Mediterranean rim and in an isolated Japanese island, although cases
are seen elsewhere as well.
• Ataxia results from vitamin E deficiency.
• The underlying mutation involves the alpha-tocopherol transfer gene, a hepatic protein involved in the packaging
of vitamin E into very low-density lipoproteins.[20]
Abetalipoproteinaemia
• Ataxia in this disease also results from vitamin E deficiency and resembles that in AVED.
• There is a defect in fat absorption related to a mutation in the gene coding for microsomal triglyceride transfer
protein.[20]
• Clinical features include ataxia, acanthocytosis, and retinal degeneration.[27]
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
• This childhood ataxia was originally described as a cluster of cases from the Charlevoix-Saguenay province of Quebec
in Canada.
• A mutation in the gene SACSIN, which codes for a possible chaperone-related protein, was found.[20]
Ataxia due to POLG 1 mutations
• Has also been named mitochondrial-recessive ataxia syndrome (MIRAS).
• POLG 1 is a nuclear-encoded polymerase involved in mitochondrial DNA synthesis.[20]
• Clinical features include ophthalmoplegia and muscle weakness, difficulty swallowing, and ataxia.
Ataxia due to SCYL1 mutation
• Presents with progressive gait ataxia with cerebellar atrophy, peripheral neuropathy, and recurrent episodes of liver
failure in childhood.[28]
Infantile-onset spinocerebellar ataxia (IOSCA)
• An infantile-onset ataxia described from Finland, this condition is rare.
• Mutations have been described in the C10orf2 gene, which codes for a mitochondrial protein Twinkle and its splice
variant Twinky.[20]
Spinocerebellar ataxia with axonal neuropathy (SCAN1)
• Caused by mutations in the TDP1 gene, which codes for tyrosyl-DNA phosphodiesterase protein, involved in
single-strand DNA break repair.[20]
• Considered rare.
Ataxia telangiectasia-like disorder (ATLD)
• Mutations have been noted in the gene MRE 11, also a part of the DNA double-strand break repair process.[20]
OVERVIEW
Marinesco-Sjogren syndrome
• The mutation involves the gene SIL 1, involved in chaperone function.[20]
• Clinical features include ataxia, cataracts, developmental delay, and short stature.
Ataxia with muscle CoQ10 deficiency
• Genetically, patients with ataxia and CoQ10 deficiency are heterogeneous. In a subset of these patients, the AOA
1 mutation can be found.[18]
Ataxia in recessively inherited (or X-linked) errors of metabolism
• In some well-recognised metabolic errors, ataxia can be a major or minor feature. In the case of diseases such as
hyperammonaemic syndromes, aminoacidurias, and pyruvate/lactate metabolic diseases, ataxia can be intermittent.
• Examples include ornithine transcarbamylase deficiency and pyruvate dehydrogenase deficiency. In other diseases,
such as cerebro-tendinous xanthomatosis and hexosaminidase deficiency, a progressive ataxia can develop.[18]
[20]
• Other diseases in which ataxia can occur include Wilson's disease, Refsum's disease, and adrenomyeloneuropathy.
Miscellaneous ataxias
• A number of childhood ataxias are as yet incompletely understood.
• Ataxia with myoclonus in one population has been related to cystatin B mutations (Unverricht-Lundborg disease);
other entities that can cause this combination include mitochondrial DNA mutations, ceroid lipofuscinosis, and
sialidosis.
• Similarly, in some children with ataxia an association with hypogonadism is found; this may also be mitochondrial
in origin in some children but related to other genetic disorders in others.
Note: IOSCA, SCAN1, ATLD, Marinesco-Sjogren syndrome, and the miscellaneous ataxias will not be discussed in further
detail in this monograph owing to their rarity.
Niemann-Pick disease type C (NP-C)
• Gene mutation is in either the NPC1 or NPC2 genes. This causes intracellular accumulation of cholesterol and
alterations in sphingolipid metabolism. NPC1 mutation is responsible for the majority (95%) of cases.[29]
• Manifestations vary according to the age of onset. Ataxia may be a feature of the late-infantile-, juvenile-, and
adult-onset forms. This may present with dysmetria, dysdiadochokinesia, dysarthria, and gait ataxia, and is associated
with Purkinje cell loss in the cerebellum. Cerebellar ataxia is a common presentation of the adult-onset form. Other
neurological features include abnormalities in voluntary saccadic eye movements (often the earliest visible
neurological sign), myoclonus or myoclonic tremor, dystone, seizures, low muscle tone, developmental delay in
children, and dementia in adults. Systemic symptoms include hepatosplenomegaly and liver disease.
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• Patients generally die prematurely, although life expectancy varies. The majority of patients die between the ages
of 10 and 25 years; however, adult-onset cases may live into the seventh decade of life.[29]
OVERVIEW
Inherited causes: autosomal dominant

Spinocerebellar ataxias (SCA) all have similar clinical features, although distinctive signs can be seen in some types.[5]
[20] [7] [30] [31] However, no single feature can definitely differentiate one genotype from another. Many of the commonly
recognised SCAs are related to unstable nucleotide repeat expansions, SCA 3 (also known as Machado-Joseph disease),
SCA 2, SCA 6, and SCA 1 being the most common worldwide.[32] Many are due to expanded trinucleotide repeat mutations.
In these repeat expansion diseases, anticipation in age at onset is common and at least partly related to a tendency for
the expansion size to become larger with transmission to the younger generation.
More recently characterised SCAs have other mutational mechanisms such as point mutations, insertions, and deletions.
The clinical experience with such SCAs is more limited, and the entire phenotypic spectrum of some of these may not
yet be evident. Note that there is no SCA 9 or SCA 24. The true prevalence of some of these may be higher than is currently
recognised. As the SCAs are autosomal dominant, the utility of genetic testing in patients with personal but no family
history of progressive ataxia was unclear. Interestingly, one study using a novel technique of next-generation exome
sequencing in patients with adult onset and sporadic presentations demonstrated that this is a high-yield test, giving a
definitive diagnosis in more than one fifth of patients, and suggesting a potential diagnosis in more than one third. The
study posits that, in future, clinical exome sequencing may be considered as part of the routine evaluation of all patients
presenting with chronic progressive cerebellar ataxia.[33]
In addition, there are families in which ataxia occurs as an episodic feature, with normal periods in between or with mild
residual signs (episodic ataxias).[7]
Spinocerebellar ataxia 1 (SCA 1)
• The first autosomal-dominant ataxia to be localised to a chromosome, and probably the fourth most common type
of autosomal-dominant ataxia worldwide.
• Clinical features include ataxia as well as upper motor neuron signs, hypermetric saccades, peripheral neuropathy,
dysarthria, and onset in young adulthood.
• Death results from complications of poor mobility such as aspiration and pneumonia, poor nutrition, and urinary
tract infections.
• The mutation is an unstable expansion of a CAG repeat in the ataxin 1 gene (ATXN1) on chromosome 6p23.
• Phenotype closely resembles that of SCA 1.
• Large Cuban founder population.
• The mutation is an unstable CAG repeat expansion in the ataxin 2 gene, ATXN2 (chromosome 12q).
• May present in infancy with hypotonia, mental retardation, and retinitis pigmentosa, or in adulthood with ataxia,
slow saccades, peripheral neuropathy, and hyporeflexia.[34] [35]
Spinocerebellar ataxia 3 (SCA 3 or Machado-Joseph disease [MJD])
• The MJD mutation is a CAG repeat expansion in the ataxin 3 protein encoded by the MJD 1 gene, ATXN3 (chromosome
14q).
• Large Portuguese founder population.
• The most common spinocerebellar ataxia.
• Clinical features include ataxia, as well as slow saccades, lid retraction, nystagmus, cognitive impairment, and
extrapyramidal signs such as dystonia or parkinsonism.
• May have either upper motor neuron signs (spasticity, hyper-reflexia, and upgoing toes) or lower motor neuron
signs (fasciculations and decreased tone).
OVERVIEW
• There is limited experience with SCA 4, which has been localised to chromosome 16q.
• Japanese cases segregate with a nucleotide polymorphism in the puratrophin gene at this locus, but the pathogenic
role of this is not clear.
• Sensory axonal neuropathy and deafness.
Spinocerebellar ataxia 5 (SCA 5, or Lincoln ataxia)
• There are a limited number of families worldwide with documented SCA 5. The members of the original family that
allowed localisation of SCA 5 to chromosome 11q were descendants of the family of Abraham Lincoln.
• Has a relatively better prognosis than SCA 1, 2, and 3; early onset but slow course.
• Point mutations and insertions in the beta-spectrin gene, SPTBN2, have been found to cause SCA 5.
• Presents in early adulthood with a pure cerebellar syndrome.
• The mutation is a small CAG repeat expansion in the alpha-subunit of the neuronal P/Q type calcium-channel gene,
CACNA1A, on chromosome 19q.
• Presents during a wide age range, from early adulthood up to the 6th decade of life, with slowly progressive ataxia.
• Clinical features include horizontal and vertical nystagmus.[36]
• Different mutations in this same gene cause episodic ataxia type 2 and familial hemiplegic migraine. There is some
clinical overlap between these three disorders.[37]
• A highly unstable CAG expansion in the ataxin 7 (ATXN7) gene (chromosome 3q) is responsible for the disease.
• Clinical features include retinal degeneration with subsequent vision loss and ataxia; often rapidly progressive.
Childhood onset is associated with seizures and myoclonus.
• Unusual in that it is caused by a trinucleotide repeat mutation with bidirectional expression (CTG*CAG) to form two
mutant genes. The gene ataxin 8 (ATXN8) is encoded in the CAG direction, while the ataxin 8-opposite-strand gene
expresses a noncoding CUG expansion RNA. Both products probably contribute to disease state.[38]
• SCA 8 has very poor penetrance, particularly when inherited from the father. CTG repeats may contract in sperm.[39]
• Clinical features include ataxia, and hyper-reflexia with oculomotor dysfunction in more advanced disease; slowly
progressive.
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• Described so far only in families of Mexican and other Central and South American descent, and may be confined
to people with American Indian heritage.
• The causative mutation is an unstable pentanucleotide (ATTCT) expansion in a 5' UTR of the ataxin 10 gene on
chromosome 22q.
OVERVIEW
• Gene is expressed throughout the brain; patients have both cerebellar and cortical atrophy.
• Ataxia and occasional seizures.
• Very limited experience with this disease.
• The mutation has been found to involve the TTBK 2 gene, which is involved in the tau protein pathway. Locus is on
chromosome 15q.
• Mild ataxia.
• Rare in most of the parts of the world, but a number of families have been reported from India.
• The mutation is a CAG expansion, but this tract is located in the promoter region of the PPP2R2B gene on
chromosome 5q.
• Slowly progressive ataxia, dementia, parkinsonism, hyperreflexia, and action tremor.
• Mutations in a potassium channel gene (KCNC3) on chromosome 19q.
• Short stature and mild cognitive impairment.
• A small number of families have been described. The mutation involves the PRKCG gene on chromosome 19q.
• Axial myoclonus.
Spinocerebellar ataxia 15/16 (SCA 15/16)
• In an Australian kindred with pure cerebellar ataxia and slow progression, deletions involving two contiguous genes
(SUMF1 and ITPR1) were found on chromosome 3q.
• Japanese families with slowly progressive ataxia and head tremor, originally labelled SCA 16, were also found to
have deletions in the ITPR1 gene, which makes it likely that this is the causative gene.[40] [41]
• A number of families, as well as sporadic cases, with this mutation have been described.
• Caused by a CAG repeat expansion in the TATA-binding protein gene (TBP) on chromosome 6q.
• Cognitive decline and extrapyramidal symptoms, including chorea, dystonia, myoclonus, and epilepsy.
Spinocerebellar ataxia 18 (SCA 18), also called autosomal dominant sensorimotor neuropathy with ataxia
• Reported in a single family with a gene locus on chromosome 7q.
• Candidate gene is IFRD1.
• Nystagmus, hyporeflexia, dysarthria, sensorimotor neuropathy.
OVERVIEW
Spinocerebellar ataxia 19/22 (SCA 19/22)
• Described in a single Dutch family and localised to chromosome 1p.
• The same region is a possible locus for SCA 22,[42] reported to cause isolated ataxia of late onset in a Chinese family.
• Mutation in the voltage-gated potassium channel KCND3.
• Cognitive impairment, myoclonus, tremor, hyperreflexia, slowly progressive.[42] [43] [44] [45]
• Described in a single Australian family. The genetic abnormality is on chromosome 11 and involves the duplication
of a segment of DNA.
• Characterised by slowly progressive ataxia and dysarthria.
• Two-thirds of those affected display palatal myoclonus and spasmodic dysphonia; dysphonia may precede ataxia
by years. Bradykinesia and hyperreflexia also present.
• Dentate calcification on computed tomography (CT).
• Mutation in TMEM240 on chromosome 7p.
• Cognitive impairment and extrapyramidal signs, including rigidity, akinesia, and hyporeflexia.
• Reported to cause ataxia in four Dutch families.
• Caused by mis-sense mutation in prodynorphine gene.[46]
• Reported in one French family. Localised to chromosome 2p.
• Peripheral sensory neuropathy and areflexia.
• Causes isolated ataxia. Reported in a single family and localised to chromosome 19p.
• Dysarthria.
• Gene is EEF2.
• Reported in a single family.
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• Mutation found in the fibroblast growth factor (FGF) 14 gene (chromosome 13 q).
• Early onset tremor, facial dyskinesia, and sensory neuropathy.

