Assessment of ataxia

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Ataxia can be caused by an array of conditions. The aetiology of ataxia may be broadly categorised as acquired or inherited.

The list of acquired causes is extensive. In patients with acquired causes, ataxia may be a major clinical finding or may be overshadowed by other signs.

Many acquired lesions can be easily identified on imaging studies. In some cases, imaging reveals cerebellar atrophy only. This is a non-specific finding, necessitating further diagnostic work-up.

Genetic ataxias may be 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) Opens in new window In general, genetic forms of ataxia result in cerebellar atrophy and atrophy of related structures, which can be seen on imaging studies.

Acquired causes

Toxic

Alcoholic cerebellar degeneration is one of the most frequent forms of acquired ataxia.[6] 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. Some patients do have upper limb, speech or oculomotor involvement.
Many medications can result in ataxia, including anticonvulsants such as phenytoin, carbamazepine, oxcarbazepine, vigabatrin, topiramate, lamotrigine and phenobarbital.[7] Chemotherapy, particularly fluorouracil and cytarabine, but also intrathecal methotrexate, procarbazine, epothilones, vincristine, and capecitabine can cause ataxia.[8][9] Other drugs include lithium, amiodarone, ciclosporin, and bismuth salts. Ketamine may cause acute ataxia.[10]
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 subacute 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/post-infectious

Viral or bacterial meningoencephalitis, including infection with varicella zoster virus, Epstein-Barr virus, Lyme borreliosis, Listeria monocytogenes, Mycobacterium tuberculosis, Streptococcus pneumoniae, or Neisseria meningitidis, can cause an acute ataxia.
Acute ataxia can occur in the weeks following a viral infection such as chickenpox, Epstein-Barr, or after immunisation (i.e., acute cerebellitis and acute cerebellar ataxia of childhood).[11][12] The cerebellum may be afflicted by a diffuse encephalomyelitis, which is thought to be an autoimmune problem triggered by the 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 people with HIV dementia may exhibit ataxia at onset.[13][14]
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.[15]
Whipple's disease may have ataxia as a neurological complication.[16]

Neurosyphilis may cause ataxia, when damage to the dorsal columns of the spinal cord causes a syndrome known as tabes dorsalis.[17]

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.[18] 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.
Non-neoplastic causes of cerebellar compression include skeletal abnormalities at the craniovertebral junction, such as basilar invagination and Arnold-Chiari malformation.

Autoimmune

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. OMA is associated with paraneoplastic, infectious (e.g., West Nile virus), or post-infectious aetiologies in adults.
An immune basis for isolated ataxia has been proposed, involving antibodies to gliadin (coeliac disease) and antibodies to glutamic acid decarboxylase.[19][20][21]

An acute form of neuropathy, the Miller-Fisher variant of Guillain-Barre syndrome, causes ataxia, ophthalmoplegia, and areflexia evolving over a few days. A similar clinical picture can be caused by brain stem encephalitis (Bickerstaff's encephalitis).

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.[22][23]
Ataxia related to vitamin B1 deficiency is often part of Wernicke-Korsakoff syndrome in people with a history of alcohol dependence and other patients who have severe nutritional deficiency.[24]
Severe vitamin E deficiency, as occurs in fat malabsorption or certain genetic syndromes, may result in ataxia.[25]

Sensory neuropathies

Pure sensory neuropathies that primarily affect large myelinated fibres in the peripheral nerves cause sensory ataxia because of loss of proprioceptive sensation.[26]
These patients exhibit gait and limb incoordination with no involvement of eye movements or bulbar coordination. 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.

Inherited causes

Inherited ataxias usually have a chronic evolution, measured in many years. Ataxia can be a major clinical symptom in autosomal-recessive, autosomal-dominant, and X-linked genetic defects, as well as in defects involving mitochondrial genes.

