Incoordination and clumsiness that may affect balance and gait , limb and eye movements, and/or speech.
Ataxia may be the result of damage to the cerebellum (the part of the brain concerned with coordination) or to nerve pathways in the brainstem (a stalk of nerve tissue linking the brain to the spinal cord) and/or spinal cord. Possible causes include injury to the brain or spinal cord. In adults, ataxia may be caused by alcohol intoxication;a stroke or brain tumour affecting the cerebellumor brainstem; a disease of the balance organ in the ear; or multiple sclerosis or other types of nerve degeneration. In children, causes include acute infection, brain tumours, and the inherited condition Friedreich's ataxia.
Symptoms of ataxia depend on the site of damage within the nervous system, although a lurching, unsteady gait is common to most forms. In addition, damage to certain parts of the brain may cause nystagmus (jerky eye movements) and slurred speech.
Diagnosis and Treatment
CT scanning or MRI (techniques that produce cross-sectional or three-dimensional images of body structures) may be used to determine the cause of ataxia. Treatment of the condition depends on the cause.
Ataxic disorders - in detail - technical
- Symptoms of ataxic disorders
- Signs of cerebellar disease
- Disorders of the cerebellum
- Progressive metabolic ataxias
- Autosomal recessive ataxias
Ataxia is a feature of disorders of the cerebellum and its connections. It may be found in a large range of neurological conditions, in some of which it is the principal or main feature, but clinical assessment is complicated by the fact that few ataxic patients have disease restricted to the cerebellum alone.
Symptoms—common presenting complaints are:
- gait unsteadiness—particularly with lesions of the vermis,
- limb incoordination and tremor—particularly with lesions of the cerebellar hemisphere,
- slurring of speech, and
- visual and oculomotor symptoms, although these are rare in pure cerebellar disease.
- a broad-based gait with a poor turn,
- scanning dysarthria,
- limb ataxia—manifest as dysmetria and dysdiadochokinesis,
- intention tremor,
- abnormal eye movements.
Key points in differential diagnosis:
- age of onset—early onset is before 20 to 25 years;
- rate of onset and the nature of the progression of the illness;
- other features of neurological involvement, which enables differentiation of the ‘pure’ ataxias from the ‘complicated’ ataxias.
Investigation and treatment—high-resolution imaging, genetic testing and other investigative tools enable a diagnosis to be made in over 50% of cases.
The mainstay of management is supportive: there are no drugs that help cerebellar balance problems, but active engagement in physiotherapy can help to lessen the impact of the physical disorder.
Particular causes of ataxia
Ataxias with early onset:
- acute and subacute ataxias with onset in childhood—should raise the possibility of infectious, para-infectious or vascular conditions;
- chronic progressive ataxias of early onset—very often genetic in aetiology, typically autosomal recessive, with the commonest cause being Friedreich’s ataxia; a clear molecular genetic diagnosis can be established in some cases (e.g. abnormality of the frataxin gene in Friedreich’s ataxia).
Chronic progressive ataxia—causes include:
- genetic—with inheritance typically being autosomal dominant;
- chronic alcohol abuse—probably the most common cause of progressive cerebellar degeneration in adults;
- deficiency disorders—e.g. vitamin E;
- toxic agents—drugs (e.g. phenytoin), solvents and heavy metals;
- structural lesions in the posterior fossa; and
- other—e.g. Wilson’s disease, other metabolic disorders.
No cause can be found in many cases, labelled as ‘idiopathic late-onset cerebellar ataxia’, with the commonest pattern recognized being that of multiple system atrophy, where there is typically ataxia complicated by autonomic failure and (in some cases) Parkinsonism.
Rapid, subacute onset ataxia—should always raise the possibility of paraneoplastic or other inflammatory conditions.
Acute ataxia—the two main causes are:
- cerebellar haemorrhage—usually associated with headache, vertigo, vomiting, altered consciousness and neck stiffness; and
- cerebellar infarction—in which cerebellar signs are usually combined with signs of brainstem ischaemia.
The term ‘ataxia’ derived from the Greek means ‘irregularity’ or ‘disorderliness’. Unsteadiness can result from a number of causes, including poor vision, impairment of postural reflexes, or a deficiency of sensory input, i.e. sensory ataxia. This article is devoted to the symptoms, signs, and pathological and clinical features of the disorders of the cerebellum (and its connections). There are two basic clinical rules that can be applied: (1) lesions of the vermis generally cause ataxia of midline structure (i.e. truncal and gait ataxia); and (2) output from the cerebellar hemisphere is to the contralateral cerebral hemisphere, which provides output to the contralateral limbs, so cerebellar hemisphere lesions are ipsilateral. It should, however, be noted that clinical assessment is complicated by the fact that few patients with ataxia have disease restricted to the cerebellum alone; there is often additional pathology in the brainstem, spinal cord, or elsewhere.
