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A 16-year-old girl presented because her mother had noticed her speech had changed over the preceding 3 months. She had also been clumsy since the age of 10 years. Her family history was unremarkable. On examination, there was dysarthria with a full range of eye movements but the saccades were broken up. Tone and power were normal but there were occasional choreiform movements. She was areflexic with flexor plantar responses. She had symmetrical limb ataxia and a broad based gait. Sensory testing was normal. There were no telangiectasias.
What is your differential diagnosis and which investigations would you recommend at the first consultation?
The clinical picture is predominantly of cerebellar ataxia with mild chorea and possible sensory involvement (areflexia in the presence of normal tone and power). The main differential can be broken down into genetic and acquired causes. A symmetrical ataxia progressing over several years is not typical of acquired causes but nonetheless the initial emphasis should be on diagnosing a reversible condition; the commoner acquired causes which may present with an isolated ataxia are listed in table 1.
Initial blood tests were normal: full blood count, urea and electrolytes, bone profile, liver function, angiotensin converting enzyme, lupus anticoagulant, α-fetoprotein, vitamins A and E, antitissue transglutaminase and anti-Purkinje cell antibodies, and white cell lysosomal enzymes. Antinuclear antibodies were present at 1:100 but anti-dsDNA and extractable nuclear antigens were normal. MR brain, chest x-ray and ECG were all normal. Further investigations included a normal CSF (glucose, protein and cytology, no oligoclonal bands) but nerve conduction studies revealed absent sensory action potentials with normal motor action potentials and motor conduction velocities.
What differentiates an acquired from an inherited ataxia?
The young age of onset and the suggestion that the problem has been progressing slowly for several years suggest a degenerative (and probably inherited) cause in this case. However, the apparent recent ‘stepwise’ change is against. The negative family history is against a dominantly inherited condition although a new mutation or anticipation in a triplet repeat disease could still be on the cards. Acute or subacute onset or lateralising signs generally suggest an acquired cause.
How are the different forms of inherited ataxia recognised clinically and what are they?
Most genetic ataxias presenting under the age of 20 years are recessively inherited whereas those presenting above the age of 25 years are mainly dominant, the vast majority autosomal (X linked causes being very rare). The rate of progression is generally slow. The commonest cause in childhood is Friedreich's ataxia (autosomal recessive) but this may rarely present as late as age 40 years.1 Conversely, spinocerebellar ataxia (SCA) 2 (autosomal dominant) has presented at age 2 months.2 Causes of early onset ataxias are listed in table 2 (autosomal recessive unless stated otherwise).
Several autosomal dominant genetic disorders may present later in life with ataxia. SCA refers to the autosomal dominant cerebellar degenerative disorders. It is not normally possible to make an accurate genetic diagnosis from the clinical phenotype alone (due to overlap between the clinical manifestations of different mutations) but the phenotype should be used to rationalise the investigative process.
What would you do next in this case?
Further tests which were normal included: frataxin (no expansion—repeated to show two normal sized repeats; sequencing showed no mutation in exons 1, 2, 3, 4 or 5a), SCA 1, 2, 3, 6 and 7 (negative), mitochondrial mutations (negative—3243, 8344, 8993), dentatorubropallidoluysian atrophy (negative) and very long chain fatty acids (normal).
The patient continued to become more ataxic and was admitted for further investigation. The following tests were performed: repeat CSF—normal, including syphilis serology; throat swab—no growth; antistreptolysin-O titre—normal; anti-basal ganglia antibodies—positive, binding 60 and 80 kDa antigens; antiglutamic acid decarboxylase—low positive; serum copper and caeruloplasmin—normal; and plasma immunoglobulins—normal. Muscle biopsy did not show any definite ragged red fibres but there was increased peripheral staining in the trichrome preparation and oxidative stains were highly suggestive of mitochondrial myopathy. Respiratory chain analysis of muscle biopsy was unremarkable. MR brain scan showed some cerebellar atrophy. Electroretinogram and visual evoked potentials were normal. MRI chest (for thymoma) was negative and whole body positron emission tomography scan was normal.
How would you treat this patient now?
She was treated with vitamin E and coenzyme Q10 and then with intravenous immunoglobulin for a presumed autoimmune mediated ataxia (positive anti-basal ganglia antibodies).3 Six months after starting intravenous immunoglobulin, she had deteriorated and her treatment was changed to azathioprine and prednisolone. Six months later, she continued to deteriorate and these agents were stopped.