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 ion channel dysfunction, among others.[5][27][28][29]

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 of inheriting the variant allele. By convention, progressive autosomal-dominant ataxias are labelled spinocerebellar ataxia, followed by a number to denote a particular gene locus. In addition, there are autosomal-dominant ataxias with episodic symptoms (episodic ataxias).

X-linked ataxias primarily affect men but are passed on through women. Fragile-X tremor-ataxia syndrome, an unusual late-onset disorder, is caused by a premutation in the FMR1 gene.

Mitochondrial DNA mutations, either sporadic or maternally inherited, can result in ataxia.

Inherited causes: autosomal recessive

Friedreich's ataxia

Most common autosomal-recessive ataxia; mean age at onset is 10 to 15 years.[4][30]
Gene mutation is an expanded trinucleotide repeat in the first intron of the frataxin gene on chromosome 9. The mutation seems confined to Indo-European populations.[27]
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, spasticity, peripheral neuropathy, dysarthria, foot deformity, corticospinal tract signs, scoliosis, diabetes, visual and hearing dysfunction, and restless leg syndrome.[31]
Hypertrophic cardiomyopathy is a cardinal feature; therefore, all patients with Friedreich's ataxia should be screened for cardiomyopathy with an ECG and echocardiogram.[32][33] Patients with classical Friedreich ataxia often die before age 40 years.[34] Patients with less severe symptoms (those with a lower number of GAA repeats) can have a long life, especially if cardiomyopathy is not present.

RFC1 associated cerebellar ataxia[35]

Likely the most common cause of late-onset inherited ataxia.

Gene mutation is a biallelic expansion of a pentanucleotide repeat, AAGGG, in an intron of the RFC1 gene.

The single most common cause of a syndrome of cerebellar ataxia, neuropathy/neuronopathy, and vestibular areflexia: the so-called CANVAS syndrome.

The exact pathogenesis of disease remains to be determined.

Ataxia telangiectasia

The most common cause of inherited ataxia presenting at <5 years of age.[6]
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.[6][36]
Clinical features include ataxia, oculocutaneous telangiectasias, 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.[6]

Late-onset ataxia telangiectasia is associated with extrapyramidal features, later age at ataxia onset, slower progression, and an extended lifespan.[37]

SPG7 associated cerebellar ataxia

Is a common cause of recessive ataxia.[38]

Most often associated with compound heterozygous mutations in SPG7, a gene implicated in hereditary spastic paraplegia.

SPG7 encodes paraplegin, which is a component of the mitochondrial AAA protease, and the binding partner of AFG3L2. Mutations in AFG3L2 cause spinocerebellar ataxia type 28.[38]

Ataxia with oculomotor apraxia 1 (AOA1)

A rare form of autosomal-recessive ataxia. The second most common form of autosomal-recessive ataxia in some areas such as Portugal, and perhaps the most common in Japan.
The causative mutations involve the aprataxin gene, possibly involved in single-strand DNA break repair.[36][39]
Clinical features include ataxia, peripheral neuropathy, and oculomotor apraxia.
Patients exhibit hypoalbuminaemia and hypercholesterolaemia.

Ataxia with oculomotor apraxia 2 (AOA2)

Mutations involve the senataxin gene, again associated with single-strand DNA break repair and RNA processing.[36][39][40]
Clinical features are similar to those seen in AOA1.

Ataxia with vitamin E deficiency (AVED)

Many cases have been described from the Mediterranean rim and from an isolated Japanese island, although cases are seen elsewhere.[41]
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.[36]

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.[36]
Clinical features include ataxia, acanthocytosis, and retinal degeneration.[42]

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay

This childhood ataxia was originally described as a cluster of cases from the Charlevoix-Saguenay province of Quebec, Canada.
A mutation in the gene SACS, which codes for a possible chaperone-related protein called sacsin, was found.[36]

Ataxia due to POLG1 mutations

A common cause of mitochondrial-recessive ataxia syndrome (MIRAS).
POLG1 is a nuclear-encoded polymerase involved in mitochondrial DNA synthesis.[36]
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.[43]

Infantile-onset spinocerebellar ataxia (IOSCA)

Described in 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.[36][44]

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.[36]
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.[36]
Considered rare.

