Inherited ataxia with slow saccadesRT Chakor, H Bharote
Department of Neurology, Topiwala National Medical College, B. Y. L. Nair Hospital, Dr. A. L. Nair Road, Mumbai Central, Mumbai, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.105471
Source of Support: None, Conflict of Interest: None
Ataxia is a symptom of cerebellar dysfunction. Slowly progressive ataxia, dysarthria in an adult with a positive family history suggests an inherited cerebellar ataxia. We present an adult with gradually progressive ataxia and slow saccades. There was history of similar illness in his son. Genetic testing for spinocerebellar ataxia 2 was positive. We discuss the various inherited ataxias, causes of acute, progressive ataxia syndromes, episodic ataxias and ataxia associated with other neurological signs like peripheral neuropathy, pyramidal features, movement disorders and cognitive decline.
Keywords: Ataxia, cerebellar ataxia, spinocerebellar ataxia, SCA2
A 45-year-old painter presented with history of speech disturbances for six months, clumsiness while painting for one and half years and unsteadiness while walking for two years. The patient was asymptomatic two years ago when he noticed unsteadiness while walking in crowded places and on an uneven surface. Six months later he had unsteadiness even on level ground. This progressed to the extent that he swayed to either side like a drunkard. He also noticed clumsiness in his hands while painting and hence gave up his job. For the past six months he noticed his speech was broken into individual words. There was no worsening of symptoms in the dark. There was no history of weakness or thinning of limbs, bladder/bowel complaints, cognitive decline, behavioral changes, slowness of activities, seizures, diminished vision headache, vomiting, vertigo, deafness tinnitus, and involuntary movements. He was non-alcoholic and was not on any medications. There was no exposure to toxins. His son aged 12 years had history of similar complaints of imbalance while walking, clumsiness in hands and difficulty in speaking since six years of age. There was no history of similar illness in his parents, siblings and no parental consanguinity.
Could you summarize the history?
This is an adult with history of chronic progressive cerebellar ataxia and history of similar illness in his son in whom the onset is at an early age.
What do you mean by ataxia?
The term ataxia literally means without order. It is derived from the Greek word 'taxi' meaning order. Cerebellar ataxia is a clinical syndrome of incoordination of movement caused by lesions of the cerebellum, its afferent or efferent connections.  Ataxia can be of different types like cerebellar, sensory or vestibular. Sensory ataxia is due to loss of proprioception, vestibular ataxia is due to vestibular dysfunction. Although ataxia is a symptom the term ataxia is sometimes used to designate specific diseases of the nervous system in which progressive cerebellar ataxia is the prominent clinical manifestation. 
What are the clinical features of ataxia?
Ataxia itself is a symptom of cerebellar dysfunction. The symptoms due to ataxia are imbalance while walking, clumsiness of hands and dysarthria. Imbalance can lead to falls and frequent tripping, especially when walking on uneven surfaces or in crowded places. As far as the hands are concerned there is difficulty in doing fine motor acts like typing on the keyboard or threading a needle. While eating the hand may not reach the mouth and the face may get smeared with food. Incoordination of the palato-pharyngeal and laryngeal musculature leads to scanning speech with variable tone. Tremors during purposeful movement termed action tremor and intention/terminal tremor are peculiar. The cerebellar outflow tremor, rubral tremor or wing beating tremor is seen with lesions of the superior cerebellar peduncle (dentatorubrothalamic pathway). This tremor is maximal when the arms are held in front of the trunk with elbows flexed looking similar to a bird flapping its wings.  This type of tremor is absent at rest, is seen with posture and increases with action. In cerebellar ataxia there is irregularity or fragmentation of the normal smooth motor sequences involved in any given act. This deficit is most apparent in the execution of rapidly alternating movements, referred as dysdiadochokinesis by Babinski. These abnormalities of voluntary movements are classified as cerebellar incoordination orataxia. Dyssynergia (impaired synergistic movements of agonists and antagonists), dysmetria (difficulty in judging distance of the target) and dysdiadochokinesis are cerebellar abnormalities of movement. Holmes has referred to these as abnormalities in the rate, range, and force of movement. Cerebellar dysarthria is a scanning dysarthriawith variable tone. The words are broken up into individual syllables. Speech is slow, each syllable is interrupted and is articulated with variable emphasis. Syllable may be uttered with less force or more force leading to explosive speech. 