Symptoms of ataxic disorders
The history is critical for eliciting the most common presenting complaints: gait unsteadiness or slurring of speech. On direct enquiry many patients all admit to receiving ‘jokes’ or accusations of being drunk by acquaintances. The joke tends to wear thin. Some refer to ‘giddiness’ or ‘dizziness’ when they really mean unsteadiness of gait without associated vertigo or light-headedness. A particular note in the history of the age, speed of onset, and development of other features may indicate the cause. Rate of progress and any precipitating or relieving factors should also be noted. There has been a prodigious improvement in our understanding of the genetic basis of many ataxia disorders and a detailed family history is paramount (see: Inherited neurodegenerative disorders).
Disturbances of gait
Disturbed gait is the most frequent presenting feature in ataxic disorders. Patients may report an inability to walk in a straight line and a tendency to collide with objects that others are able to avoid. If the symptoms are exaggerated in darkness, a sensory ataxia and involvement of the proprioceptive pathways may be present. Sudden changes of direction are particularly difficult. The duration of the gait disturbance should be established and it is worth asking about early motor milestones and athletic ability at school which may bring out a much longer history than previously appreciated. Collateral history should be sought, especially if an insidious onset is suspected. A question as to diurnal variation, particularly a history of morning unsteadiness that wears off later in the day, often associated with morning headache, suggests raised intracranial pressure, even if the examination is normal.
Limb incoordination and tremor
Clumsiness of the arms is often noted later in the course of the illness. Generally a tremor that is worse on action is reported and, as this worsens, patients notice clumsiness carrying objects and deterioration in their handwriting. Marked tremor is more common in multiple sclerosis than in degenerative disease. Disturbance to the midline structures may result in titubation and, in combination with action tremor in the upper limbs and only minor gait disturbance, should raise the suspicion of Wilson’s disease.
Abnormal speech may first be noted by friends and relatives. Classically described as having a staccato quality, this manifestation is a useful discriminatory feature against a purely sensory ataxia.
Visual and oculomotor symptoms
Visual symptoms are relatively rare in pure cerebellar disease and if present suggest brainstem disturbance, especially when there is episodic or persistent diplopia associated with ataxia. Vertical oscillopsia suggests downbeat nystagmus and a structural foramen magnum lesion should be suspected. Acute or subacute oscillopsia, with chaotic involuntary eye movements, may emerge from the history of patients with viral cerebellitis, paraneoplastic cerebellar degeneration, and the dancing eyes syndrome (opsoclonus). There are very rare degenerative ataxias associated with gradual visual loss, due to either optic neuropathy or retinopathy.
Details of any headache or vomiting should be sought; their occurrence may suggest a posterior fossa mass lesion. If the history is acute then a vascular event, in particular a cerebellar haemorrhage, should be considered; a protracted course renders a tumour more likely. Ancillary signs of infection should raise the possibility of an abscess. Intermittent symptoms could indicate the presence of an episodic ataxia (see later) or, if found in the presence of malaise and fever, raise the possibility of posterior fossa cysticercosis. A history of vertigo is more suggestive of neoplastic, inflammatory, and vascular disease, than a slow degenerative process.
Direct questioning should explore the urinary system, skeletal deformities, cardiac disease and cognitive abilities, since many ataxias are associated with disease in other systems (Table 1).
A detailed enquiry into drug use (for both medical and recreational purposes, including alcohol) as well as occupational exposure to toxins is also required.
Signs of cerebellar disease
It is good practice to observe patients rising from a chair and shaking hands, and listening carefully to their speech. In the patient with ataxia this sequence provides much useful information about the disorder.
Gait and posture
The patient may have a broad-based gait, with a poor turn; there is often a lurching quality to the overall sequence. More detailed assessment of mild gait ataxia may be obtained by asking the patient to tandem walk (heel–toe). Asking the patient to stand still may reveal the broad base and also permits the assessment of proprioception using Romberg’s test.
It is often stated that cerebellar speech is very distinctive with an explosive quality—the so-called scanning dysarthria. Although this is characteristic, a combination of cerebellar and spastic features is more frequent. Additional signs such as a slow moving tongue and brisk jaw jerk may confirm the spasticity.
|Table 1 Differential diagnosis of ataxic disorders: associated general physical signs|
|General physical signs||Differential diagnosis|
|Short stature||Mitochondrial encephalomyopathy, ataxia telangiectasia, Sjögren–Larsson syndrome, Cockayne’s syndrome|
|Hypogonadism||Recessive ataxia with hypogonadism, ataxia telangiectasia, Sjögren-Larsson syndrome, mitochondrial encephalomyopathy, adrenoleukomyeloneuropathy|
|Skeletal deformity||Friedreich’s ataxia, Sjögren–Larsson syndrome, many other early onset inherited ataxias, hereditary motor and sensory neuropathy|
|Immunodeficiency||Ataxia telangiectasia, multiple carboxylase deficiencies|
|Malnutrition||Vitamin E deficiency, alcoholic cerebellar degeneration|
|Tight curls||Giant axonal neuropathy|
|Loss||Thallium poisoning, hypothyroidism, adrenoleukomyeloneuropathy|
|Low hairline||Foramen magnum lesions|
|Kayser–Fleischer rings||Ataxia telangiectasia|
|Fever||Abscess, viral cerebellitis, cysticercosis, dominant periodic ataxia, intermittent metabolic ataxias|
|Haemorrhage, infarction, demyelination, posterior fossa mass lesions, intermittent metabolic ataxias|
|Hepatosplenomegaly||Niemann–Pick disease type C, some childhood metabolic ataxias, Wilson’s disease, alcoholic cerebellar degeneration|
Some authorities state firmly that cerebellar disease gives rise to hypotonia, and some even include it within the symptoms. Not only do patients never complain of hypotonia, it is also rarely detectable in symmetrical, slowly progressive, or chronic disorders. Pendular knee jerks are also difficult to detect without the eye of faith; indeed, many patients with ‘cerebellar’ ataxic disorders have disease of the spinal cord, peripheral nerves, or both, which complicates the clinical picture.