OVERVIEW
• Reported in a single Italian family.
• May be due to mutation in AFG3L2 gene on chromosome 18.[47]
• Hyperreflexia, ptosis, and ophthalmoparesis.
• Reported in a single family with congenital non-progressive ataxia and localised to chromosome 3p, gene ITPR1.
• Pure ataxia.
• Reported in a single Australian family with locus at chromosome 4q.
• Pure ataxia.
• Caused by a complex pentanucleotide repeat containing TAAAA, TAGAA, and TGGAA. lying in an intro shared by
two different genes, BEAN and TK2, which are transcribed in opposite directions.[48]
• Ataxi and progressive sensorineural hearing loss.
• Common in Japan.[30]
• Unknown gene on 7q32-q33.
• Cognitive impairment.
• Azoospermia in males.
• Gene ELOVL4 on 16p12.
• Neurocutaneous syndrome and hyporeflexia; skin changes disappear in adulthood.
• Mutation in TGM6 on 20p13.
• Pseudobulbar palsy, tremor, hyperreflexia, and torticollis.
Spinocerebellar ataxia 36 (SCA 36/Asidan)
• Caused by a hexanucleotide GGCCTG repeat expansion of the nucleolar protein 56 (NOP56) gene. This presents
with truncal ataxia, ataxic dysarthria, limb ataxia, hyper-reflexia, and progressive lower motor neuron disease. There
is cerebellar Purkinje cell degeneration with loss of lower motor neurons as well. Typical age of onset is 50 years
and older.[49]
OVERVIEW
• Unknown gene on chromosome 1p32.
• Abnormal vertical eye movements.
• Mutation in ELOVL5 on 6p12.
• Adult onset ataxia, sensory axonal neuropathy.
• Gene CCDC88C on 14q32.
• Adult onset ataxia.
• Spasticity and brisk reflexes.
Dentatorubral-pallido-luysian atrophy (DRPLA)
• This disorder is grouped under the ataxias, despite not having an SCA designation, because ataxia forms a major
feature of the disease.
• Pathologically characterised in the 1970s in a US family with ataxia, and shown to have degenerative changes in
the cerebellar dentate, red nucleus, the pallidum, and the subthalamic nucleus.
• Clinical features include, in addition to ataxia, seizures, chorea, dystonia, myoclonus, dementia, and parkinsonism.
• There are many more families with DRPLA in Japan, where the underlying mutation was found to be a CAG expansion
in the atrophin gene on chromosome 12. The expansion is highly unstable, and large anticipation can occur with
childhood onset of disease.
Episodic ataxia type 1 (EA 1)
• Reported to cause very brief episodes (minutes) of imbalance that begin in childhood.
• Interictally, there are no neurological deficits except the presence of skeletal muscle myokymia.
• A mutation in a potassium-channel gene (KCNA 1) on chromosome 12q is responsible.[7]
Episodic ataxia type 2 (EA 2)
• Causes episodes of ataxia that last several hours, often associated with a variable set of features.
• Due to a point mutation (usually nonsense) in the same calcium-channel subunit (CACNA 1A) that is affected in
SCA 6. In addition, missense mutations in the same gene are associated with familial haemiplegic migraine.[7]
Other episodic ataxias
• There is limited experience with additional genetic types of episodic ataxias.
• Mutations have been found in a calcium-channel subunit (CACNB4) in EA 5 and in a glutamate transporter gene
(SLC1A3) in EA 6.
15
• EA 3, EA 4, and EA 7 are genetically distinct, but the mutations are unknown.
Note: SCAs for which DNA diagnostics are not easily available (SCA 4, SCA 15/16, SCA 18, SCA 19, SCA 21, SCA 22, SCA
23, SCA 25, SCA 26, SCA 27, SCA 29, SCA 30, SCA 31, and SCA 36) are not discussed in further detail in this monograph.
OVERVIEW
Inherited causes: X-linked

A few families with ataxia have an X-linked pattern of inheritance, but these have not been characterised genetically. A
more interesting situation occurs with fragile-X tremor-ataxia syndrome (FXTAS). Fragile X syndrome is the most common
cause of male mental retardation and is related to the expansion of a CGG repeat (repeated more than 200 times) in the
FRAXA gene on the X chromosome.[50] Both mothers and maternal grandfathers of FXTAS patients may harbour a
pre-mutation (55 to 200 copies) in the affected allele. Men who carry such a pre-mutation (but rarely the women) may
develop a neurological syndrome in late adult life characterised by cerebellar ataxia, intentional tremor, and peripheral
neuropathy. Parkinsonism may be observed.[51] However, some studies focused on sporadic ataxia have shown that the
fragile-X pre-mutation is over-represented in such patients compared with controls.[8]
Inherited causes: mitochondrial DNA mutations