His general examination was normal and vitals were stable. Higher mental function examination was normal. Cortical functions and frontal assessment battery was normal. He had scanning dysarthria with variation in tone and individual syllables were broken. Cranial nerve examination revealed slow horizontal and vertical saccades. Rest of the cranial nerve examination was normal. Motor system examination revealed mild asymmetric spasticity of the lower limbs. Power was normal. The reflexes were brisk with bilateral extensor plantar response. Sensory examination was normal. There were bilaterally symmetrical cerebellar signs. There was bilateral dysmetria and dysdiadokinesia. Tandem walking was impaired. The gait was wide-based and ataxic. There were no involuntary movements.
What is your conclusion after examination?
This is an adult with slowly progressive cerebellar ataxia and slow saccades. Examination confirms a pancerebellar syndrome with slow saccades and pyramidal signs. Spinocerebellar ataxia (SCA) with slow eye movements is characteristic of SCA 1, SCA 2, SCA 5 and SCA 8. There is considerable heterogeneity and clinical overlap among the common SCAs namely SCA 1, SCA 2 and SCA 3. 
What diagnostic tests would you do in this patient?
Magnetic resonance imaging (MRI) brain is useful in the diagnosis of SCA but is not diagnostic. In the early stages of SCA the MRI may be normal. In advanced stages of SCA there is pure cerebellar atrophy in SCA 6, olivopontocerebellar atrophy in SCA 2 and 7.  DNA Polymerase chain reaction PCR for several SCAs is commercially available.
What is the utility of MRI brain in a case of cerebellar ataxia?
MRI brain can identify causes of cerebellar ataxia like stroke, neoplasm, demyelinating disease, trauma, or cerebellar anomalies as a cause of cerebellar ataxia. Some hereditary or acquired ataxic conditions such as Wilson's disease, leukodystrophies, or prion disease can also demonstrate characteristic features on MRI. The predominant MRI finding in patients with SCA is atrophy of the cerebellum with or without brainstem [olivopontocerebellar] atrophy. , Cerebellar and brainstem atrophy is more in SCA2 than in SCA 1 and 3; SCA 6 has characteristic atrophy of the cerebellar vermis and hemispheres in sagittal section. ,, There is pancerebellar atrophy in SCA 5 similar to SCA 6. ,, Toxins like ethanol and anticonvulsants like phenytoin cause cerebellar vermian atrophy which is typically seen in the sagittal MRI images. ,,
The [Figure 1] for clinical approach to ataxia. MRI brain revealed pontocerebellar atrophy [Figure 2]. DNA PCR for SCA 2 demonstrated 50 cytosine adenine guanine (CAG) repeats (Normal 16 -30 repeats).
What is the utility of electrophysiology in patients presenting with spinocerebellar ataxia?
Electrophysiology is useful to demonstrate clinical or subclinical involvement of peripheral nerves or visual pathway in spinocerebellar ataxias.  SCA 1 and 2 have features of neuronopathy while SCA 3 and 7 have neuronopathy and axonal degeneration.  In SCA 2 visual-evoked potentials (VEP), event-related potentials, motion onset VEPs show delayed response. Among these the motion onset VEP has the highest sensitivity to the duration of SCA 2. The CAG repeats do not correlate with the VEPs.  . Nerve conduction studies are useful in SCAs with neuropathy as discussed later.
What are the causes of ataxia and peripheral neuropathy?
The autosomal recessive inherited ataxias are generally associated with peripheral sensorimotor neuropathy with loss of proprioception and vibration sense with areflexia. Friedreich's ataxia is the typical example of autosomal recessive cerebellar ataxia with peripheral neuropathy. Other autosomal recessive ataxias with peripheral neuropathy are ataxia telangiectasia (AT), ataxia telangiectasia-like disorder (ATLD), ataxia with vitamin E deficiency (AVED), abetalipoproteinemia (ABL), ataxia with oculomotor apraxia Type 1 and 2 (A OA 1,2), Refsum's disease, late-onset Tay-Sachs' disease (LOTS), cerebrotendinous xanthomatosis (CTX), mitochondrial recessive ataxia syndrome (MIRAS), spinocerebellar ataxia with axonal neuropathy (SCAN1) due to mutation of the DNA repair protein tyrosyl-DNA phosphodiesterase 1 (TDP1),  autosomal recessive ataxia of Charlevoix-Saguenay (ARSACS), infantile-onset spinocerebellar ataxia (IOSCA),  late-onset Hexosaminidase A deficiency or GM2 gangliosidosis. Among the autosomal dominant SCAs, types 4, 18 and 25 are associated with peripheral neuropathy.  SCA1, SCA2, SCA3, SCA 6, SCA8, and SCA12 are also associated with neuropathy. , Leukodystrophies like adrenoleukodystrophy, metachromatic leukodystrophy have ataxia and peripheral neuropathy. The mitochondrial disease neuropathy ataxia retinitis pigmentosa (NARP) presents with gradually progressive weakness, sensory neuropathy, ataxia and diminished vision.