Limb ataxia is usually assessed by seeking evidence of dysmetria and dysdiadochokinesis. Dysmetria refers to errors in the range and force of movement resulting in an erratic, jerky movement, which may under- or overshoot the target. This is most simply assessed using finger–nose and heel–shin tests. Dysdiadochokinesis is demonstrated by asking the patient to tap one hand on the other, alternately pronating and supinating the tapping hand, or rapidly opening and closing the fist. The tapping out of simple rhythms (with the hand or foot) is also useful for assessing both the rhythmicity and the force of the tap.
Traditionally, testing of coordination is undertaken after the motor and sensory tests because the presence of weakness or sensory loss can confuse the picture. It should be remembered that there is a natural asymmetry in cerebellar function, with better performance, particularly for rapid alternating movements, in the dominant limb. About 40% of patients with lesions of the cerebellar vermis do not have limb ataxia but have prominent gait ataxia.
Intention tremor is present if a rhythmical side-to-side oscillation is seen on finger–nose testing. A combination of gross intention tremor and a postural component is often called rubral or red nucleus tremor, although peduncular tremor is probably a more accurate label. It is most commonly seen in multiple sclerosis and occasionally in late-onset degenerative ataxias. A nodding head tremor (titubation) with a frequency of 3 to 4 Hz may be seen with midline cerebellar disease.
It is very uncommon to find patients with cerebellar disease with a completely normal oculomotor examination. However, one may need to search hard for the abnormal signs.
In the primary position one should seek for the presence of square-wave jerks; these are inappropriate saccades that disrupt fixation and are followed by a corrective saccade within 200 ms. Assessment of pursuit usually reveals a jerkiness with saccadic intrusions. Additional isolated or multiple lesions of the cranial nerves III, IV, and VI suggest brainstem pathology. Examination of the saccadic system permits an assessment of saccadic initiation, velocity, and accuracy; the presence of an internuclear ophthalmoplegia may be found, indicated by slowness of an adducting eye, thus suggesting a diagnosis of multiple sclerosis, but can also rarely be associated with some degenerative ataxias. The vestibulo-ocular reflex (doll’s head manoeuvre) should then be used to investigate for any supranuclear component, because inability to suppress the reflex is evidence of pathology involving the vestibulocerebellum. Acute or subacute presentation of almost any of the above eye movements, especially if associated with alcohol abuse or vomiting, raises the possibility of Wernicke’s encephalopathy—this requires urgent treatment with thiamine.
Gaze-evoked nystagmus is the most common type of nystagmus associated with cerebellar disease; eccentric gaze cannot be maintained, and the slow phase of the nystagmus is toward the primary position, with rapid corrective movements. Apart from down-beat nystagmus which may indicate a foramen magnum lesion, gaze evoked nystagmus is of limited localization value in most forms of ataxia. Positional nystagmus in a patient with vertigo and unsteadiness should be attributed to benign labyrinthine disease only if it is transient, torsional, and fatigable; if it does not have these features, a posterior fossa lesion should be suspected.
Other neurological signs and general examination
As the causes of ataxia are numerous, a large variety of other neurological and general physical signs may be found on examination. The range of these and their possible diagnostic significance is shown in Table 18.104.22.168.
Disorders of the cerebellum
Numerous conditions affect cerebellar function; several such as multiple sclerosis and neoplasia are discussed elsewhere. Here a classification is based on clinical characteristics.
The cerebellum has a long developmental period and is not fully mature until about 18 months of age. It is therefore susceptible to many insults, including intrauterine infections, ischaemic damage, toxins, and genetically determined syndromes (Table 2). Some of these developmental anomalies, such as dysgenesis or agenesis of the vermis, the cerebellar hemispheres, or parts of the brainstem, give rise to congenital ataxia. These are nonprogressive disorders, and in most cases coordination improves somewhat with age.
|Table 2 Congenital inherited ataxic disorders (see also )|
||With episodic hyperpnoea, abnormal eye movements, and intellectual disability|
||With intellectual disability and partial aniridia|
|Congenital ataxia with intellectual disability and spasticity||
||Includes pontoneocerebellar and granule cell hypoplasia|
|Disequilibrium syndrome||Autosomal recessive|
|Paine’s syndrome||X-linked recessive ataxia—no gene identified||With spasticity, intellectual disability, and microcephaly|
Cerebellar dysfunction in an infant or young child may be overlooked, as it often gives rise to nonspecific abnormalities of motor development. Later there is nystagmus, obvious incoordination on reaching for objects, and truncal ataxia when first attempting to sit; intellectual disability is common but its presence usually does not provide useful diagnostic information.