Ataxia can occur in many diseases related to primary abnormalities of mitochondrial DNA and resultant respiratory chain
defects. Often, the ataxia is just one of many nervous system and systemic features of the disease. Thus, ataxia can
complicate such diseases as: myoclonic epilepsy with ragged red fibres (MERRF); mitochondrial encephalomyopathy with
lactic acidosis (MELAS) and stroke-like episodes; neurogenic weakness, ataxia, and retinitis pigmentosa (NARP); and
Kearns-Sayre syndrome (KSS). Some of these syndromes appear in a sporadic fashion (e.g., KSS); others are maternally
inherited.[52]
Idiopathic (sporadic)
This term is used for progressive ataxia, usually with onset in late adult life (i.e., >50 years of age), with or without other
nervous system signs for which no definite cause can be established.
Although there are no definite guidelines established, it is the author's view that onset of ataxia below the age of 50 years
is much more likely to be the result of a monogenic disorder, even if no definite diagnosis can be established. These
patients' ataxias clinically resemble many of the SCAs, but the family history is negative and they have no demonstrable
gene mutations.
It should be pointed out that a small number of clinically diagnosed "sporadic" ataxia patients (i.e., with no family history)
will have an ataxia gene mutation on molecular testing. The mutations reported with some frequency are those associated
with Friedreich's ataxia, SCA 6, SCA 8, SCA 2, SCA 3, and FXTAS.
Truly sporadic ataxia patients often fall into 2 groups: those in whom non-ataxic signs appear during follow-up (such as
brain stem signs, extrapyramidal signs, and autonomic failure), and those in whom the ataxia remains the sole feature.
These groups can also often have distinctive imaging features, with pontocerebellar atrophy in the former and isolated
cerebellar atrophy in the latter.
Sporadic ataxia patients in whom additional signs appear to transition into a syndrome indistinguishable from multiple
system atrophy (MSA) and who tend to have a relatively shorter course towards death (about 9 years from onset) compared
with the pure cerebellar group may have MSA-cerebellar type (MSA-C) ataxia.[53] These patients develop signs such as
parkinsonian features and dysautonomia in addition to ataxia and exhibit characteristic glial cytoplasmic inclusions on
pathological examination of the nervous system.
Assessment of ataxia Emergencies
Urgent considerations
(See Differential diagnosis for more details)
Ischaemic stroke
Cerebellar strokes can result in increased intracranial pressure because of attendant oedema over the course of a few
days. Close monitoring of patients for increasing lethargy and signs of brain stem compression is needed, preferably in
an intensive care unit (ICU) setting. Occasionally, ventricular drainage or urgent decompression of the posterior fossa
can be life-saving.
Additionally, both cerebellar strokes and brain stem strokes that initially present with ataxia may develop additional and
sometimes life-threatening problems related to extension of the stroke. Recognition of this with judicious monitoring
and use of various forms of anticoagulation and thrombolysis are important. It should be stated that, in some patients
with posterior circulation strokes, the symptoms may seem very non-specific, such as dizziness indistinguishable from
more common vestibular pathologies. Ataxia can be distinguished from a vestibular problem by the presence of vertigo
and oscillopsia. Hearing loss and tinnitus are more typically associated with lesions in cranial nerve 8 or the vestibular
apparatus. A direction-changing nystagmus and subtle skew deviation that can be detected by the "cover" test may be
EMERGENCIES
clinical indicators of a brain stem infarct, rather than a vestibular lesion. MRI scans with appropriate diffusion-weighted
sequences can detect small acute ischaemic lesions and should be obtained when in doubt.
Cerebellar haemorrhage
Can result in increased pressure in the posterior fossa with both upward transtentorial herniation and downward tonsillar
herniation. These are life-threatening and may need ventriculostomy and urgent decompression.
Acute cerebellitis
Oedema and raised pressure in the posterior fossa is a rare complication of acute cerebellitis in children. Children in
whom oedema is detected or who develop signs of such (e.g., lethargy) require ICU monitoring and may need
ventriculostomy and decompression of the posterior fossa.
Miller-Fisher syndrome
This is a variant of Guillain-Barre syndrome and can soon evolve to affect the muscles of swallowing, as well as respiratory
and limb muscles. These patients need monitoring of their respiratory function and, often, prophylactic placement in
the ICU and even elective intubation if indicated. Guillain-Barre syndrome is also associated with autonomic dysfunction
such as arrhythmia, and warrants cardiac telemetry.
Wernicke-Korsakoff syndrome
This is usually seen in severely alcoholic people with nutritional deficiency, although other causes of nutritional deprivation,
such as gastric pathology, may be present. Patients have rapid onset of a confusional state with an amnestic problem
(problem forming new memories, often associated with confabulation), nystagmus, oculomotor palsies, and ataxia. This
needs to be recognised urgently and treated with high-dose parenteral vitamin B1 in addition to general nutritional
support.
Acute intoxication
Many cerebellotoxic drugs can cause acute ataxia, as can alcohol inebriation. Careful drug history and serum drug levels
(if appropriate) are diagnostic, and management usually involves discontinuing the offending drug.
Red flags
• Ischaemic stroke (cerebellum)
17
Assessment of ataxia Emergencies
• Ischaemic stroke (brain stem)
• Haemorrhage in the cerebellum
• Acute cerebellitis
• Cerebellar abscess
• Paraneoplastic sensory neuropathy
• Miller-Fisher syndrome
• Wernicke-Korsakoff syndrome
EMERGENCIES
Assessment of ataxia Diagnosis
Step-by-step diagnostic approach

Ataxia can be caused by such an array of conditions that the diagnosis needs to be approached in an orderly fashion.
Various factors can be utilised as decision branch points to direct the diagnostic approach. Given the numerous disorders
and the extreme variability of presentation of ataxic diseases, it is useful to consider patients in some broad groups before
attempting a specific diagnostic approach.
The following factors are important modifiers of the approach:
• Age at onset
• Tempo of disease
• Presence or absence of overt structural abnormality by computed tomography (CT) or magnetic resonance imaging
(MRI)
• Presence or absence of a family history of the same disease
• Whether ataxia is cerebellar or sensory in nature
• Presence of non-ataxic neurological signs
• Presence of certain systemic features.
The broad groups of patients are as follows:
• Patients with acute ataxia
• Patients with subacute or chronic ataxia, with definitive structural abnormalities on imaging, with or without a
positive family history
• Patients with subacute or chronic ataxia in whom imaging shows atrophy of the cerebellum and associated structures
(or, rarely, no abnormalities at all), with or without a family history.
Acute ataxia
DIAGNOSIS
Patients present with acute onset of balance problems, with or without additional symptoms. Age at onset is an important
determinant of cause. Ataxia of acute onset in a child is most likely to result from acute cerebellitis or may be drug-induced
(e.g., anticonvulsants). In adults, the most frequent causes are ischaemic or haemorrhagic stroke in the cerebellum or
brain stem, intoxications (such as therapeutic drugs, alcohol, and drugs of abuse), and Wernicke-Korsakoff syndrome
related to nutritional deprivation (usually, but not always, in alcoholic people). Demyelinating lesions such as multiple
sclerosis can also have a rapid onset and, if they occur in the cerebellum or its connections, present with acute ataxia.
The Miller-Fisher variant form of Guillain-Barre syndrome needs to be considered.
History
• Age at onset is a very important determinant.
• Other critical pieces of information are the evolution of symptoms (months or a few years versus very chronic), an
imaging study of the brain (preferably MRI), and a family history of ataxia.
• If the family history is positive, the pattern of inheritance (autosomal recessive, autosomal dominant, X-linked)
should be determined if possible, as this will narrow the differential diagnosis.
• Obtain history of alcohol abuse and nutritional deficit, as well as a complete drug history, including any drug of
abuse.
19
• In patients with imbalance alone, history of vertigo, tinnitus, and hearing problems may indicate a peripheral
vestibular problem.
• Explore symptoms that indicate increased intracranial pressure (e.g., headache, nausea, vomiting) and symptoms
that may indicate problems in structures contiguous to the cerebellum, such as the brain stem. These include
weakness or sensory problems in the limbs, and cranial nerve deficits. Obtundation can be prominent with brain
stem involvement.
• Rarely in children and young adults, presentation may herald an illness in which repeated episodes of ataxia occur.
History of such episodes and similar problems in other family members can point to an episodic ataxia syndrome.
Inborn metabolic errors may have episodes of such ataxia as well.
Physical examination
• Ataxia is incoordination of intentional movement.
• Look for oscillations of the head and trunk, or titubation.
• Evaluate the speech for dysarthria and scanning speech. In scanning speech, the volume of the patient’s voice
varies from low to high.
• Evaluate eye movements for nystagmus, jerkiness on attempted smooth pursuit, and slowed saccades. Oculomotor
palsy can be associated with some disorders.
• Primary position nystagmus and lateralised past pointing may suggest an acute vestibulopathy, but distinction
between vestibulopathy and a small brain stem infarct can be difficult.
• Look for neck stiffness.
• Include a fundoscopic examination.
• Evaluate the gait by checking for broad-based stance and gait. Test tandem walking.
• Inspect for limb dysmetria by testing finger-to-nose, and heel-to-shin, dysdiadokokinesia, and heel-tapping test.
• Check for overshooting with the wrist-tapping test, in which the patient is unable to maintain postures against an
unexpected displacement.
DIAGNOSIS
• The Miller-Fisher variant form of Guillain-Barre syndrome needs to be considered if there is ataxia, oculomotor palsy,
and areflexia, with or without additional weakness in the limbs, bulbar muscles, and trunk.
Investigations:
• Work-up with imaging of the brain (CT scan, MRI with diffusion-weighted imaging [DWI] sequence) is required to
look for signal changes associated with strokes, demyelination, or cerebellitis. [Fig-1] [Fig-2] [Fig-3] [Fig-4]
• If an ischaemic lesion or haemorrhage cannot be confirmed, or findings compatible with multiple sclerosis or
cerebellitis are found, cerebrospinal fluid (CSF) examination should be done to look for infectious/inflammatory
parameters and immunoglobulin (Ig)G synthesis.
• If an ischaemic infarct is found in the cerebellum or brain stem, studies to image the vascular system may need to
be done acutely in selected cases; these include CT angiogram, MR angiogram, and routine catheter angiography.
• Wernicke-Korsakoff syndrome is diagnosed primarily on a clinical basis and by a rapid response to vitamin B1 and
other nutritional replacement.
• Suspected Miller-Fisher syndrome patients need electrophysiological examination of the neuromuscular system
and CSF examination, which may reveal high protein levels. Antibody to GQ1b is often elevated in Miller-Fisher
syndrome, but results cannot be obtained in a rapid fashion.
• Screening for substance abuse, including alcohol, in patients with no structural lesions, and measurement of
appropriate drug levels in those taking cerebellotoxic drugs, should be undertaken.
Subacute or chronic ataxia: definite structural abnormalities on imaging