Marinesco-Sjogren syndrome

The mutation involves the gene SIL 1, involved in chaperone function.[36]
Clinical features include ataxia, cataracts, developmental delay, and short stature.
Considered rare.

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.[26]

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.[26][36]
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 topic 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.[45]

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, dystonia, seizures, low muscle tone, developmental delay in children, and dementia in adults. Systemic symptoms include hepatosplenomegaly and liver disease.

Patients generally die prematurely, although life expectancy varies. The majority of patients die between the ages of 10 and 25 years; however, people with adult-onset forms may live into the seventh decade of life.[45][46][47]

Inherited causes: autosomal dominant spinocerebellar ataxias (SCAs)

Spinocerebellar ataxias (SCA) are autosomal dominant and tend to present after age 20 years.[33] All have similar clinical features, although distinctive signs can be seen in some types.[5][28][36][48][49] No single feature can definitely differentiate one genotype from another.

Many of the commonly recognised SCAs are related to unstable trinucleotide repeat expansions. SCA3 (also known as Machado-Joseph disease), SCA2, SCA6, and SCA1 are the most common worldwide.[50] 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 SCAs may not yet be evident. Also, the true prevalence of some SCAs may be higher than is currently recognised.

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).[28]

Note that there is no SCA9 (initially designated but not substantiated) or SCA24.[6]

Spinocerebellar ataxia 1 (SCA1)

The first autosomal-dominant ataxia to be localised to a chromosome, and probably the fourth most common type of autosomal-dominant ataxia worldwide.[51]
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 ATXN1 gene on chromosome 6p23.

Spinocerebellar ataxia 2 (SCA2)

Phenotype closely resembles that of SCA1.
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, developmental delay or regression, and retinitis pigmentosa, or in adulthood with ataxia, slow saccades, peripheral neuropathy, and hyporeflexia.[52][53]

Spinocerebellar ataxia 3 (SCA3 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).[54]
Large Portuguese founder population.[55]
The most common spinocerebellar ataxia.[56]
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).

Spinocerebellar ataxia 4 (SCA4)

Due to a GGC repeat expansion in the ZFHX3 gene chromosome on 16q22. There is a strong inverse correlation between repeat length and age at onset.[57][58].
Characterised by adult-onset, slowly progressive ataxia. Dysautonomia is common.[59]

Spinocerebellar ataxia 5 (SCA5, or Lincoln ataxia)

There are a limited number of families worldwide with documented SCA5. Localised to chromosome 11q.[60][61]
Has a relatively better prognosis than SCA1, SCA2, and SCA3; early onset but slow course.
Point mutations and insertions in the beta-spectrin gene, SPTBN2, have been found to cause SCA5.
Presents in early adulthood with a pure cerebellar syndrome.

Spinocerebellar ataxia 6 (SCA6)

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.[62]
Different mutations in this same gene cause episodic ataxia type 2 and familial hemiplegic migraine. There is some clinical overlap between these three disorders.[63]

Spinocerebellar ataxia 7 (SCA7)

A highly unstable CAG expansion in the 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.[64][65]

Spinocerebellar ataxia 8 (SCA8)

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 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.[66]
SCA8 has very variable penetrance, particularly when inherited from the father. CTG repeats may contract in sperm.[67]
Clinical features include ataxia, and hyper-reflexia with oculomotor dysfunction in more advanced disease; slowly progressive.

Spinocerebellar ataxia 10 (SCA10)

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.[68]
The causative mutation is an unstable pentanucleotide (ATTCT) expansion in a 5' UTR of the ataxin 10 gene on chromosome 22q.
Gene is expressed throughout the brain; patients have both cerebellar and cortical atrophy.
Ataxia and occasional seizures.