Ataxia of acute or subacute onset
Cerebellar ataxia with extremely acute onset has two main causes: cerebellar haemorrhage (usually associated with headache, vertigo, vomiting, altered consciousness, and neck stiffness) and cerebellar infarction (in which cerebellar signs are usually combined with signs of brainstem ischaemia, and the presentation may mimic that of haemorrhage). Diagnosis should be made as a matter of urgency by imaging.
Subacute, reversible ataxia may occur as a result of viral infection in children aged 2 to 10 years. There is usually pyrexia, limb and gait ataxia, and dysarthria developing over hours or days. Recovery occurs over a period of weeks and is usually complete, but improvement may still be observed over 6 months. In older patients the possibility of a postinfectious encephalomyelitis, particularly that related to varicella-zoster virus infection, should be considered. The post-infectious Miller–Fisher variant of the Guillain–Barré syndrome may present with a triad that includes subacute ataxia, areflexia, and ophthalmoplegia. Nerve conduction studies and cerebrospinal fluid examination may be helpful, but the former are often normal. Other infective agents are shown in Table 3. Viral titres and cerebrospinal fluid examination may be helpful although serological evidence of viral infection may be difficult to establish.
Other causes of subacute ataxia include paraneoplastic disorders (see ), hydrocephalus, foramen magnum compression, posterior fossa tumour (primary or secondary), abscess, or parasitic infection in any age group. Several important toxins and drugs also need to be considered, including thallium, lead, barbiturates, phenytoin, piperazine, alcohol, solvents, and antineoplastic drugs.
|Table 3 Infections causing cerebellar disease|
|Coxsackievirus groups A and B||Legionella pneumoniae|
|Herpes simplex virus||Lyme disease|
|Epstein–Barr virus||Typhoid fever|
|Varicella virus||Plasmodium falciparum|
|Congenital rubella virus||Tick paralysis|
Vascular disorders of the cerebellum
Cerebrovascular disease is dealt with in detail in
Transient ischaemic attacks involving the vascular supply to the cerebellum rarely produce a pure ataxic syndrome and usually there are associated symptoms of brainstem dysfunction. Cerebellar infarction (from embolus or, more commonly, vertebrobasilar occlusive disease) and haemorrhage (usually on a background of hypertension or, less commonly, secondary to a vascular malformation or tumour) are relatively rare. Imaging is often necessary for early diagnosis as the later the diagnosis the worse the prognosis. Both infarction and haemorrhage may be amenable to surgical therapy, principally to relieve pressure.
Ataxia with an episodic course
These attacks may be considered bizarre and some patients are misdiagnosed as nonorganic; however, a good history can usually distinguish between the main causes (in order of frequency): drug ingestion, multiple sclerosis, transient vertebrobasilar ischaemic attacks, foramen magnum compression, intermittent obstruction of the ventricular system due to a colloid cyst or cysticercosis, and a growing list of inherited episodic ataxias (see ). Autosomal dominant episodic ataxia is characterized by childhood or adolescent onset of attacks of ataxia, dysarthria, vertigo, and nystagmus. Not all patients have affected relatives. There are at least two forms of this disorder: episodic ataxia 1 (EA1) and episodic ataxia 2 (EA2).
EA1 is typified by brief attacks (minutes and occasionally hours) and clinically and electrophysiologically myokymia may be seen. Mutations in a potassium channel (Kv1.1) have been found. These patients may benefit from acetazolamide or phenytoin; between attacks patients usually have no neurological abnormalities.
In EA2 the attacks tend to be longer lasting hours or even days; they are usually associated with vertigo and consequent nausea and vomiting. The illness is more severe in childhood with associated drowsiness, headache, and fever. Although when the disease first begins the patients are well between attacks, an interictal nystagmus can be seen. As the disease progresses a slow deterioration in the ataxia is seen. MRI may reveal cerebellar atrophy. These patients tend to respond better to acetazolamide therapy than patients with EA1. Point mutations in a calcium channel gene (CACNA1A) have been demonstrated in some families with this disorder. However, increasingly other varieties of episodic ataxia are being recognized although the cause remains unknown.
In children and young adults, a metabolic disorder should be suspected, particularly defects of the urea cycle, aminoacidurias, Leigh’s syndrome, and mitochondrial encephalomyopathies. Screening investigations include serum ammonia, pyruvate, lactate and amino acids, and urinary amino acids.