Most of these patients are adults and have a clinical course that is relatively more rapid (measured in months or 1 to 2
years) than that seen in inherited forms of ataxia or sporadic/idiopathic ataxia. In addition, family history of a similar
disorder is usually negative. Such problems include vascular lesions (residuals of previous ischaemic/haemorrhagic
stroke, vascular malformations), demyelinating disease (multiple sclerosis), neoplastic lesions (primary and metastatic
tumours), [Fig-5] and compressive lesions of a non-neoplastic nature (i.e., craniovertebral junction anomalies).
Patients may have nervous system signs, often of a "contiguous" nature (signs of lesions in adjacent structures such as
brain stem and upper cervical cord), of raised pressure, or signs in remote areas of the nervous system such as the optic
nerve, hemispheres, and lower spinal cord (the latter indicates a demyelinating disease).
In any patient presenting with chronic/subacute ataxia, MRI of the brain with and without contrast should be done. Most
of the entities in this subgroup can be definitively diagnosed based on clinical history, the nature of clinical signs, and
the imaging abnormalities. The only situations where such patients may have similar problems in the family are some
rare familial tumour or malformation syndromes such as von Hippel-Lindau syndrome.
Subacute or chronic ataxia: cerebellar, brain stem, and spinal cord atrophy in
varying combinations or no imaging abnormality: negative family history
Childhood onset
• Even when there is no family history, these children are likely to have a monogenic disease, as the various acquired
causes are uncommon in children. Thus, the focus in this group is on uncovering a genetic aetiology, either by DNA
analysis or by finding an inborn metabolic error by biochemical testing, or both. Skin biopsy and fibroblast culture
is required if Niemann-Pick disease type C is suspected.
• Most of these disorders are autosomal-recessive entities. Other types of genetic disease that may present in this
group are those that have an X-linked or mitochondrial inheritance. Rarely, an autosomal-dominant ataxia can
present in childhood before the affected parent becomes symptomatic; this is especially likely with SCA 7 and
dentatorubral-pallido-luysian atrophy (DRPLA). The details of the work-up of these children are presented in the
section on childhood ataxia with a positive family history.
DIAGNOSIS
• One form of acquired ataxia in children is the myoclonus-opsoclonus syndrome, which is characterised by the rapid
or subacute onset of ataxia, myoclonic jerks, and chaotic eye movements of an involuntary nature. This is believed
to be autoimmune in origin and may be triggered by an underlying malignancy, usually a neuroblastoma. Imaging
studies of the brain and abdomen and CSF examination may be helpful.
Adult onset
• Acquired causes of ataxia predominate in this group and should be excluded as the first priority.
• This is the average adult "singleton" patient with ataxia in whom family history is negative for a similar disease. To
be sure of a negative family history, it is useful to construct a pedigree with at least 3 generations and enquire into
possible similar disease in as many relatives as possible. Parental age at death may be important because a negative
family history may be due to the early death of an affected parent.
• History should explore alcohol abuse, nutritional status (e.g., weight loss, chronic gastrointestinal [GI] disease),
endocrine symptoms, history of significant hypoxia or heat stroke, medications being taken (including
over-the-counter drugs), drug abuse, and the presence of organ-specific autoimmune disease such as diabetes or
hypothyroidism. History or risk factors for HIV infection should be obtained.
• Physical examination should determine whether the ataxia is cerebellar or sensory in nature. Sensory ataxias are
less common and have a very differential diagnosis. Ataxia in this group of patients (i.e., with an atrophic process
21
on imaging) tends to be symmetrical on both sides of the body. Ataxia in patients with overt lesions detected by
imaging can often be asymmetrical.
• Investigations of value include an imaging study of the brain (MRI), which excludes structural lesions and documents
cerebellar atrophy with or without brain stem or upper spinal cord atrophy. [Fig-9] Thyroid studies, vitamin levels
(i.e., B1, B6, B12), methylmalonic acid and homocysteine levels (which indicate B12 status), drug levels (e.g.,
phenytoin, carbamazepine, phenobarbital as indicated), antibodies to glutamic acid decarboxylase (GAD), gliadin,
and endomysium (tissue transglutaminase), parietal cell antibodies, paraneoplastic antibodies, HIV serology,
polymerase chain reaction (PCR) for Whipple's disease, monoclonal spike studies (such as serum
immunoelectrophoresis [IEP]), anti-MAG antibodies, intestinal biopsy, and peripheral nerve electrophysiology may
all contribute to the diagnosis. Specific tests should be selected based on clinical information.
• If the clinical picture is suspicious, a search should be performed for a visceral cancer such as that of lung, ovary,
or breast, including full physical examination and scans.
• Although non-genetic diseases dominate in this group, in people in whom one of the above diagnoses cannot be
established, an autosomal-recessive, X-linked, or mitochondrial mutation needs to be looked for. In selected cases,
autosomal-dominant mutation analysis may also be done if the clinical picture is worrisome for one of these and
there is concern that the family history is not reliable. The common DNA abnormalities that have been seen in
series of such patients include Friedreich's ataxia, fragile-X tremor-ataxia syndrome, spinocerebellar ataxia (SCA) 6,
SCA 8, and mitochondrial DNA mutations.
• In addition, some of the "inborn errors of metabolism" may rarely present in this age group. Laboratory studies that
may point to some of these disorders include serum creatine kinase, alpha-fetoprotein, lactate and pyruvate levels,
very long-chain fatty acid levels, phytanic acid levels, plasma chitotriosidase, and ammonia levels. The yield for
individual analyses is small, however.
Subacute or chronic ataxia: cerebellar, brain stem, and spinal cord atrophy in
varying combinations or no imaging abnormality: positive family history
Childhood onset
• Most of these are autosomal-recessive diseases, but X-linked, mitochondrial, and autosomal-dominant ataxias may
also present in childhood. Although autosomal-recessive inheritance is indicated by affected siblings and parental
consanguinity, many of these children present as singleton patients. Many autosomal-recessive ataxias may
DIAGNOSIS
occasionally present for the first time in adult life, and need to be considered in adults as well.
• Rarely, autosomal-dominant ataxias can present in childhood before an affected parent becomes symptomatic
(e.g., SCA 7 and dentatorubral-pallido-luysian atrophy [DRPLA]).
• Age at onset should be determined. Some entities such as ataxia with oculomotor apraxia 1 (AOA 1) and ataxia
telangiectasia (AT) begin in the first decade, whereas the more common Friedreich's ataxia and ataxia with oculomotor
apraxia 2 (AOA 2) typically have their onset in the second decade.
• Many of these cases, including most children with Friedreich's ataxia, have absent tendon reflexes, reflecting
co-existent peripheral nerve disease. Rarer diseases can have associated spasticity and brisk tendon reflexes. Eye
movement apraxia is seen (but not universally) in AT, AOA 1, and AOA 2. Associated choreic movements are also
seen in AT, AOA 1, and AOA 2, but not in Friedreich's ataxia. Head tremor and retinopathy can be seen in ataxia with
vitamin E deficiency (AVED) and retinopathy in mitochondrial DNA abnormalities. Pes cavus may be seen in
Friedreich's ataxia. [Fig-6] Examine for systemic abnormalities.
• Unlike autosomal-dominant ataxias, autosomal-recessive ataxias often show affected non-central nervous system
(CNS) tissues. Examples include cardiomyopathy and diabetes in Friedreich's ataxia, conjunctival and cutaneous
telangiectasia in AT, [Fig-7] lymphoreticular malignancy in AT, elevated serum alpha-fetoprotein in AT and AOA 2,
low serum albumin in AOA 1, Kayser-Fleischer (KF) rings and liver disease in Wilson's disease, and tendon xanthomas,
[Fig-8] and cataracts in cerebrotendinous xanthomatosis.
• In these children, MRI of the brain and upper spinal cord should be done first. High cord atrophy is seen in Friedreich's
ataxia. Cerebellar atrophy is seen in AT, AOA 1, and AOA 2. Peripheral nerve electrophysiology may point to prominent
nerve involvement, seen in Friedreich's ataxia and to a lesser degree in AVED and the AOAs.
• The most common autosomal-recessive mutation is the FA GAA expansion (confined to Indo-European populations),
then AOA 2. AT can often be clinically diagnosed and then confirmed either by targeted mutation analysis or by
protein truncation tests. Radiosensitivity of cultured fibroblasts is another test that can be employed.
• As AVED can be treatable, serum tocopherol levels should be obtained in any child or adult with chronic ataxia of
otherwise undetermined cause.
• Other autosomal-recessive mutations that can be obtained include those causing AOA 1, mitochondrial-recessive
ataxia syndrome (MIRAS), autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and AVED. These
are more common in certain populations.
• A mitochondrial DNA abnormality should be considered next. Exclude an autosomal-dominant ataxia by careful
family history, examination of the parents, and mutation analysis (common considerations SCA 7, SCA 2, and DRPLA,
the latter being more common in Japan) if necessary.
• As genetic disorders with "inborn errors of metabolism" often present in this age group, such diseases need to be
excluded by metabolic or DNA studies. Laboratory studies include serum and urine amino acids, urine organic acids,
serum ammonia, tests for lysosomal storage diseases, and serum cholestanol. Other useful tests may include MR
spectroscopy to detect vanishing white matter disease, serum ceruloplasmin and copper levels for Wilson's disease,
and phytanic acid levels. These are probably best done in collaboration with a metabolic disease expert.
Adult onset
• Most commonly, onset in this age group is associated with a family history consistent with autosomal-dominant
inheritance (SCAs).
• In this scenario, an imaging study may be done to exclude a coincidental structural lesion, but this may not be
needed if the clinical picture is entirely consistent and the clinician is knowledgeable about other family members.
• If the mutation in the family is already established, another family member with the typical clinical signs as having
the same disease can be diagnosed by clinical criteria alone or by obtaining only the mutation already known in
the family. If the family mutation is unknown, the clinical picture and prevalence pattern of different SCAs can be
useful in determining the most likely genotype, although all experts agree that one cannot make a genotypic
DIAGNOSIS
diagnosis based on the phenotype alone.
• The most common SCA worldwide in the current state of knowledge is SCA 3, also known as Machado-Joseph
disease (MJD). Certain parts of the world, such as Portugal (especially the Azores) and some previously
Portuguese-occupied territories such as Brazil, have an even higher prevalence of MJD. This is followed by SCA 2,
SCA 6, and SCA 1, probably in that order for most areas of the world. All of these, together with SCA 7 (in which
there is associated retinopathy and visual loss), are caused by unstable CAG expansions in their respective genes
and probably should be the first line of mutation analysis in a patient with SCA.
• SCA 1, SCA 2, and SCA 3 have a wide range of age of onset, but the mean is in the third decade. The disease course
is steadily progressive, with death commonly in the fifth decade. In contrast, SCA 6 generally has a later onset in
the fourth decade and a disease course often compatible with a normal lifespan. SCA 7 and DRPLA have both
childhood and adult onset; the disease course is more aggressive with early onset. Visual loss in SCA 7 is not universal
but tends to occur with earlier onset.
• A good family history with details of the phenotype in other family members may indicate the genotype. Once the
CAG expansions are excluded, mutation analysis might be considered for the CTG expansion of SCA 8, other
nucleotide expansion disorders such as SCA 12, SCA 10, and SCA 17, and those in which other mutational
mechanisms have been uncovered (e.g., SCA 13, SCA 14).
• Still other SCAs have had mutations uncovered recently, but these are often available for testing only in research
laboratories.
23
• Adult-onset ataxia with clear autosomal-recessive inheritance is less common but will need work-up as for children
with this type of ataxia.
• Finally, adult-onset (usually >50 years) ataxia with an atrophic process on imaging studies, with no family history,
no mutation established, and all known acquired causes ruled out, is labelled sporadic or idiopathic ataxia. In this
group, detection of dysautonomia by detailed autonomic function tests and anal sphincter denervation by
electromyogram may allow a diagnosis of probable multiple system atrophy.
DIAGNOSIS
Differential diagnosis overview
Common
Alcoholic cerebellar degeneration
Ischaemic stroke (cerebellum)
Ischaemic stroke (brain stem)
Haemorrhage in the cerebellum
Multiple sclerosis (MS)
Wernicke-Korsakoff syndrome
Uncommon
Drug-induced ataxia
Toxic neuropathies
Von Hippel-Lindau syndrome
Sequel to hypoxic encephalopathy or heat stroke
Acute cerebellitis
DIAGNOSIS
HIV
Gerstmann-Straussler syndrome
Creutzfeldt-Jakob syndrome (ataxic variant)
Cerebellar abscess
Whipple's disease
Posterior fossa tumours
Craniovertebral junction anomalies
Paraneoplastic sensory neuropathy
Ataxia with anti-glutamic acid decarboxylase (GAD) antibodies
25
Uncommon
Coeliac disease
Myoclonus-opsoclonus syndrome
Paraneoplastic cerebellar degeneration
Miller-Fisher syndrome
Sjogren's syndrome
Neuropathy related to monoclonal gammopathy
Hypothyroidism
Hypoparathyroidism
Vitamin B1 deficiency
Vitamin B12 deficiency
Friedreich's ataxia
Ataxia telangiectasia

