Medical Guidelines Diagnosis Genetics Referral to Genetics Services Read more When requesting genetic investigations it is essential to discuss the implications of the test with the patient prior to testing. In view of the potential implications for family members of patients who undergo testing, it is essential that neurologists liaise with their clinical genetics counterparts (as highlighted in the National Service Framework for long-term conditions; quality requirement 2.10)25. The situation is simplest in the case of symptomatic patients, when the test is being performed primarily for diagnostic purposes. However, even in these situations testing can be complex, for example where there are other children at risk or where there may be extreme anticipation which may result in a pre-symptomatic test in the parent of the child. Therefore it is important that the patient and their family are informed about the potential implications in case the test is positive and the availability of genetic counselling should be indicated to the patient and their family. This service should be provided by healthcare professionals with expertise in genetic counselling (eg, clinical geneticists, genetic counsellors or neurologists with expertise in this field). Consultations should include discussions on the implications of having a genetic test for the individual with ataxia and their family and any reproductive choices they may make. The situation is more complicated in the case of ‘at-risk’ subjects, where an individual is clinically unaffected at that point in time. These people should also be offered genetic counselling from a suitable healthcare professional to discuss whether they wish to undergo genetic testing. In the case of at-risk minors this should be done by the regional genetic service. However, testing of at-risk minors is not generally recommended, but should be considered on a case by case basis. In cases of recessive ataxias it is important to consider the implications of the carrier status of the patient’s family members who may at some point be making reproductive decisions. Genetic counselling should thus be offered to these individuals too. It is important to consider that there are approaches for pre-natal testing and pre-implantation genetic diagnosis available for some inherited ataxias. This is generally provided by genetic services in conjunction with local obstetrics or prenatal units. In cases where genetics services are not already involved and when a genetic mutation is found, the individuals should be referred in a timely way to collaborating clinical geneticists, with all of the available data (including the genetic diagnosis of the index case if available and the patient agrees to the release of this information). Good communication between the different specialties and professionals is vital. When samples for genetic tests are being obtained from patients and their families, informed consent must be sought, preferably in written form using routine consent forms available from genetics centres. Consent should include access to information to assist family members. Clinicians who take samples for genetic tests should be made aware of guidelines on best practice for the ataxias produced by the European Molecular Genetics Quality Network: www.emqn.org. Many genetic tests are available on a research basis (eg: by exome sequencing) and almost invariably the ethics committee submission in connection with the study will have clarified the appropriate consent to be obtained. It is important that patients understand the implications of any genetic test. Usually participant patients are given the option of being informed about any results that may emanate from studies, especially were this to be of relevance to them and their family members. Any genetic results from research studies would need to be validated by an accredited genetics laboratory before a formal result is given to the patient. Genetic tests available Read more Table 6 shows the currently available genetic tests, grouped according to modes of inheritance and Harding classification types I to III (see section Guidance for genetic testing below for an explanation of this classification). Some of these are available via the UK Genetics Testing Network (ukgtn.nhs.uk), and their website gives details of accredited laboratories across the UK where the tests are undertaken along with turnaround times. These genetic tests are performed individually using Sanger DNA sequencing or PCR techniques. New technologies for sequencing genes are being developed and this means genetic testing is undergoing a major revolution. Most genetic tests have been done “in series”, ie: one test after another. Next generation sequencing (NGS) is a different technology that allows massively parallel sequencing and has resulted in the identification of many new genes associated with ataxia, new patterns of inheritance and new diagnostic pathways. Targeted “panel” tests are increasingly used and are highly reliable, but only have limited numbers of genes. A next generation sequencing panel is now available as an NHS diagnostic service from the Oxford Molecular Genetics Service. This panel includes around 99 genes causing ataxia (with more genes being added as new genes are found). More information on this service can be found here. An NGS panel including hereditary ataxias is also available at the Sheffield Children’s NHS Foundation Trust Research studies involving whole exome sequencing or whole genome sequencing are ongoing and patients could be informed of these as potential studies they may wish to consider taking part in. Exome sequencing targets the coding parts of genes, whereas genome sequencing obtains information