Ataxia with a chronic progressive course
Chronic alcohol abuse is probably the most common cause of progressive cerebellar degeneration in adults. Thiamine deficiency is the main (but not the sole) explanation for the chronic progressive cerebellar syndrome found in people with alcohol problems. Patients with this syndrome are frequently malnourished. Ataxia may develop during periods of abstinence, and an identical cerebellar degeneration has been observed in nonalcoholic patients with severe malnutrition. Cerebellar ataxia is common in the Wernicke–Korsakoff syndrome, and the pathological features of both this syndrome and a cerebellar degeneration are frequently found together. With administration of thiamine some improvement may occur in early cases of alcoholic cerebellar degeneration, but, if the patient is already chairbound, the response to treatment is limited. There are other deficiency disorders that can give rise to a progressive ataxia. There is a rare syndrome associated with zinc deficiency which responds to oral replacement therapy. Deficiency of vitamin E, either genetic (e.g. isolated vitamin E deficiency due to mutations in α-tocopherol transfer protein, or abetalipoproteinaemia) or acquired, may produce a progressive ataxia. It is important to establish the diagnosis of vitamin E deficiency as treatment with vitamin E may prevent progression of the neurological syndrome and can in rare circumstances lead to some improvement.
There are a number of toxic agents that can produce progressive cerebellar dysfunction, including pharmaceutical products, solvents, and heavy metals. The most common cause of a cerebellar syndrome due to drug toxicity in neurological practice is that associated with anticonvulsant medication, particularly phenytoin. Transient ataxia, dysarthria, and nystagmus usually develop when serum concentrations of phenytoin, carbamazepine, or barbiturates are above the therapeutic range, and remit when they return to the therapeutic range. Chronic phenytoin toxicity may cause persistent cerebellar dysfunction, and this is associated with loss of Purkinje’s cells. A persistent cerebellar deficit, with dysarthria and limb and gait ataxia, and cerebellar atrophy on imaging, has also been described as a sequel to the acute encephalopathy of lithium toxicity that is usually precipitated by fever or starvation.
Recreational or accidental exposure to a number of solvents, including carbon tetrachloride and toluene, causes cerebellar ataxia along with other neurological problems, including psychosis, cognitive impairment, and pyramidal signs in the case of toluene. The neurological deficit is potentially reversible but may persist after prolonged exposure in solvent abusers. Exposure to heavy metals including inorganic mercury, lead, and thallium can also produce cerebellar damage.
Structural lesions such as posterior fossa tumours, foramen magnum compression, or hydrocephalus must be excluded by imaging studies. Tumours that may involve the posterior fossa include: astrocytomas, ependymomas, haemangioblastomas, and cranial nerve neuromas.
Paraneoplastic cerebellar degeneration (PCD) related to carcinomas of the lung or ovary usually follows a subacute course, with patients losing the ability to walk within months of onset. A variety of antineuronal antibodies may be found in these patients and help to confirm the diagnosis. Approximately half the patients with PCD have demonstrable antibodies directed against neurons in serum and CSF. The most common antibody seen in PCD is anti-Yo which specifically stains the cytoplasm of Purkinje’s cells. A search for the underlying malignancy should then be undertaken involving imaging and analysis of tumour markers. Presentation with ataxia precedes diagnosis of the malignancy in 70% of cases and is usually subacute, progressing to severe disability over several months or even weeks, and then arresting. Onset may be acute and is sometimes accompanied by vertigo, mimicking a vascular event. There is severe truncal, gait, and limb ataxia, and dysarthria. Opsoclonus may be combined with myoclonus, producing a disorder in adults similar to the dancing eyes syndrome of childhood. The latter is sometimes associated with neuroblastoma. There is currently no proof that immunosuppressant therapy, or plasma exchange, improves the outlook but there are anecdotal reports of some improvement or stabilization after removal of the primary tumour. The best method of screening for the underlying malignancy is debated but standard MRI may be complemented by whole-body positron emission tomography (PET). Searching for primary tumour markers may also be useful (see review by Rees in Further reading).
Rarely, infectious agents can cause slowly progressive ataxia (see Table 3); these include the chronic panencephalitis of congenital rubella infection in children and, in adults, Creutzfeldt–Jakob disease (CJD), particularly the iatrogenic form, should be considered. A specific enquiry about potential risk factor exposure should be sought, especially growth hormone replacement, although in the past decade, after the introduction of stringent controls on source material, this has become extremely rare. Ataxia with psychiatric disturbance may be the presenting features of variant CJD. Multiple sclerosis only exceptionally presents as an isolated chronic progressive cerebellar syndrome.
Some conditions that are not generally considered primarily as ataxic disorders may present with clumsiness, tremor, or definite cerebellar signs, particularly in childhood or adolescence. These include Wilson’s disease and several inherited neuropathies, such as hereditary motor and sensory neuropathy (HMSN; Charcot–Marie–Tooth disease, including the so-called Roussy–Levy syndrome). Although intention and postural tremor are quite frequent in the demyelinating type of HMSN (type I), dysarthria and pyramidal signs do not occur. Other chronic demyelinating neuropathies, such as chronic inflammatory and paraproteinaemic neuropathies and Refsum’s disease, may give rise to prominent tremor and ataxia; the same applies to giant axonal neuropathy.