DIAGNOSIS
Ataxia with vitamin E deficiency (AVED)
Abetalipoproteinaemia
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
Ataxia due to POLG 1 mutation
Ataxia due to SCYL1 mutation
Ataxia associated with CoQ10 deficiency
Ataxia associated with metabolic errors
Uncommon
DIAGNOSIS
Dentatorubral-pallido-luysian atrophy (DRPLA)
Episodic ataxia type 1
Episodic ataxia type 2
Fragile-X tremor-ataxia syndrome (FXTAS)
Mitochondrial cytopathy
Niemann-Pick disease type C (NP-C)
27
Differential diagnosis
Common
◊ Alcoholic cerebellar degeneration
History Exam 1st Test Other tests
subacute or chronic gait ataxia with »MRI brain: atrophy of

evolution of symptoms, broad-based gait, cerebellar vermis
history of alcohol abuse nystagmus, and dysarthria
are infrequent
◊ Ischaemic stroke (cerebellum)
acute onset of symptoms, poor standing and walking »MRI brain: high signal on »CT head: normal in early
presence of risk factors, ability, neck stiffness diffusion-weighted hours; may see infarct after
headache, nausea, imaging (DWI) and the first day
vomiting, imbalance fluid-attenuated inversion »catheter cerebral
recovery (FLAIR) sequence angiography: vascular
in area of infarct occlusions
◊ Ischaemic stroke (brain stem)
acute onset of symptoms, ataxia may be one-sided, »MRI brain : high signal on »CT or MR angiogram
imbalance, speech and cranial nerve palsies, DWI in area of infarct neck/intracranial
DIAGNOSIS
swallowing difficulties, paralysis, decreased vessels : occlusion of

numbness and weakness consciousness posterior circulation
of limbs, obtundation arteries
»catheter cerebral
angiography: occlusion of
posterior circulation
arteries
More definitive for
occlusions. Often done
with a view to
thrombolysis.
◊ Haemorrhage in the cerebellum
acute onset of symptoms, poor standing and walking »CT head: high signal in
headache, nausea, ability, neck stiffness cerebellum
vomiting, imbalance May be difficult to see due
to artifact.
Common
◊ Multiple sclerosis (MS)
acute onset of symptoms, optic nerve dysfunction, »MRI brain: T2 and FLAIR »lumbar puncture with
common in adults, upper motor neuron signs with high signal in many CSF analysis including
relapsing and remitting (e.g., brisk tendon reflexes areas, especially MS panel: evidence of IgG
course, many CNS and Babinski's sign), ocular periventricular (may be synthesis and oligoclonal
structures affected (e.g., palsy, sensory loss asymmetrical) bands; may be normal in
vision, spinal cord, eye early disease
movements) »visual evoked potential:
delayed response
Establishes optic nerve
dysfunction when clinically
it is normal.
◊ Wernicke-Korsakoff syndrome
acute onset of symptoms, confusion, sixth-nerve »CT head: normal

confusion, oculomotor palsies, nystagmus (excludes other lesions)
palsy, history of alcoholism »MRI brain : may show
or nutritional deficiencies symmetrical signal
changes in thalami,
periaqueductal area,
mamillary bodies
»therapeutic trial of
parenteral thiamine :
DIAGNOSIS
clinical response to
treatment to counteract
the test finding of low
thiamine
An unequivocal clinical
response to parenteral
thiamine, which can be
seen in a few hours or days.
The degree of response will
depend on the duration
and severity of symptoms
before therapeutic
correction of thiamine
deficiency.
29
Uncommon
◊ Drug-induced ataxia
acute onset of symptoms, nystagmus »serum phenytoin level

common in children, ataxia : >79 micromols/L (>20
in temporal relation with mg/L)
administration of Supratherapeutic levels
cerebellotoxic drugs (e.g., may not always cause
phenytoin, carbamazepine, ataxia.
vigabatrin, gabapentin,
phenobarbital, fluorouracil, »serum carbamazepine
cytarabine, intrathecal level : >51 micromols/L
methotrexate, lithium, (>12 micrograms/L)
amiodarone, ciclosporin, Supratherapeutic levels
bismuth salts, and may not always cause
epothilones) ataxia.
»serum phenobarbital
level: >172.4 micromols/L
(>40 micrograms/L)
Supratherapeutic levels
may not always cause
ataxia.
◊ Toxic neuropathies
gradual onset of gait ataxia, loss of deep »clinical diagnosis: no

symptoms, exposure to tendon reflexes, loss of tests required
DIAGNOSIS
neurotoxic drug (e.g., sensation in limbs

platinum drugs, large
doses of vitamin B6),
imbalance, numbness
◊ Von Hippel-Lindau syndrome
imbalance; characterised retinal lesions »MRI brain: cerebellar

by multiple tumours such haemangioblastoma
as renal cell carcinoma,
phaeochromocytoma,
retinal
haemangioblastoma, and
endolymphatic sac tumour
Uncommon
◊ Sequel to hypoxic encephalopathy or heat stroke
history of recovery from intention myoclonus »MRI brain: cerebellar

hypoxic episode such as atrophy
cardiac arrest or significant
heat stroke
◊ Acute cerebellitis
common in children, acute gait ataxia, appendicular »MRI brain : T2 »CSF examination:
onset of symptoms, ataxia, dysarthria, hyperintense signal normal or cell count mildly
imbalance, history of viral titubation, nystagmus; following the grey matter elevated
illness (or, rarely, mutism is rare of the cerebellum Not done if MRI shows
immunisation) May be normal. Look for oedema.
evidence of oedema and
compression of brain stem.
◊ HIV
HIV positive, symptom cognitive impairment on »HIV serology: positive