What are the causes of ataxia with cognitive decline?
Ataxia associated with cognitive decline is seen in inborn errors of metabolism, ataxia telangiectasia, mitochondrial cytopathies, SCAs and the cerebellar variant prion disease Creutzfeldt-Jakob disease More Details (CJD).  Among the SCAs executive dysfunction is prominent in SCA 1, deficits in verbal memory are seen in SCA 1, SCA 2 and SCA 3.  Deficits in memory and executive function are more prominent in SCA 3 than in SCA 6.  Dementia has been described with SCA 2, SCA 17 and dentatorubral-pallidoluysian atrophy DRPLA.  Cognitive disturbance, specifically executive dysfunction and dementia occur in 19-42% of patients with SCA 2. The cognitive decline correlates with the age of onset of cerebellar symptoms. Cognitive dysfunction may be an important part of SCA 2. 
What are the causes of ataxia with pyramidal features?
Spasticity, upper motor neuron UMN signs are seen in posterior circulation strokes with cerebellar and pyramidal infarcts, tumors or malformations compressing the brainstem, multiple sclerosis, many SCAs (SCAs 1, 2, 3, 4, 12, 13 and 17) and Friedreich's ataxia. 
What are the causes of ataxia with movement disorder?
Chorea/dystonia are seen in Huntington's disease, DRPLA, ataxia telangiectasia, ataxia with oculomotor apraxia Type 1 and 2, Friedreich's ataxia, and Wilson's disease. Ataxia with myoclonus is seen in mitochondrial cytopathies, neuronal ceroid lipofuscinosis, prion disease (CJD), Unverricht Lundborg (Baltic myoclonus) and celiac disease (gluten ataxia) 
What are the causes of chronic progressive ataxia?
Ataxia with an insidious onset and progression over years is typically due to genetic/inherited, degenerative, or sporadic ataxias. Immune mediated (anti-cerebellar antibody-mediated, gluten sensitivity) or paraneoplastic cerebellar degeneration presents with subacute ataxia with progression over months or few years are discussed later. ,,, Antibodies to voltage gated calcium channels are seen in a subgroup of sporadic late-onset cerebellar ataxia with progression over years.  The genetic ataxias are classified on the basis of inheritance pattern. See [Table 1] for classification by inheritance pattern.
What are episodic ataxias?
Episodic ataxias (EA) are a clinically and genetically heterogeneous group of autosomal dominant disorders characterized by spells of ataxia (incoordination and imbalance) with or without progressive ataxia. There are now six recognized episodic ataxia syndromes numbered 1 to 6. The genes are known for EA1, EA2, EA5 and EA6.  The best characterized are EA1 and EA2 while the others are exceptionally rare. EA2 and EA1 present in childhood, EA2 being more common than EA1. EA1 is characterized by episodes of ataxia lasting for seconds to minutes and interictal myokymia. Myokimia also termed as neuromyotonia are involuntary rippling movements of muscles. These may respond to acetazolamide or phenytoin. In both EA1 and EA2 the episodes of ataxia are commonly triggered by physical and emotional stress. In EA1 the episodes may recur up to 30 times a day. Sometimes patients have seizures. Progression of ataxia does not occur. The gene responsible is KCNA1 on Chromosome 12 q.  EA2 is characterized by episodes of ataxia lasting for hours to days with interictal nystagmus and mildly progressive ataxia. About half of affected individuals have migraine headache. EA2 is allelic with familial hemiplegic migraine Type 1 (FHM1). The gene responsible is CACNA1A on Chromosome 19 p. There is no interictal myokymia but gaze-evoked nystagmus is seen. The attacks are dramatically responsive to acetazolamide. 
What are the causes of rapidly progressive or subacute-onset ataxia?
Subacute ataxia progresses over weeks to months. The common causes are posterior fossa (cerebellum and brainstem) tumors such as medulloblastoma, astrocytoma, ependymoma, hemangioblastoma, metastases, meningioma, and cerebellopontine angle schwannoma. These patients present with gait ataxia usually with headache and papilledema. Progressive hydrocephalus can also present with subacute-onset ataxia.