Spinocerebellar ataxia 11 (SCA11)

The mutation has been found to involve the TTBK2 gene, which is involved in the tau protein pathway. Locus is on chromosome 15q.[60]
Mild ataxia.
Very limited experience with this disease.

Spinocerebellar ataxia 12 (SCA12)

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.[69]
Slowly progressive ataxia, dementia, parkinsonism, hyper-reflexia, and action tremor.

Spinocerebellar ataxia 13 (SCA13)

Mutations in a potassium channel gene (KCNC3) on chromosome 19q.[70]
Short stature and mild cognitive impairment.

Spinocerebellar ataxia 14 (SCA14)

A small number of families have been described. The mutation involves the PRKCG gene on chromosome 19q.[71]

Relatively pure cerebellar ataxia.

Axial myoclonus.

Spinocerebellar ataxia 15/16 (SCA15/16)

Initially identified in an Australian kindred with pure cerebellar ataxia and slow progression, deletions involving two contiguous genes (SUMF1 and ITPR1) were found on chromosome 3q.[72]
Japanese families with slowly progressive ataxia and head tremor, originally labelled SCA16, were also found to have deletions in the ITPR1 gene, indicating that this is the causative gene.[73][74]

Spinocerebellar ataxia 17 (SCA17)

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 on chromosome 6q.[75]
Cognitive decline and extrapyramidal symptoms, including chorea, dystonia, myoclonus, and epilepsy.

Spinocerebellar ataxia 18 (SCA18), also called autosomal dominant sensorimotor neuropathy with ataxia

Reported in two families with a gene locus on chromosome 7q.[76]
Candidate gene is IFRD1.
Nystagmus, hyporeflexia, dysarthria, sensorimotor neuropathy.

Spinocerebellar ataxia 19/22 (SCA19/22)

Described initially in a single family from the Netherlands, and localised to chromosome 1p.
The same region is a locus for SCA22, initially reported to cause isolated ataxia of late onset in a Chinese family.[77]
Mutation in the voltage-gated potassium channel KCND3.
Variable cognitive impairment, myoclonus, tremor, hyper-reflexia, slowly progressive.[77][78][79][80]

Spinocerebellar ataxia 20 (SCA20)

Described in a single Australian family. The genetic abnormality is on chromosome 11 and involves the duplication of a segment of DNA.[81]
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 hyper-reflexia are also present.
Dentate calcification on computed tomography.

Spinocerebellar ataxia 21 (SCA21)

Mutation in TMEM240 on chromosome 7p.[82][83]
Behavioural and cognitive impairment and extrapyramidal signs, including rigidity, akinesia, and hyporeflexia.

Spinocerebellar ataxia 23 (SCA23)

Reported to cause ataxia in four families from the Netherlands.
Caused by mis-sense mutation in prodynorphin (PDYN) gene.[84]

Spinocerebellar ataxia 25 (SCA25)

Reported in one French family. Localised to chromosome 2p.[85]
Peripheral sensory neuropathy and areflexia.

Spinocerebellar ataxia 26 (SCA26)

Causes isolated ataxia. Reported in a single family and localised to chromosome 19p.[86]
Dysarthria.
Gene is EEF2.

Spinocerebellar ataxia 27A (SCA27A)

Reported in a single family.
Mutation found in the fibroblast growth factor 14 (FGF14) gene (chromosome 13 q).
Early onset tremor, facial dyskinesia, and sensory neuropathy.[87]

Spinocerebellar ataxia 27B (SCA27B)

May be one of the most common late-onset ataxias.[88][89][90]
Caused by an intronic GAA repeat expansion in the FGF14 gene.[90][91] Since FGF14 has already been implicated in ataxia, this new entity has been designated as SCA27B.
Relatively pure progressive cerebellar ataxia, with episodic symptoms. Clinical evaluation often reveals downbeat nystagmus.[88]

Spinocerebellar ataxia 28 (SCA28)

Reported in a single Italian family.
May be due to mutation in AFG3L2 gene on chromosome 18.[92]
Hyper-reflexia, ptosis, and ophthalmoparesis.