Superficial siderosis is a rare disorder that causes slowly progressive cerebellar ataxia, mainly of gait, and sensorineural deafness, often combined with spasticity, brisk reflexes, and extensor plantar responses. The diagnosis may not be suspected clinically, but the neuroradiological abnormalities are striking, MRI showing a black rim of haemosiderin around the posterior fossa structures and spinal cord, and less often the cerebral hemispheres, on T2-weighted images. Superficial siderosis is most commonly secondary to chronic leaking of blood into the subarachnoid space. Treatment relies on identifying the source of bleeding; chelation therapy with iron-binding agents given systemically does not appear to be effective.
After excluding acquired causes of ataxic disorders, there remains a considerable number of patients with degenerative ataxias, not all of which are overtly genetically determined. The inherited ataxias can largely be classified according to their clinical and genetic features (see below), and in a small proportion of cases a recognizable metabolic defect can be detected. It is important to make as accurate a diagnosis as possible in these disorders for the purposes of prognosis, genetic counselling, and, occasionally, specific therapy.
Progressive metabolic ataxias
Ataxia may be a minor feature of storage and other metabolic neurodegenerative disorders developing in early childhood (see Chapters ). Some enzyme deficiencies that usually give rise to diffuse neurodegenerative disorders, in which ataxia is a feature, developing in infancy or early childhood, include the sphingomyelin lipidoses, which are lysosomal diseases: metachromatic leukodystrophy, galactosylceramide lipidosis (Krabbe’s disease), and the β-hexosaminidase deficiencies which give rise to GM2 gangliosidosis—Tay–Sachs disease and Sandhoff’s disease. Also within this group are adrenoleukomyeloneuropathy, a peroxisomal disorder, and its phenotypical variant of adrenoleukodystrophy (see Chapter 12.9). This diagnosis is supported by an increase in very long chain fatty acids or by direct genetic analysis of the AMN gene. Although X linked about 10% of carrier females may manifest neurological abnormalities. The role of diet and dietary supplements (e.g. oleic acid and Lorenzo’s oil) remains to be established. Ataxia may be prominent in Niemann–Pick disease type C (juvenile dystonic lipidosis), combined with a supranuclear gaze palsy. Sphingomyelinase activity is normal, but foamy storage cells are found in the bone marrow (see ).
Cholestanolosis (also called cerebrotendinous xanthomatosis—CTX) is a rare autosomal recessive disorder caused by defective bile salt metabolism, as a result of a deficiency of mitochondrial sterol 27-hydroxylase. It gives rise to ataxia, dementia, spasticity, peripheral neuropathy, cataract, and tendon xanthomas in the second decade of life. Treatment with chenodeoxycholic acid appears to improve neurological function (reviewed by Gallus—see Further reading).
Various phenotypes that are classifiable as hereditary ataxias have been described in the mitochondrial encephalomyopathies, many of which are associated with a defect of mitochondrial DNA. These include late-onset ataxic disorders associated (e.g. the Kearns–Sayre syndrome) with such features as dementia, deafness, and peripheral neuropathy. These features overlap with the syndrome of progressive myoclonic ataxia, which may also be caused by ceroid lipofuscinosis, sialidosis, or Unverricht–Lundborg disease, or the so-called Baltic myoclonus (see ).
Acquired metabolic and endocrine disorders causing cerebellar dysfunction
Acquired metabolic and endocrine disorders causing cerebellar dysfunction include hepatic encephalopathy, pontine and extrapontine myelinolysis related to hyponatraemia, and hypothyroidism. The last is only very rarely a cause of a cerebellar syndrome.
The degenerative cerebellar and spinocerebellar disorders are a complex group of diseases, most of which are genetically determined (see ). In some there is an underlying metabolic disorder, and it is important to diagnose these, because there may be important implications for treatment and genetic counselling. There has been a rapid growth in our knowledge of the genetic basis of many of the spinocerebellar degenerations. The current phase of research is focused on how these genes and the abnormal proteins that they produce cause cell-specific neuropathology. Inherited ataxic disorders can be divided according to their mode of inheritance (see Table 22.214.171.124). Most autosomal recessive disorders are of early onset (less than 20 years), and autosomal dominant disorders are usually of later onset (over 20 years).
Autosomal recessive ataxias
This is the most common of the autosomal recessive ataxias (Table 4) and accounts for at least 50% of cases of hereditary ataxia in most large series reported from Europe and the USA. The prevalence of the disease in these regions is similar—between 1 and 2 per 100 000.
The age of onset of symptoms, generally with gait ataxia, is usually between the ages of 8 and 15 years, but onset between 20 and 30 years, although fulfilling all other diagnostic criteria, have been described. In addition to the progressive ataxia, one finds a number of variable features, including dysarthria and pyramidal tract involvement. Initially this latter feature may be mild, with just extensor plantar responses, but after 5 or more years of the disease, invariably a pyramidal pattern of weakness in the legs is seen. Eventually this can lead to paralysis. Distal wasting, particularly in the upper limbs, is seen in about 50% of patients with Friedreich’s ataxia. Skeletal abnormalities are also commonly found including scoliosis (85%) and foot deformities, typically pes cavus in approximately 50% of patients. Additional clinical support for one’s suspicions include optic atrophy which can be seen in 25%; however, it is rare (<5%) for Friedreich’s ataxia to produce major visual impairment. Deafness is found in less than 10%, but rather more have impairment of speech discrimination. Nystagmus is seen in only about 20%, but the extraocular movements are nearly always abnormal, with broken-up pursuit, dysmetric saccades, square-wave jerks, and failure of fixation suppression of the vestibulo-ocular reflex.