Although the patient had no telangiectasias, ataxia telangiectasia (AT) may present without them. Testing for AT demonstrated low levels of the protein ATM (ataxia telangiectasia mutated) on immunoblotting; levels of chromosomal radiosensitivity were twice the normal value. Both suggest AT, an autosomal recessive condition normally presenting in early childhood. The symptoms of AT are typically truncal ataxia followed by limb ataxia (which she had) and eye signs such as oculomotor apraxia (which she did not have). Extrapyramidal features such as chorea and dystonia are common and large fibre sensory and motor neuropathies may occur (she had chorea and sensory neuropathy). In a small proportion of cases, as here, there are no telangiectasias—this is more common in those with a later age of onset and a less severe phenotype.4,–,7 Raised levels of α-fetoprotein occur in most typical and atypical cases of AT5 6 8 although this is also seen in ataxia with oculomotor apraxia type 2. However, if used in combination, α -fetoprotein levels, immunoblotting for ATM and chromosomal radiosensitivity (detected by irradiating lymphocytes then examining chromosomal structure; lymphocytes from AT patients show increased chromosomal breakage and rearrangement compared with controls) can indicate AT. A normal α-fetoprotein level occasionally occurs in AT patients. In this case, the clinical phenotype, low ATM levels and the degree of chromosomal radiosensitivity confirmed the diagnosis.
AT is caused by mutations in the ATM gene.9 Mutations on MRE11 may result in an AT-like phenotype but with normal levels of ATM protein.10 Direct detection of ATM mutations is possible but is a major undertaking and hence expensive, in part because of the large size of the gene (66 exons) and the fact that mutations are located throughout the gene (rather than in hotspots).11 Because of this, bioassays for chromosomal radiosensitivity and ATM levels12 are more useful initial diagnostic tests for AT. Patients with AT have shortened lifespans and a higher risk of neoplasia and cardiovascular disease relative to the normal population.13 The absolute risk is difficult to quantify, in part because different mutations give different levels of risk. Patients with a milder neurological phenotype have longer survival.13 Of all AT patients, 10–15% develop a malignancy in childhood or early adulthood14 and the risk of neoplasia is 100 times higher than age matched controls.15 16 Most of the malignancies are leukaemia and lymphoma, particularly of T cell origin.15 17 AT patients are exquisitely sensitive to radiotherapy18 and this should be avoided. Routine x-rays, while not absolutely contraindicated, should be used with care.
Female AT patients have an increased risk of breast cancer. The advice from the NHS Cancer Screening Programme (2011) is that women with AT (with confirmed ATM mutations) should be offered annual breast MRI surveillance from 25 years of age. MRI has a high sensitivity for the early detection of breast cancer in young women. Patients should be aware of the risk and undergo clinical review and participate in appropriate screening programmes.
AT patients also show impaired immune function with some children requiring immunoglobulin infusions.9 However, this, like neurological function, is variable. The immune deficit is not progressive and severe infections are rare.19
Several studies have suggested that heterozygotes for ATM mutations have an increased risk of neoplasia, particularly breast cancer.14 20 Swift and colleagues16 described a relative risk of neoplasia of 3.8 for men and 3.5 for women, whereas the relative risk of breast cancer alone compared with the general population is between 2.3721 and 2.2322 in patients heterozygous for ATM mutations. This equates to approximately 1 in 6 women heterozygous for ATM mutations developing breast cancer compared with 1 in 11 in the UK background population. The National Institute for Health and Clinical Excellence provides guidelines for assessing and screening such patients.23 Clinicians should bear in mind these factors, and their potential impact on families, when counselling patients prior to genetic testing.
■ Consider a genetic cause for any symmetrical, slowly progressive ataxia, even without a family history.
■ Inherited ataxias presenting under the age of 20 years are predominantly autosomal recessive whereas those over the age of 25 years are normally autosomal dominant.
■ Defining the additional features—neurological and systemic, both clinically and by investigation—may narrow the differential diagnosis.
■ Diagnostic genetic tests should not be undertaken without appropriate counselling and consideration of the implications for the patient and their family.
In general, symptomatic diagnostic testing (when patients have already developed symptoms) for any genetic disease, including ataxia telangectasia and the other inherited cerebellar ataxias, may have several benefits. However, testing should not be undertaken without appropriate discussion(s) with the patient. A positive diagnosis has implications for other family members—existing and potential—and some patients prefer not to know. There is currently a moratorium on the disclosure of genetic test results to insurance companies but this is voluntary, not legally enforced. Possible benefits of a genetic diagnosis include:
■ Prognosis—for example, SCA6 and SCA1 have different rates of progression, so patients may be better able to plan their lives appropriately.
■ Counselling—patients can make informed decisions about the risk to any potential offspring.
■ A confirmed diagnosis may prevent inappropriate treatment or further investigation.
■ Many patients gain reassurance from having a specific diagnosis even if it is not treatable.
■ Monitoring these conditions may allow disease progression to be modified—for example, the cardiomyopathy of Friedreich's ataxia or screening for malignancy in ataxia telangiectasia.
Patient consent Obtained.
Competing interests None.
Provenance and peer review Commissioned; not externally peer reviewed.
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