on most (but not all) of the entire genome. In England, the 100,000 genomes project run by Genomics England and delivered by Genomic Medicine Centres, aims to increase the diagnostic rate, and patients with ataxia who have so far eluded a genetic diagnosis may be invited. Patients from Northern Ireland can also participate and the project will be rolled out to Scotland and Wales. Further information see: www.genomicsengland.co.uk. Interpretation of NGS data can be very complex and clinicians should seek advice about performing such tests and how to interpret the data before embarking on them. For more information on ataxia research studies contact Ataxia UK. A number of inherited ataxias have been identified although not all genes have yet been found. More information on inherited ataxias can be seen in selected research publications26,27. Table 6: Genetic tests (underlined tests available ‘routinely’ via the UK Genetic Testing Network) Autosomal recessive FRDA ATa AOA1b and AOA2b Ataxia with Vitamin E deficiency POLG1 ARSACS Autosomal dominant Type I Type II Type III EA type 1 EA type 2 DRPLA GSSc POLG 1 SCA1, SCA2, SCA3 SCA10, SCA12, SCA13 SCA17, SCA23 (or type III), SCA27, SCA28, SCA35, SCA36 SCA7 SCA5, SCA6 SCA11, SCA14, SCA15 Mitochondriald ‘X-linked’ NARP, MELAS, MERRF FXTAS (Fragile X associated Tremor and Ataxia Syndrome) Genetic tests marked a-d are also available; contact details for arranging these tests are given. Testing for A-T – The national ataxia-telangiectasia service provides a laboratory testing service for A-T and related disorders through Prof Malcolm Taylor’s laboratory at the University of Birmingham. It also provides both paediatric (Nottingham City Hospital, Director Dr Mohnish Suri) and adult (Papworth Hospital, Director Dr Nick Oscroft) Centres of expertise. Referral for testing or clinics can be made either via the A-T Society (Tel: 01582 760733, email firstname.lastname@example.org) or directly with the appropriate Centre. Testing for AOA1 and AOA2 – Professor Malcolm Taylor, School of Cancer Studies, University of Birmingham (email@example.com) or Dr Penny Clouston, Oxford Regional Genetics Laboratories, Churchill Hospital, Oxford, OX3 7LJ. (firstname.lastname@example.org). At the Oxford Regional Genetics Laboratories testing for AOA1 and AOA2 is offered as part of a gene panel including multiple ataxia genes; for clinical advice contact email@example.com. Testing for GSS syndrome (Gerstmann-Straussler-Scheinker syndrome) and other prion-related genetic disorders can be carried out can be carried out at the National Creutzfeldt-Jakob Disease Research & Surveillance Unit, Western General Hospital, Edinburgh. Contact details: Main office telephone: 0131 537 1980/2128/3103; website: www.cjd.ed.ac.uk. Testing for prion-related disorders is also available at the National Prion clinic at the National Hospital for Neurology and Neurosurgery. Rare mitochondrial disease service. This service has been nationally commissioned by the National Commissioning Group (www.mitochondrialncg.nhs.uk). There are three designated sites: London - National Hospital for Neurology and Neurosurgery, Newcastle upon Tyne - Royal Victoria Infirmary and Oxford – John Radcliffe Hospital and Churchill Hospitals. For further details of other laboratories in European countries providing diagnostic tests go to www.orpha.net (ORPHA97). Guidance for genetic testing Read more With the numerous autosomal dominant (AD) spinocerebellar ataxias that have been identified, the Harding classification of considering these as types I, II or III is of some utility, and may inform genetic testing. Type I is so-called ‘complicated’ disease, where in addition to the ataxia, other neurological findings such as dementia, ophthalmoplegia, pyramidal signs and extrapyramidal features may be present. In type II disease there is progressive retinopathy and resulting blindness, and most cases to date have been associated with SCA7. Type III disease is reasonably ‘pure’ spinocerebellar ataxia. In Table 7, the currently available AD ataxia genes are tabulated, and the corresponding Harding group and any especially distinguishing clinical characteristics are indicated. Table 7: The autosomal dominant spinocerebellar ataxias (SCAs) in which causative genes have been identified SCA Harding type Gene Clinical/other features SCA1 I ATXN1 Pyramidal involvement, ophthalmoplegia SCA2 I ATXN2 Slow saccades, peripheral neuropathy SCA3 I ATXN3 Also known as Machado-Joseph. Bulging eyes, ophthalmoplegia, peripheral neuropathy, pyramidal involvement, in a subgroup Parkinsonian phenotype, SCA5 I SPTBN2 Adult onset ataxia; a more severe childhood onset ataxia with intellectual disability can be caused by de novo missense mutations. SCA6 III CACNA1A Allelic with EA2 / Familial Hemiplegic Migraine, mild ataxic syndrome SCA7 II ATXN7 Macular degeneration SCA8 III ATXN8OS Not specific test* SCA10 I ATXN10 Seizures, Mexican origin SCA11 III TTBK2 Adult onset ataxia SCA12 I PPP2R2B Tremors, common in India SCA13 I KCNC3 Some have intellectual disability SCA14 III PRKCG Adult onset ataxia SCA15 III ITPR1 Very variable age of onset, slowly progressive; some have intellectual disability. SCA16 Now known to be SCA15 SCA17 I TBP Psychiatric features, dementia, chorea SCA19/22 I or III KDND3 Slowly progressive adult onset ataxia, occasionally pyramidal signs and urinary symptoms SCA23 I or III PDYN Some have neuropathy, limb spasticity, cognitive decline, myoclonus or seizures SCA27 I FGF14 Variable age of onset, dyskinesias, learning difficulties SCA28 I AFG3L2 Slow saccades, ophthalmoplegia SCA31 III BEAN1 Pyramidal signs, hearing difficulties, decreased vibration sense, occasionally tremor SCA35 I TGM6 Dystonia