evolution over a few screening questionnaires »MRI brain: signal changes
months in the cerebellum
(excludes other lesions)
DIAGNOSIS
◊ Gerstmann-Straussler syndrome
family history (autosomal mild cognitive impairment »MRI brain: normal »genetic mutation
dominant), relatively rapid on screening (excludes other lesions) testing: mutation in prion
symptom evolution over questionnaires, brisk protein gene
»lumbar puncture with
months to 1 to 2 years reflexes, myoclonus CSF 14-3-3 protein »brain biopsy: spongiform
analysis: elevated changes and plaques
31
Uncommon
◊ Creutzfeldt-Jakob syndrome (ataxic variant)
symptom evolution over a cognitive impairment on »EEG: periodic slow and »brain biopsy: spongiform
few months screening questionnaires, sharp wave complexes changes
myoclonus May be more relevant in
»lumbar puncture with
some patients to exclude
CSF 14-3-3 protein
treatable lesions in atypical
analysis: elevated
cases.
»MRI brain: hyperintensity
in basal ganglia, cortical »tonsillar biopsy:
ribboning on abnormal prion protein by
diffusion-weighted immunocytochemistry
imaging For suspected CJD variant
related to contaminated
meat.
◊ Cerebellar abscess
symptom evolution over asymmetrical ataxia, signs »MRI brain with and
few days to weeks, of middle ear infection without contrast: typical
headache, vomiting ring enhancing lesion in
cerebellum
◊ Whipple's disease
DIAGNOSIS
ataxia is part of a broader gaze palsy, memory »PCR for Whipple »CSF examination: may
picture of memory loss and impairment, unusual organism in blood: have a few extra cells,
seizures oculomasticatory positive some with PAS+ material
movement »intestinal biopsy: PAS
stain positive for
macrophages with bacteria
Tropheryma whipplei
◊ Posterior fossa tumours
subacute or chronic gait and limb ataxia, »MRI brain with contrast:
balance problems, nystagmus, cranial nerve overt mass lesion in
headache, nausea deficits such as facial palsy, cerebellum, brain stem, or
upper motor neuron signs posterior fossa
(hyper-reflexia, increased
tone)
Uncommon
◊ Craniovertebral junction anomalies
gradual neurological gait and limb ataxia, »MRI brain and cervical
problems including downbeat nystagmus, spine: overt malformation
pyramidal weakness upper motor neuron signs such as Arnold-Chiari or
(hyper-reflexia, spasticity, basilar invagination
weakness), lower cranial
nerve palsies
◊ Paraneoplastic sensory neuropathy
subacute evolution of gait and limb ataxia, »nerve conduction »malignancy

symptoms (weeks to asymmetrical or studies: sensory assessment: malignancy
months), numbness in symmetrical loss of neuropathy Chest x-ray and
hands and feet (often position and vibration pelvic/body scans (e.g., CT,
»paraneoplastic
asymmetrical), onset in sense, loss of deep tendon MRI, PET) should be
antibodies: positive
upper limbs not reflexes performed.
Examples of specific
uncommon; ask about antibodies and associated
weight loss, tobacco cancers include anti-Yo or
history PCA 1 (ovarian, uterine,
breast cancer), anti-Tr or
PCA-Tr (Hodgkin's), anti-Hu
or ANNA 1 (small cell lung
cancer), anti-CRMP-5
(small cell lung cancer,
thymoma), anti-Ri or ANNA
2 (lung or breast cancer),
DIAGNOSIS
anti-Zic4 (small cell lung
cancer), anti-VGCC (small
cell lung cancer),
anti-mGluR1 (Hodgkin's).
◊ Ataxia with anti-glutamic acid decarboxylase (GAD) antibodies
gradually progressive, may be associated with »anti-glutamic acid

often associated with other oculomotor problems, stiff decarboxylase (GAD)
autoimmune disorders lower limbs antibody: elevated
(e.g., diabetes, thyroid Levels are higher than
dysfunction), more those found in diabetes
common in women and stiff person syndrome.
Marginal elevations may be
insignificant.
33
Uncommon
◊ Coeliac disease
neuropathy, may be gait and limb ataxia, »antigliadin antibody: »tissue

associated with GI peripheral neuropathy elevated transglutaminase IgA
symptoms related to antibody: elevated
coeliac disease »endomysium IgA
antibody: elevated
»intestinal biopsy: normal
or typical inflammatory
changes of coeliac disease
Not usually needed unless
there are GI symptoms of
concern.
◊ Myoclonus-opsoclonus syndrome
rapid or subacute onset of myoclonic jerks, chaotic »MRI brain: cerebellar

symptoms, history of eye movements of atrophy
neuroblastoma involuntary nature »CT abdomen: suprarenal
mass consistent with
neuroblastoma
»CSF examination: mild
pleocytosis
DIAGNOSIS
◊ Paraneoplastic cerebellar degeneration
rapidly progressive severe severe ataxia of gait and »paraneoplastic »CSF examination: mild
ataxia over a few weeks or limbs, dysarthria, antibodies: elevated pleocytosis, elevated
months, nausea, vomiting, nystagmus Examples of specific protein
known triggering antibodies and associated »malignancy
malignancy in some but in cancers include anti-Yo or assessment: malignancy
others ataxia occurs before PCA 1 (ovarian, uterine, Chest x-ray and
diagnosis of cancer breast cancer), anti-Tr or pelvic/body scans (e.g., CT,
PCA-Tr (Hodgkin's), anti-Hu MRI, PET) should be
or ANNA 1 (small cell lung performed.
cancer), anti-CRMP-5
(small cell lung cancer,
thymoma), anti-Ri or ANNA
2 (lung or breast cancer),
anti-Zic4 (small cell lung
cancer), anti-VGCC (small
cell lung cancer),
anti-mGluR1 (Hodgkin's).
Uncommon
◊ Miller-Fisher syndrome
acute onset of symptoms, oculomotor paralysis, »MRI brain : normal »nerve conduction
imbalance, trouble moving absent tendon reflexes, (excludes lesions such as studies: sensory
eyes over a few days may reveal or develop infarct or encephalitis) neuropathy
other signs of generalised May be sensory only or
»CSF examination:
paralysis including sensorimotor
elevated protein; normal
dysphagia and respiratory demyelinating neuropathy.
cell count
weakness
»serum anti-GQb1
antibodies: positive
◊ Sjogren's syndrome
gradual evolution of gait and limb ataxia, loss of »nerve conduction »lip biopsy: inflammatory
symptoms, numbness, and deep tendon reflexes, loss studies: sensory changes
paraesthesias in hands and of vibration and position neuropathy
legs (often asymmetrical), sense »anti-SSA antibodies:
dry eyes and mouth elevated
»anti-SSB antibodies:
elevated
◊ Neuropathy related to monoclonal gammopathy
DIAGNOSIS
numbness gait and limb ataxia, loss of »nerve conduction »anti-MAG antibody:
deep tendon reflexes, loss studies: sensory elevated
of vibration and position neuropathy
sense »serum
immunoelectrophoresis:
M-spike detected
◊ Hypothyroidism
symptoms of mild gait ataxia »thyroid-stimulating

hypothyroidism (e.g., hormone: elevated
weight gain, fatigue, dry
skin)
35
Uncommon
◊ Hypoparathyroidism
symptoms of tetany, Trousseau's sign »serum calcium: low

hypoparathyroidism (e.g., (carpal spasm with »serum immunoreactive
muscle twitches or occlusion), cerebellar parathyroid hormone:
spasms, cramps, ataxia low or normal
numbness or tingling,
confusion), recent history
of neck surgery
◊ Vitamin B1 deficiency
neuropathy, often history midline ataxia, gait ataxia »serum vitamin B1 level: »RBC transketolase:
of alcoholism decreased decreased
◊ Vitamin B12 deficiency
imbalance, sensory loss in loss of vibration and »serum vitamin B12 »serum methylmalonic
lower limbs position sense, pyramidal level: decreased acid level: elevated
signs, positive Romberg May detect deficient B12
test status even with low
normal B12 levels.
»serum homocysteine
DIAGNOSIS
level: elevated
May detect deficient B12
status even with low
normal B12 levels.
◊ Friedreich's ataxia
onset usually <25 years of gait ataxia, kyphoscoliosis, »GAA repeat in frataxin »MRI brain and cervical
age (mean 11-12 years), scanning dysarthria, loss of gene: normal <33; cord: high cord atrophy,
may have onset in adult vibration and position pathogenic 66-1700 in normal cerebellum
life, history of diabetes, sense, loss of tendon both alleles; if only one »echocardiography or
hearing loss, restless leg reflexes, square wave jerks allele is expanded, the ECG: normal or
syndrome, or hypertrophic of eyes, later weakness of other allele may have to be hypertrophic
cardiomyopathy lower limbs and extensor sequenced cardiomyopathy[22]
plantars, some may have In a minority of cases the
retained or brisk deep expansion is only one allele »nerve conduction tests:
with point mutation on the absent sensory nerve
other. Affects only action potentials
Uncommon
◊ Friedreich's ataxia
tendon reflexes, pes cavus Indo-Europeans. It is

may be seen possible for an allele as
small as 44 repeats to
cause disease if it is
somatically unstable (i.e., it
has bigger size in other
tissues). Alleles with 35-65
repeats are "pre-mutation"
alleles.
◊ Ataxia telangiectasia
onset of postural instability gait and limb ataxia; truncal »MRI brain: cerebellar »immunoblotting for
early in first decade of life instability; titubation; atrophy ATM protein: 90% have no
and then progressive ataxia absent tendon reflexes; protein; <10% have trace
»ATM mutation analysis:
choreic movements; poor protein; 1% have normal
pathogenic sequence
initiation of ocular protein that has no kinase
alterations
saccades (oculomotor activity
apraxia); telangiectasia »colony survival assay:
over conjunctivae, ear abnormal radiosensitivity
lobes, and popliteal fossa of lymphoblasts
»protein truncation
tests: truncating
mutations
DIAGNOSIS
»serum
alpha-fetoprotein: >10
nanograms/mL
◊ Ataxia with oculomotor apraxia 1 (AOA 1)
progressive ataxia starting oculomotor apraxia very »aprataxin mutation »serum albumin level:
at <10 years of age, common, chorea analysis (sequence <3.8 g/L
occasionally later analysis): mutation »serum cholesterol level:
detected elevated
37
Uncommon
◊ Ataxia with oculomotor apraxia 2 (AOA 2)
progressive ataxia starting oculomotor apraxia, »senataxin mutation »serum

in childhood (mean 15 chorea analysis (sequence alpha-fetoprotein: >20
years of age), occasionally analysis as well as micrograms/L (>20
later testing for nanograms/mL)
deletions/duplications):
mutation detected
◊ Ataxia with vitamin E deficiency (AVED)
progressive ataxia from loss of tendon reflexes, »serum vitamin E level: »alpha-thrombotic
childhood, occasionally head tremor, retinopathy <39.5 micromols/L (1.7 thrombocytopenia
later mg/L) purpura (TTP) mutation
analysis (sequence
analysis): mutation
detected
»alpha-TTP targeted
mutation analysis:
744delA mutation
◊ Abetalipoproteinaemia