Investigation of patients reveals an axonal sensory neuropathy and an abnormal ECG in 65% of patients with widespread T-wave inversion. Diabetes mellitus occurs in 10% of patients with Friedreich’s ataxia, and a further 10–20% have impaired glucose tolerance.
The gene frataxin was identified in 1996. The predominant mutation is a trinucleotide repeat (GAA) in intron 1 of this gene. Expansion of both alleles is found in over 96% of patients. The remaining patients have one expansion and a point mutation in the frataxin gene. This was the first autosomal recessive condition found to be caused by a dynamic repeat and it has permitted the introduction of a specific and sensitive diagnostic test, as it is a relatively simple matter to measure the repeat size. On normal chromosomes the number of GAA repeats varies from 7 to 22 units, whereas, on disease chromosomes, the range is anything from around 100 to 2000 repeats. The length of the repeat is a determinant of the age of onset and therefore to some degree influences the severity in that early onset tends to progress more rapidly.
There is now good evidence that frataxin is located in the mitochondria and appears to be involved in iron transport. Mitochondrial dysfunction does fit with the clinical picture of ataxia and neuropathy, in association with diabetes, cardiomyopathy, deafness, and optic atrophy.
Ataxic disorders associated with defective DNA repair
There are several rare disorders that are characterized at a molecular level by a reduced capacity to repair DNA. The most well known is ataxia telangiectasia. Characteristically, motor development is often delayed and ataxia noted at the time of first walking. Growth retardation and delayed sexual development are frequent, and there is mild intellectual disability in some cases. A mixed movement disorder may be seen, often with a combination of ataxia, dystonia, and chorea. The cutaneous telangiectasia of ataxia telangiectasia tends to develop on the conjunctivae between the ages of 3 and 6 years, but occasionally are inconspicuous or absent in adult life. Ataxia telangiectasia is associated with abnormalities of both humoral and cell-mediated immunity. The gene for ataxia telangiectasia has now been cloned and is called ATM and genetic analysis can be undertaken in appropriately selected cases. A rarer clinically similar disease due to mutations in hMRE11 has been identified and is termed ‘ataxia telangiectasia-like disorder’.
|Table 4 Autosomal recessive ataxias (see also )|
|Syndrome||Gene defect||Clinical notes|
|Friedreich’s ataxia||GAA repeat (and rarely point mutations in FRDA gene)||Neuropathy, pyramidal signs, skeletal abnormalities, diabetes, cardiomyopathy|
||Oculomotor apraxia, mixed movement disorder, humoral immune difficulties, increased cancer risk|
|Xeroderma pigmentosum||ERCC2 but also probably genetically complex||Skin disorder and an increased risk of skin cancer|
|Hypogonadism||Not known||Hypogonadotropic hypogonadism|
|Marinesco–Sjögren syndrome||SIL1 on chromosome 5q31||Cataracts and intellectual disability|
|Progressive myoclonic ataxia (Ramsay Hunt syndrome)||Genetically complex||Epilepsy is common|
|Behr’s and related syndromes, e.g. 3-methylglutaconic aciduria type III (Costeff’s syndrome)||
||Optic atrophy, spasticity, and intellectual disability|
|Congenital or childhood-onset deafness||Genetically complex||Syndromic diagnosis—likely to have several causes|
|Autosomal recessive late-onset ataxia||Heterogeneous||Wide clinical variability|
Onset usually before 20 years of age.
AOAI, ataxia associated with oculomotor apraxia.
Clinically related conditions, xeroderma pigmentosum and Cockayne’s syndrome (see Table 4), are also due to defects in DNA repair; they are much rarer and associated with additional features, most frequently skin abnormalities.
Ataxia associated with oculomotor apraxia
There are two genetically distinct but clinically similar disorders associated with the distinctive feature of oculomotor apraxia—types 1 and 2. Oculomotor apraxia represents a deficit of the voluntary saccadic system and should be suspected in the presence of head thrusts or synkinetic blinking, which are used to help initiate a voluntary saccade. Ataxia associated with oculomotor apraxia type 1 (AOA1) was shown to be due to mutations in a gene called aprataxin on chromosome 9p13. It is characterized by the association of ataxia with chorea early in the disease course, oculomotor apraxia, peripheral neuropathy, and variable but mild learning difficulties. MRI reveals cerebellar atrophy and serum analysis may show hypercholesterolaemia and hypoalbuminaemia.