SCA36 I NOP56 Motor neuron signs SCA38 III? ELOVL5 Slowly progressive ataxia, nystagmus SCA40 III CCDC88C Only one family reported, adult onset SCA41 III TRPC3 Only one case reported, adult onset The table above lists the SCA type, the gene causing the condition, Harding classification and some distinguishing clinical features19,28. *SCA8 – The clinical validity of genetic testing for SCA8 by CAG repeat sizing has not yet been established, thus SCA8 testing should not be offered as a routine genetic test if family history is unknown. However, SCA8 testing may be appropriate in large pedigrees where the expansion has been proven to be segregating with the disease. It is still important to note that finding an expansion for SCA8 in a patient does not exclude the presence of another causative mutation. Some of the distinguishing clinical features for the more common recessively inherited ataxias can be found in Table 827. For information on treatable inherited ataxias see section Treatable ataxias. Table 8: Distinguishing clinical features for more common autosomal recessive ataxias Ataxia type Gene Clinical/other features Friedreich’s ataxia FXN Mixed cerebellar and sensory ataxia; cardiomyopathy, spasticity, diabetes, scoliosis and pes cavus may develop Ataxia oculomotor apraxia type 1 APTX Extrapyrimidal signs, mild cognitive impairment, variable oculomotor apraxia, peripheral neuropathy Ataxia oculomotor apraxia type 2 SETX Similar to AOA1 but presents later ARSACS SACS Pyramidal signs and peripheral sensorimotor neuropathy with amyotrophy, spasticity Ataxia caused by mutation in SPG7 gene SPG7* Increasingly recognised as a relatively common cause of both childhood and adult onset ataxia, often (but not always) with spasticity Ataxia telangiectasia ATM For information on ataxia telangiectasia refer to the AT Guidelines obtained via the AT Society. *Mutations in SPG7, a gene causing recessive hereditary spastic paraplegia, has emerged as a relatively common cause of ataxia (often with spasticity) 29. Prevalence of inherited ataxias There is limited information on the prevalence of inherited ataxias in the UK, however some are believed to be rarer than others and the information below may provide some guidance on diagnostic testing. Recessive ataxias Friedreich’s ataxia – the most common inherited ataxia in Caucasian populations30. Ataxia with oculomotor apraxia type 2 and ataxia telangiectasia – the two second most common recessive ataxias worldwide31. Dominant ataxias Common spinocerebellar ataxias – SCA3 is thought to be the most common dominant ataxia worldwide, followed by SCA2. SCAs 1 and 6 are also found in many populations worldwide31. The most common SCA in the UK is SCA6. There is high prevalence of SCA3 in Portugal, Brazil and Japan32, SCA7 in South Africa and SCA2 in Cuba and parts of Spain31. Dentatorubral Pallidoluysian Atrophy (DRPLA) – was thought to be rare in Caucasian populations and most commonly reported in Japan. However, a recent study in Wales suggests that DRPLA may not be as geographically restricted as thought and the diagnosis should be considered in UK patients33. SCA13 and SCA14 – in a recent UK screening study no SCA13 families were found, although it has been reported in a sporadic case34. At least seven SCA14 families have been identified in the UK35. X-linked ataxias Generally rare, but Fragile X associated Tremor and Ataxia Syndrome is increasingly recognised, and may mimic other patterns of inheritance. Genetics testing should be specifically requested,as it is usually a repeat disorder and will not be detected using sequencing technologies. There are major implications for family members. Recommendations Grade 1. The clinical context (speed of evolution, episodic/fluctuating versus progressive etc) should determine the investigation of individual cases. GPP 2. Ataxia in adults can arise due to serious neurological disease and urgent referral for secondary care (to a neurologist) should be made without delay following primary care investigation. GPP 3. Children presenting with ataxic symptoms should be referred urgently for paediatric assessment (usually by local specialists, who may liaise with paediatric neurologists, clinical geneticists etc). GPP 4. Rapid progression (over weeks or months) can denote a paraneoplastic cause, prion disease or multiple system atrophy, thus urgent investigations are required. GPP 5. When a diagnosis of progressive ataxia is made referral to a Specialist Ataxia Centre is encouraged. GPP 6. Neurologists should liaise with their clinical genetics counterparts given the potential implication for family members of patients who undergo genetic testing. GPP 7. Informed consent should be sought from all those undergoing genetic testing. GPP 8. It is essential to offer genetic counselling to patients and discuss the implications of a genetic test prior to testing. GPP 9. Genetic counselling should include the implications of having a genetic test for the individual and their family and any reproductive choices they may make. GPP 10. Asymptomatic ‘at risk’ subjects should be offered genetic counselling. GPP 11. Genetic testing of asymptomatic ‘at-risk’ minors is not generally recommended, but should be considered on a case-by-case basis. GPP 12. Any genetic test results from research studies need to be validated by an accredited laboratory before a formal result is given to the patient. GPP This information is taken from Management of the ataxias - towards best clinical practice third edition, July 2016. This document aims to provide recommendations for healthcare professionals on the diagnosis and management of people with progressive ataxia. To view the full document, including references, click here.