Paraneoplastic cerebellar degeneration (PCD) presents with subacute ataxia in a patient with known carcinoma, usually of breast or ovary. The other tumors associated with PCD are small-cell lung cancer, gynecological tumors, and Hodgkin's lymphoma. Cerebellar dysfunction is one of the most common presentations of paraneoplastic syndromes. There is often an evidence of other paraneoplastic syndromes like Lambert-Eaton myasthenic syndrome, opsoclonus myoclonus, brainstem encephalitis, and encephalomyelitis in these patients. Specific anti-cerebellar antibodies (anti-Hu, anti-Ri, anti-purkinje cell antibodies) are present particularly with breast and ovarian carcinoma. 
Cerebellar variant of Creutzfeldt Jakob disease,  Gerstmann-Straussler-Scheinker syndrome,  cerebellar abscess, whipple disease (often with myoclonus and oculomasticatory movements), , gluten enteropathy ,, and multiple sclerosis can cause subacute progressive ataxia.
What are the causes of acute-onset ataxia?
The causes of acute onset of ataxia are cerebrovascular diseases like cerebellar infarction or hemorrhage. Hemorrhage into a posterior fossa neoplasm or hemangioblastoma can present with acute-onset ataxia. Overdose of antiepileptic medications like carbamazepine, phenytoin, benzodiazepine, phenobarbital or metronidazole can cause acute-onset ataxia and drowsiness. Alcohol intoxication is a common cause of acute cerebellar ataxia leading to ataxic gait and dysarthria. Miller Fisher variant of Guillain-Barre syndrome (GBS) presents with acute-onset ataxia, ophthalmoparesis and arreflexia. Acute massive exposure to toxins like thallium, lead can cause acute cerebellar ataxia with encephalopathy and peripheral neuropathy. Exposure to methyl mercury leads to ataxia, tremors and encephalopathy (Minimata disease in Japan). Demyelinating disorders like multiple sclerosis and acute disseminated encephalomyelitis can present as acute-onset ataxia with or without other neurological features.
Lithium in toxic doses, piperazine, high-dose 5-fluorouracil and cytosine arabinoside can cause an ataxic syndrome. Acute exposure to industrial solvent toluene causes ataxia with encephalopathy. Hypoxic encephalopathy, heat stroke and hypothermia can cause acute cerebellar ataxia with encephalopathy.
Acute viral cerebellitis is a common cause of acute-onset cerebellar ataxia in children and occasionally in adults. There is near-complete recovery in over 80 % of cases of viral/post-viral ataxias. Post-infectious demyelination as a part of disseminated encephalomyelitis can present as acute-onset ataxia with other signs of focal neurological deficit and encephalopathy.
Discuss various stroke syndromes presenting with acute-onset cerebellar ataxia
Vascular lesions of the cerebellum or the cerebellar connections like cerebellar peduncles result in ataxia. Infarcts in the territory of the posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), superior cerebellar artery (SCA) present with prominent ataxia in addition to other deficits. Infarction in any of these three arteries results in limb and gait ataxia. PICA infarcts involving the dorsolateral medulla and cerebellum typically present with Wallenberg's lateral medullar syndrome. PICA infarct that spares the medulla presents with limb and gait ataxia with acute-onset vertigo, nausea and vomiting. SCA infarct presents with acute-onset gait, ipsilateral limb ataxia, dysarthria with nausea and vomiting. AICA infarct presents with vertigo, ipsilateral hearing loss, peripheral facial palsy and ipsilateral limb ataxia.  Ataxic hemiparesis is a presentation of lacunar infarct with the most common sites being posterior limb of internal capsule, pons, corona radiate and lateral thalamus.
What are congenital ataxias?
Incoordination and clumsiness from birth which is not due to spasticity, hypotonia, weakness or sensory disturbance is due to cerebellar ataxia. In congenital ataxia the clumsiness seen in all newborns persists and the ataxia manifests when the child begins to sit, stand or walk. The gait is unsteady, the child has frequent falls and is not able to run or keep up with peers. There is instability of the trunk and upper limbs as well. The child is not able to reach an object with the hands. The congenital cerebellar ataxias due to cerebellar developmental anomalies are typically non-progressive and have to be distinguished from progressive hereditary ataxias, viral cerebellar ataxia and drug intoxication.