DIAGNOSIS
early childhood onset of loss of tendon reflexes and »serum vitamin E level: »red blood cell
intestinal malabsorption sensation decreased morphology:
acanthocytes detected
»serum lipoprotein level:
decreased (possibly to
zero)
◊ Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
ataxia and spasticity spasticity, muscle atrophy, »SACSIN targeted »SACSIN mutation
starting in first decade myelinated fibres in optic mutation analysis: analysis: mutation
nerve (not universal) 6594delT mutation and detected
5254 C>T »MRI brain: cerebellar
atrophy
Uncommon
◊ Ataxia due to POLG 1 mutation
childhood onset, common progressive cerebellar »POLG1 mutation

in Finnish population signs (e.g., ataxia, analysis: mutation
nystagmus), myoclonus, detected
neuropathy, tremor
◊ Ataxia due to SCYL1 mutation
recurrent episodes of ataxia, peripheral »SCYL1 mutation

acute liver failure in early neuropathy analysis: mutation
infancy detected
◊ Ataxia associated with CoQ10 deficiency
childhood onset, cognitive mild decline in IQ »muscle biopsy with

changes CoQ10 analysis: low levels
◊ Ataxia associated with metabolic errors
DIAGNOSIS
childhood onset (rarely ataxia with many other »serum amino acid »urine organic acids:
young adult onset), ataxia neurological signs levels: specific pattern specific pattern changes
often overshadowed by depending on specific changes depending on depending on disorder
other neurological disease (e.g., tendon disorder »serum ammonia level:
problems such as cognitive xanthoma in high in urea cycle defects
decline, seizures, and cerebrotendinous
encephalopathy, ataxia is xanthomatosis) »serum lactate: elevated
often intermittent in mitochondrial
defects/PDH deficiency
»serum pyruvate:
elevated in mitochondrial
»CSF lactate: elevated in
mitochondrial
»CSF pyruvate: elevated
in mitochondrial
39
Uncommon
◊ Ataxia associated with metabolic errors
»very long-chain fatty

acids: elevated in
adrenomyeloneuropathy
»serum cholestanol
level: elevated in
cerebrotendinous
xanthomatosis
»serum ceruloplasmin
level: deficient in Wilson's
disease
◊ Spinocerebellar ataxia 1 (SCA 1)
age at onset is childhood nystagmus, dysarthria, gait »ataxin 1 gene targeted »MRI brain:
to >60 years but mean is problems, upper motor mutation analysis: CAG pontocerebellar atrophy
early 30s; gradual neuron signs, such as expansion to pathogenic
progression of symptoms, spasticity and brisk tendon range of 39-91 repeats
incoordination, speech reflexes, hypermetric 39-44 repeat alleles are
problems saccades, peripheral pathogenic if they are not
neuropathy interrupted by CAT. This
can be detected by
additional study using Sfa
NI restriction analysis.
Larger repeats cause
DIAGNOSIS
earlier onset of disease.

36-38 uninterrupted alleles
are "mutable normal", i.e.,
do not cause disease but
can expand to
disease-causing range in
the next generation.
mean onset age is early dysarthria, early »ataxin 2 gene targeted »MRI brain:
30s; positive family history, occurrence of very slow mutation analysis: CAG pontocerebellar atrophy
progressive ataxia, speech saccades, tendon reflexes expansion to pathogenic
problems often completely absent, range of 32 or more
parkinsonism, and repeats
myoclonia PCR detects alleles with
<100 repeats. For larger
expansions, Southern
Uncommon
blotting is needed; this is

the case with infantile and
very early onset of disease.
mean onset age is early dysarthria; nystagmus; »MJD 1 gene targeted »MRI brain:
30s; progressive ataxia, upper motor neuron signs mutation analysis: CAG pontocerebellar atrophy
diplopia, stiffness such as spasticity, brisk expansion to pathogenic
tendon reflexes, and range 52-86 repeats
Babinski's sign; (normal <44 repeats)
extrapyramidal signs may 45-51 repeat alleles are
dominate in some patients considered
(akinetic-rigid syndrome, reduced-penetrance
dystonia); slow saccades alleles and may cause very
later in course with late-onset symptoms if a
ophthalmoparesis; person lives long enough.
older-onset patients have
ataxia and peripheral
neuropathy
DIAGNOSIS
slow progression of ataxia nystagmus (downbeat »beta-spectrin gene
sometimes), gait and limb mutation analysis:
ataxia, dysarthria, upper mutation detected
motor neuron signs such Limited experience;
as brisk deep tendon sequence variations of
reflexes uncertain significance may
be found.
mean onset age is 40s; nystagmus (often »neuronal calcium »MRI brain: isolated
slowly progressive ataxia downbeat), gait and limb channel gene (targeted cerebellar atrophy
with relatively normal ataxia, abnormal pursuit mutation analysis): CAG
lifespan, diplopia, and and inaccurate saccadic expansion to pathogenic
other visual complaints range 20-33 repeats
(normal <18 repeats)
41
Uncommon
eye movements, saccade A 19-repeat allele may

velocity relatively normal, cause atypical symptoms
non-cerebellar signs or may produce no
minimal and often symptoms, and may
incidental expand to disease-causing
range in the next
generation. A person with
19 repeats on both alleles
has SCA 6.
age at onset very variable, prominent spasticity, »ataxin 7 gene targeted »MRI brain:
from childhood to older maculopathy with mutation analysis: CAG pontocerebellar atrophy
adult depigmentation, low visual expansion to pathogenic »Farnsworth colour
acuity; childhood onset range 37-460 repeats vision testing: retinal
can result in more rapid (normal <19 repeats) disease
course with added A 28-33-repeat allele is Subclinical retinal disease
cognitive changes and considered "mutable can be detected using
seizures normal": the person does Farnsworth colour vision
not have the disease, but testing and
the repeat can expand to a electroretinography.
disease-causing range in
the next generation. 34-36 »electroretinography:
DIAGNOSIS
repeats are retinal disease

reduced-penetrance Subclinical retinal disease
alleles. PCR detects alleles can be detected using
with <100 repeats. For Farnsworth colour vision
larger expansions, testing and
Southern blotting is electroretinography.
needed. This is the case
with infantile or very early
onset.
upper limb incoordination, gait and limb ataxia, »SCA 8 gene targeted
family history may be nystagmus, dysarthria, mutation analysis: CTG
negative expansion to pathogenic
range 80-250 repeats
(normal <50 repeats)
Uncommon
some upper motor neuron Interpretation of the SCA

signs such as brisk tendon 8 expansion analysis can
reflexes, decreased be difficult. It is often
vibratory sense, cognitive positive in "sporadic"
deficits (singleton) patients with
ataxia but can be found in
families with
autosomal-dominant
inheritance. Also, an
expansion to the
pathogenic range can be
seen in asymptomatic
patients.
seizures nystagmus, gait and limb »ataxin 10 gene targeted »MRI brain: cerebellar
ataxia, dysarthria, seizures, mutation analysis: ATTCT atrophy
and cognitive dysfunction expansion to pathogenic
range 800-4500 repeats
(normal 10-29 repeats)
Seems to be confined to
Central and South
American populations.
DIAGNOSIS
280-370 repeats likely to
be reduced penetrance.
Brazilian people with SCA
10 have had 400-760
repeats.
progressive symptoms gait and limb ataxia, »tau tubulin kinase 2

nystagmus, occasional (TTBK 2) gene targeted
upper motor neuron signs mutation analysis:
such as brisk deep tendon pathogenic sequence
reflexes, dystonia alteration detected
43
Uncommon
cognitive and psychiatric postural tremor, »expansion of CAG »MRI brain: cerebellar and
symptoms, tremor extrapyramidal signs, repeat in promoter cerebral atrophy
rigidity, dementia, action sequence of the
tremor, and parkinsonian PPP2R2B gene: CAG
features expansion to pathogenic
range 51-78 repeats
Uncommon outside India.
Rarely, people with ataxia
have had expansions in the
40-50 range and these
have to be further clarified.
childhood or adult onset, mild mental retardation »KCNC 3 gene mutation

very slow progression, (although not universal) analysis: pathogenic
cognitive subnormality in sequence alteration
some Limited experience;
sequence variations of
uncertain significance may
be found.
DIAGNOSIS
adult onset of symptoms myoclonus, facial »PKC-gamma gene

myokymia, tremor, mild mutation analysis: point
sensory loss, and cognitive mutations and small
impairment deletions detected
Limited experience;
sequence variations of
uncertain significance may
be found.
imbalance, dementia rigidity, dementia, »TBP gene targeted

inherited in dominant prominent extrapyramidal mutation analysis: CAG
Uncommon
fashion, sporadic cases signs, psychiatric expansion to pathogenic

have been described symptoms, and dystonia range 49-66 repeats
43-48-repeat alleles are
likely to be
reduced-penetrance
alleles.
progressive ataxia often gait and limb ataxia, »MRI head: cerebellar »mutation testing for
beginning with speech dysarthria, spasmodic atrophy, calcification of duplication on
problem dysphonia; diagnosis based cerebellar dentate chromosome 11:
on clinical findings and duplication detected
»CT head: cerebellar
neuroimaging Not commercially
atrophy, calcification of
available.
cerebellar dentate
progressive ataxia in young gait and limb ataxia, »AFG3L2 gene testing:
DIAGNOSIS
adulthood dysarthria, hyperreflexia, mutation
nystagmus,
ophthalmoparesis
◊ Dentatorubral-pallido-luysian atrophy (DRPLA)
cognitive decline, chorea »atrophin gene targeted

myoclonic epilepsy, mutation analysis: CAG
dementia superficially repeat expansion to 48 or
resembling Huntington's more (normal 6-35
disease repeats)
45
Uncommon
◊ Episodic ataxia type 1
onset in childhood, brief skeletal muscle myokymia »potassium channel