Spinocerebellar ataxia 29 (SCA29)

Reported in a single family with congenital non-progressive ataxia and localised to chromosome 3p, gene ITPR1.[93][94]
Pure ataxia.

Spinocerebellar ataxia 30 (SCA30)

Reported in a single Australian family with locus at chromosome 4q.[95]
Pure ataxia.

Spinocerebellar ataxia 31 (SCA31)

Caused by a complex pentanucleotide repeat containing TAAAA, TAGAA, and TGGAA, lying in an intron shared by two different genes, BEAN and TK2, which are transcribed in opposite directions.[96]
Ataxia and progressive sensorineural hearing loss.
Common in Japan.[48]

Spinocerebellar ataxia 32 (SCA32)

Unknown gene on 7q32-q33.[97]
Cognitive impairment.[65]
Azoospermia in males.[98]

Spinocerebellar ataxia 34 (SCA34)

Gene ELOVL4 on 16p12.[97]
Neurocutaneous syndrome and hyporeflexia; skin changes disappear in adulthood.[98]

Spinocerebellar ataxia 35 (SCA35)

Mutation in TGM6 on 20p13.[65]
Pseudobulbar palsy, tremor, hyper-reflexia, and torticollis.

Spinocerebellar ataxia 36 (SCA36/Asidan)

Caused by a hexanucleotide GGCCTG repeat expansion of the nucleolar protein 56 (NOP56) gene.
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.
Typical age of onset is 50 years and older.[99]

Spinocerebellar ataxia 37 (SCA37)

Unknown gene on chromosome 1p32.[65]
Abnormal vertical eye movements.

Spinocerebellar ataxia 38 (SCA38)

Mutation in ELOVL5 on 6p12.[65]
Adult onset ataxia, sensory axonal neuropathy.[100]

Spinocerebellar ataxia 40 (SCA40)

Gene CCDC88C on 14q32.[65]
Adult onset ataxia.
Spasticity and brisk reflexes.

Spinocerebellar ataxia 41 (SCA41)

Gene TRPC3 on 4q27.[101]

Adult onset ataxia.

Spinocerebellar ataxia 42 (SCA42)

Gene CACNA1G on 17q21.[102]

Variable age of onset presenting with primarily cerebellar ataxia.

Loss of function mutations in the Cav3.1 calcium channel encoded by CACNA1G.

Gain of function mutations in CACNA1G result in a neurodevelopmental disorder SCA42-ND with symptom onset at birth or early infancy. Hypotonia, psychomotor retardation and absent or severely impaired speech. Variable dysmorphic features and epilepsy.

Spinocerebellar ataxia 43 (SCA43)

Variant in the MME gene (on chromosome 3q25) that encodes membrane metalloendopeptidase.[103]

Late onset ataxia, often with neuropathy.

Spinocerebellar ataxia 44 (SCA44)

Mutations in GRM1 (located on chromosome 6q24) that encodes the metabotropic glutamate receptor type 1 (mGluR1).

Gain-of-function mutations result in late onset cerebellar ataxia.[104]

Truncating mutations that cause loss of function result in early onset developmental delay and ataxia.

Spinocerebellar ataxia 45 (SCA45)

Gene FAT2 on 5q33 encodes fat atypical cadherin 2 (FAT2).

Late onset relative pure cerebellar ataxia.[105][106]

Spinocerebellar ataxia 46 (SCA46)

PLD3 gene on 19q13 encodes phospholipase D family, Member.[107]

Late onset ataxia with sensory axonal polyneuropathy.

Spinocerebellar ataxia 47 (SCA47)

Gene PUM1 on 1p35 encodes Pumilio 1.

Late onset form with primarily cerebellar ataxia with mild cerebellar vermis atrophy, termed Pumilio 1 related cerebellar ataxia (PRCA).[54][108]

Early onset form with delayed motor development, early-onset ataxia, and short stature with variable cognitive impairment and seizures, termed Pumilio-1-associated developmental disability, ataxia, and seizure (PADDAS).