A second condition, AOA2, is very similar clinically and also overlaps with the ataxia telangiectasia phenotype (see above). Mutations in senataxin have been shown to cause this syndrome. α-Fetoprotein is elevated in virtually all cases and is therefore a useful screen for this disorder. It also appears that it may be more common than either ataxia telangiectasia or AOA1, accounting for approximately 8% of autosomal recessive ataxia. The other autosomal recessive ataxias are all individually rare and are listed in Table 4.
Testing for ATM, aprataxin, and senataxin is now possible in specialized labs.
Autosomal dominant cerebellar ataxias
The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically complex group of neurodegenerative disorders (Table 5). ADCA type I is characterized by a progressive cerebellar ataxia and is variably associated with other extracerebellar neurological features such as ophthalmoplegia, optic atrophy, peripheral neuropathy, and pyramidal and extrapyramidal signs. The presence and severity of these signs are, in part, dependent on the duration of the disease. Mild or moderate dementia may occur but it is usually not a prominent early feature. ADCA type II is clinically distinguished from ADCA type I by the presence of pigmentary macular dystrophy, whereas ADCA type III is a relatively ‘pure’ cerebellar syndrome and generally starts at a later age. This clinical classification is still useful, despite the tremendous improvements in our understanding of the genetic basis (see below), because it provides a framework that can be used in the clinic and helps direct the genetic evaluation.
The genetic loci causing the dominant ataxias are given the acronym SCA (spinocerebellar ataxia). At the time of publication there are 28 SCA loci identified. However, with the discovery of the genes it becomes apparent that some of these are duplicates and yet there are still more to be found. In general clinical practice five of these genes are established (SCA1, -2, -3, -6, and -7) (Table 6). Interestingly they are all caused by a similar mutational mechanism, an expansion of an exonic CAG repeat. The resultant proteins all possess an expanded polyglutamine tract and there are now at least eight conditions caused by these expansions (see ). Other types of ADCAs are rare and mutation testing is available only for a small number of these.
|Table 5 Autosomal dominant cerebellar ataxia (ADCA): clinicogenetic classification|
|ADCA type||Clinical features||Genetic loci and chromosomal location||Gene|
||SCA||Ataxin 1 CAG|
|SCA2||Ataxin 2 CAG|
|SCA3||Ataxin 3 CAG|
|SCA8||Kelch-like 1 CTG repeat|
|SCA12||PPP2R2B CAG repeat|
|SCA13||KCNC3 point mutations|
|SCA14||PRKCG point mutations|
||SCA7 3p12–21.1||Ataxin 7 CAG|
||SCA5||SPTBN2 beta-III spectrin D|
|SCA10||Ataxin 10 ATTCT repeat|
|SCA27||FGF14 point mutations|
|Episodic ataxias (EAs)||EA1||Kv1.1|
|Plus others yet to be defined|
a SCA6 and CACNL1A are allelic variants.
Onset usually over age of 25 years. This is a list of currently identified genes and is divided by ADCA subtype to facilitate clinical relevance. (See also: for more details.)
Idiopathic degenerative late-onset ataxias
About two-thirds of cases of degenerative ataxia developing in those aged over 20 years are isolated cases, and they represent a significant clinical problem; it is difficult even to know how to label them. The literature is confusing, mixing pathological terms such as olivopontocerebellar atrophy (OPCA) with clinical terms; the author prefers to use the term ‘idiopathic late-onset cerebellar ataxia’ (ILOCA). A proportion of patients in this group progress to develop the features of multiple-system atrophy (MSA) (see ). These patients may have or develop facial impassivity and extrapyramidal rigidity, whereas others present with features of autonomic failure such as postural hypotension, impotence, bladder dysfunction, and a fixed cardiac rate. A cerebellar presentation occurs in about 30% of patients with MSA. The distinction of idiopathic late-onset cerebellar ataxia from MSA may therefore be difficult clinically at presentation.
Most patients with ILOCA lose the ability to walk independently between 5 and 20 years after onset, and lifespan is slightly shortened by immobility. Those who develop MSA have a particularly poor prognosis. Investigations, apart from those excluding acquired causes of cerebellar degeneration such as malignancy and hypothyroidism, tend to be unhelpful. Electrophysiological evidence of a sensory peripheral neuropathy is found in about 50% of cases, which can be a useful pointer to the presence of a degenerative multisystem disorder. CT or MRI may show cerebellar and brainstem atrophy, or pure cerebellar atrophy. The prognosis is worse in patients with clinical and radiological evidence of brainstem involvement, compared with those with a pure cerebellar syndrome and cerebellar atrophy alone on MRI.
|Table 6 Clinical impact of genetics on the autosomal dominant cerebellar ataxias (ADCAs)|
|ADCA type||Genetic tests (widely available)||Relative contribution to each subclass (%)|
|I||SCA1, -2, -3||50|
The role of gliadin sensitivity in producing a chronic progressive ataxia, either as part of coeliac disease or as a purely neurological phenotype, is still being debated.
Recently, a newly recognized condition has been shown to be responsible for late-onset ataxia in men who develop a progressive phenotype of ataxia and tremor in association with an intermediate expansion in the fragile X gene. This has been termed FXTAS (fragile X tremor ataxia syndrome). This syndrome is being expanded as information emerges.