episodes (minutes) of may be seen in between (KCNA 1) gene sequence
imbalance episodes analysis: mutation
detected
◊ Episodic ataxia type 2
brief episodes of ataxia episodic dysarthria and »calcium channel »CACNA1A analysis for
(hours), nausea, vomiting, nystagmus, some may (CACNA 1A) gene duplications or deletions:
migraine-like headache, have nystagmus and mild sequence analysis : deletions in some cases
diplopia with onset usually gait difficulties between mutation detected
in teenage years episodes
◊ Fragile-X tremor-ataxia syndrome (FXTAS)
usually occurs in older tremor, autonomic deficits, »FRAXA gene targeted

males, often family history dysarthria mutation analysis: CGG
of fragile-X mental expansion to pre-mutation
retardation in a grandson, range (55-200 repeats)
rarely in a female with a »MRI brain: middle
fragile-X syndrome in a cerebellar peduncle
son, family history may not
DIAGNOSIS
hyperintensities and
be present, imbalance cerebral periventricular
white matter
hyperintensities on FLAIR
sequence[51]
◊ Mitochondrial cytopathy
co-existent myopathy, retinal pigmentary »muscle biopsy: ragged

hearing loss, degeneration, hearing loss, red fibres
cardiomyopathy muscle weakness »CSF examination:
elevated protein, elevated
pyruvate/lactate
»venous lactate and
pyruvate level: elevated
»MtDNA mutation
analysis: positive
Uncommon
◊ Mitochondrial cytopathy
Most labs perform tests for

common mutations
detected in mitochondrial
syndromes (MERRF,
MELAS, NARP, KSS). More
rare mutations may go
undetected.
◊ Niemann-Pick disease type C (NP-C)
manifestations vary gait ataxia (in late infantile »NPC1 and NPC2 »plasma chitotriosidase:
according to age: form); dystonia (in adult targeted mutation may be elevated
clumsiness, speech or form); myoclonus or analysis: mutation A non-specific screen for
developmental delay, myoclonic tremor, detected NP-C.
cataplexy (in late infantile abnormalities in voluntary »skin biopsy and
form); seizures, cataplexy saccadic eye movements, fibroblast culture:
(in juvenile form); cerebellar signs, vertical excessive lysosomal filipin
dementia (in adult form) supranuclear gaze palsy, staining in cultured skin
hepatosplenomegaly (in all fibroblasts
forms)
Diagnostic guidelines
DIAGNOSIS
Europe
EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X
syndrome and other fragile X-associated disorders
Published by: European Molecular Genetics Quality Network

Last published: 2015
International
Consensus clinical management guidelines for Friedreich ataxia
Published by: Clinical Management Guidelines Writing Group

47
North America
ACR Appropriateness Criteria: ataxia
Published by: American College of Radiology

Summary: Evidence-based guideline to assist referring physicians and other providers in making the most appropriate
imaging or treatment decision.
DIAGNOSIS
Assessment of ataxia Online resources
Online resources
1. National Ataxia Foundation (external link)
2. Online Mendelian Inheritance in Man (OMIM) (external link)
ONLINE RESOURCES
49
Assessment of ataxia References
Key articles
REFERENCES
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Cambridge, UK: Cambridge University Press; 2002:97-120.
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• Corben LA, Lynch D, Pandolfo M, et al; Clinical Management Guidelines Writing Group. Consensus clinical management
guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014;9:184. Full text Abstract
• Shakkottai VG, Fogel BL. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia. Neurol Clin.
2013;31:987-1007. Full text Abstract
• Biancalana V, Glaeser D, McQuaid S, et al. EMQN best practice guidelines for the molecular genetic testing and
reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015;23:417-425. Full
text Abstract
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53
Assessment of ataxia Images
Images
IMAGES
Figure 1: Acute bilateral cerebellar infarct, as seen on diffusion-weighted imaging sequence MRI
From the collection of Dr S. H. Subramony
IMAGES
Figure 2: Cerebellar infarct as seen on fluid-attenuated inversion recovery (FLAIR) sequence MRI: note secondary oedema
and effacement of the fourth ventricle
55
IMAGES Assessment of ataxia Images
Figure 3: Infarct in the dorsolateral medulla together with scattered infarcts in the cerebellum, as seen on diffusion-weighted
imaging sequence MRI
IMAGES
Figure 4: CT scan of the brain showing a haemorrhage in the cerebellum with extension into the fourth ventricle
57
Figure 5: Large mass lesion in the cerebellum with pressure effects, as seen on MRI
IMAGES
Figure 6: Pes cavus deformity in Friedreich's ataxia
59
Figure 7: Early conjunctival telangiectasia in a patient with ataxia telangiectasia

Figure 8: Tendon xanthoma seen in cerebrotendinous xanthomatosis

From the collection of Dr S. H. Subramony, with thanks to Dr Uday Muthane
IMAGES
Figure 9: MRI of brain showing early cerebellar and brain stem atrophy in SCA 1
61
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DISCLAIMER
Contributors:
// Authors:
Barbara Kelly Changizi, MD

Assistant Professor of Neurology
Ohio State University, Columbus, OH
DISCLOSURES: BKC has been reimbursed by Medtronic for consultation and teaching in deep brain stimulation (DBS). However,
the practice of DBS is not used for ataxia other than in research, and is not discussed in this article.
// Acknowledgements:
Dr Barbara Kelly Changizi would like to gratefully acknowledge Dr S.H. Subramony and Dr Hartmut Uschmann, previous contributors
to this monograph.
DISCLOSURES: SHS has received honoraria for lectures given from Athena Diagnostics Company. HU declares that he has no
competing interests.
// Peer Reviewers:
Thomas Klockgether, MD
Dean of Medical Faculty
Professor and Chair of Department of Neurology, University Hospital, Bonn, Germany
DISCLOSURES: TK declares that he has no competing interests.
Susan L. Perlman, MD
Clinical Professor of Neurology/Director
Ataxia Center and HD Center of Excellence, UCLA, Los Angeles, CA
DISCLOSURES: SLP is the co-author of 2 systematic reviews referenced in this monograph.

Assessment of Ataxia: The Right Clinical Information, Right Where It's Needed

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Assessment of Ataxia: The Right Clinical Information, Right Where It's Needed

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Assessment of ataxia

The right clinical information, right where it's needed

Last updated: Jan 09, 2017

Step-by-step diagnostic approach 19

◊ Disorders resembling ataxia :

Vascular and hypoxic

• Whipple's disease may have ataxia as a neurological complication.[14]

• Tumours associated with ataxia include medulloblastomas, astrocytomas, ependymomas, haemangioblastomas,

• Opsoclonus-myoclonus-ataxia (OMA) is a syndrome characterised by ataxia, involuntary multivectorial eye

• Hypothyroidism and hypoparathyroidism may present with ataxia.

Inherited causes: autosomal recessive

• Alpha-fetoprotein levels are high.

Ataxia with oculomotor apraxia 1 (AOA 1)

• A rare form of autosomal-recessive ataxia.

• Clinical features include ataxia, peripheral neuropathy, and oculomotor apraxia.

• Patients exhibit hypoalbuminaemia and hypercholesterolaemia.

Ataxia with oculomotor apraxia 2 (AOA 2)

• Clinical features are similar to those seen in AOA 1.

Ataxia with vitamin E deficiency (AVED)

• Ataxia results from vitamin E deficiency.

• Clinical features include ataxia, acanthocytosis, and retinal degeneration.[27]

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Ataxia due to POLG 1 mutations

• Has also been named mitochondrial-recessive ataxia syndrome (MIRAS).

• POLG 1 is a nuclear-encoded polymerase involved in mitochondrial DNA synthesis.[20]

Ataxia due to SCYL1 mutation

Infantile-onset spinocerebellar ataxia (IOSCA)

• An infantile-onset ataxia described from Finland, this condition is rare.

Spinocerebellar ataxia with axonal neuropathy (SCAN1)

• The mutation involves the gene SIL 1, involved in chaperone function.[20]

Ataxia with muscle CoQ10 deficiency

Ataxia in recessively inherited (or X-linked) errors of metabolism

• A number of childhood ataxias are as yet incompletely understood.

Niemann-Pick disease type C (NP-C)

Inherited causes: autosomal dominant

Spinocerebellar ataxia 1 (SCA 1)

Spinocerebellar ataxia 2 (SCA 2)

• Phenotype closely resembles that of SCA 1.

• Large Cuban founder population.

Spinocerebellar ataxia 3 (SCA 3 or Machado-Joseph disease [MJD])

• Large Portuguese founder population.

• The most common spinocerebellar ataxia.

• Sensory axonal neuropathy and deafness.

Spinocerebellar ataxia 5 (SCA 5, or Lincoln ataxia)

• Presents in early adulthood with a pure cerebellar syndrome.

Spinocerebellar ataxia 6 (SCA 6)

• Clinical features include horizontal and vertical nystagmus.[36]

Spinocerebellar ataxia 7 (SCA 7)

Spinocerebellar ataxia 8 (SCA 8)

Spinocerebellar ataxia 10 (SCA 10)

• Ataxia and occasional seizures.

Spinocerebellar ataxia 11 (SCA 11)

• Very limited experience with this disease.

Spinocerebellar ataxia 12 (SCA 12)

• Slowly progressive ataxia, dementia, parkinsonism, hyperreflexia, and action tremor.

Spinocerebellar ataxia 13 (SCA 13)

• Mutations in a potassium channel gene (KCNC3) on chromosome 19q.

• Short stature and mild cognitive impairment.

Spinocerebellar ataxia 14 (SCA 14)

Spinocerebellar ataxia 15/16 (SCA 15/16)

Spinocerebellar ataxia 17 (SCA 17)

• Reported in a single family with a gene locus on chromosome 7q.

• Candidate gene is IFRD1.