The various other causes of congenital ataxia are neonatal hypoxia, mercury poisoning and radiation exposure in utero. Congenital ataxias are due to cerebellar hypoplasia or aplasia. In Joubert syndrome there is dysgenesis of the cerebellar vermis, mental retardation, episodic hyperpnoea, and irregular, jerky eye movements with gait ataxia. In the Gillespie syndrome, cerebellar ataxia is associated with aniridia and mental retardation. In the Paine syndrome there is mental retardation, microcephaly, spasticity, optic hypoplasia, and myoclonic ataxia associated with cerebellar hypoplasia. A syndrome of pure cerebellar hypoplasia with non-progressive cerebellar ataxia has also been described.
How to differentiate congenital ataxias from hereditary ataxias?
Congenital ataxias have to be differentiated from progressive hereditary ataxias which present after infancy and are progressive in nature. In congenital cerebellar ataxias there may be apparent stability or improvement with the normal growth catch up.
What are the causes of early-onset ataxia and late-onset ataxia?
Most inherited ataxias presenting before 20 years of age are recessively inherited and are classified as early-onset. Those presenting after 25 years are dominantly inherited. Although useful, such a distinction is not universally true and much variability in age of onset can be seen. Typical early-onset, recessively inherited disorders, such as Friedreich's ataxia and Tay-Sachs disease More Details, can present in adulthood. 
MRI-Magnetic resonance imaging, ADCA-Autosomal dominant cerebellar ataxia, SCA-Spinocerebellar ataxia, DRPLA-Dentatorubropallidoluysian atrophy, ARCA-Autosomal recessive cerebellar ataxia, FA-Friedreich's ataxia, AT- Ataxia-telangiectasia, AOA-Ataxia with oculomotor apraxia, AVED-Ataxia with vitamin E deficiency, NARP-Neuropathy ataxia retinitis pigmentosa, SACD-subacute combined degeneration, MS-Multiple sclerosis, MSA-Multiple system atrophy, Alc-Alcohol, Pb-Lead, Hg-Mercury, AED-antiepileptic drugs, FLAIR-Fluid attenuated inversion recovery, DWI-Diffusion-weighted images, EMG/NCS-Electromyography/Nerve conduction studies, Echo-Echocardiography, CSF-Cerebrospinal fluid, EEG-Electroencephalogram, PET-Positron emission tomography.
The [Table 2] and [Table 3] for classification of autosomal dominant  and recessive ataxias.  The [Table 4] for diagnostic investigations in various ataxias. Episodic ataxias are autosomal dominant inherited ataxias but present at an early age and have been discussed earlier.
Which ataxias are reversible?
Most ataxic disorders are not fully reversible. Cerebellar ataxias caused by infectious, post-infectious cerebellitis, demyelination, vascular events like cerebellar infarction, hemorrhage, drug overdose-related ataxias, toxin-relatedataxias, hyponatremia, craniovertebral junction anomalies, posterior fossa tumors,hydrocephalus, paraneoplastic cerebellar degeneration are fully or partially reversible after appropriate therapy is initiated early. , The general goal in degenerative ataxias is to prevent progression.
Which SCA is the commonest worldwide and in India?
The prevalence of SCA varies from 0.3 to 3/100000.  The type of SCA varies from region to region. SCA2 is commonest in India. ,,,, Worldwide, SCA3 is the commonest SCA, followed by SCA2 and SCA6.Other SCAs reported from India are SCA1, SCA12, SCA3, SCA6 and SCA 7. , In one study SCA12 was the most common SCA in the Agarwal community followed by SCA2, SCA3 and SCA7. , SCA12 is emerging as the second most common SCA in India. , SCA1 is common in the ethnic Tamil community in India.  SCA1 is more common than SCA2 in southern India. 
What is genetic anticipation?
Anticipation is a phenomenon where some genetic conditions have more severe and early manifestations as the disorder is passed from one generation to the next. Anticipation occurs with disorders that are caused by trinucleotide repeat expansion. Anticipation is the hallmark of polyglutamine repeat disorders like SCAs.  Thetrinucleotide repeat mutation increases in size in successive generations resulting in a more significant effect when passed from one generation to the next. This occurs due to gremlin mosacism as the expanded alleles in parents are unstable and increase in size on transmission. Paternal expansions are more likely to expand during transmission (paternal expansion bias). This may be due to pre-meiotic mutations during spermatogenesis.  Anticipation is most often seen with certain disorders such as Huntington's disease, DRPLA myotonic dystrophy 1, SCA7, SCA2 and fragile X syndrome. 
Dean, T N Medical College, B Y L Hospital, Mumbai.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]