Mechanism of disease may be related to loss of repressor function and elevated ATXN1 levels.

Spinocerebellar ataxia 48 (SCA48)

Gene STUB1 on 16p13 encodes STUB1, or CHIP, a ubiquitin ligase/cochaperone that participates in protein quality control.

Gait ataxia and/or cognitive-affective symptoms in mid-adulthood.[109]

Spinocerebellar ataxia 49 (SCA49)

Gene SAMD9L on 7q21 encodes SAMD9L, a tumour suppressor gene that is also involved in regulating cell proliferation and cell cycle progression, and acts as an antiviral factor.[110][111][112][113]
Variable age of onset of adult-onset cerebellar ataxia, dysarthria and axonal polyneuropathy.

Spinocerebellar ataxia 50 (SCA50)

Gene NPTX1 on 17q5 encodes neuronal pentraxin 1.[114]
Usually presents as an adult-onset cerebellar ataxia with oculomotor abnormalities.

Spinocerebellar ataxia 51 (SCA51)

Gene THAP11 on 16q22 encodes a putative DNA binding protein. SCA51 results from a CAG repeat expansion of >45 repeats in affected individuals.[115]
SCA51 represents a rare cause of ataxia in a Chinese population where the CAG repeat expansion was identified to be associated with an adult-onset ataxia in the majority of individuals.[115]
Disease anticipation is likely present, as a single individual with a CAG repeat of 100 had onset of disease at age 4 years.

Inherited causes: other autosomal dominant hereditary ataxias or disorders with ataxia as an important feature of disease

In addition to SCAs, a number of other dominantly inherited disorders have ataxia as a major feature of the disease.

Dentatorubral-pallido-luysian atrophy (DRPLA)

Ataxia forms a major feature of the disease.[116]
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.
In addition to ataxia, clinical features include seizures, chorea, dystonia, myoclonus, dementia, and parkinsonism.
In Japan, 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.

KCNMA1 associated ataxia

Initially described in a Saudi family as a syndrome of cerebellar atrophy, developmental delay and seizures (CADEDS). Results from homozygous mutations in KCNMA1, which encodes the large-conductance calcium-activated potassium (BK) channel.
Subsequently identified as a cause for a developmental disorder resulting from de novo dominant loss-of-function mutations in this ion channel, and resulting in developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria.[117]

KCNN2 associated ataxia

Gene encoding the small-conductance calcium-activated potassium channel type 2 (SK2).
Identified as causing dominantly inherited motor and language developmental delay, intellectual disability, early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms.[118]

Episodic ataxia type 1 (EA1)

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.[28]

Episodic ataxia type 2 (EA2)

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 (CACNA1A) that is affected in SCA6. In addition, missense mutations in the same gene are associated with familial hemiplegic migraine.[28]

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 EA6.[119][120]

EA3, EA4, and EA7 are genetically distinct, but the mutations are unknown.

Inherited causes: X-linked

A few families with ataxia have an X-linked pattern of inheritance, but these have not been characterised genetically.

Fragile X syndrome is the most common cause of male intellectual impairment and is related to the expansion of a CGG repeat (repeated more than 200 times) in the FRAXA gene on the X chromosome.[121] Both mothers and maternal grandfathers of fragile X-associated tremor/ataxia syndrome (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.[122] Screening for the FMR1 pre-mutation in men with adult-onset sporadic progressive cerebellar ataxia suggests that FXTAS may be a rare cause of late-onset sporadic ataxia.[123][124]

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;
mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes;
neurogenic weakness, ataxia, and retinitis pigmentosa; and
Kearns-Sayre syndrome (KSS).

Some of these syndromes appear in a sporadic fashion (e.g., KSS); others are maternally inherited.[125][126]

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.

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.

Patients with sporadic ataxia who develop additional neurological signs may have MSA-cerebellar type (MSA-C) ataxia.[127] 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.

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