EXCITING NEWS FROM DR PETYA BOGDANOVA (Ataxia Clinic Registrar) – December 2015

The term ‘ataxia’ originates from Greek (α- [no] + -τάξις [order]) and means "lack of order". Ataxia can affect almost all movements, including walking, speech, eye movements, and hand control. It describes a symptom but is no more specific than ‘headache’ or ‘abdominal pain’. Ataxias include a diverse collection of underlying neurological disorders and their cause may vary from common acquired causes to rare inherited conditions that may only affect a very small number of individuals or families.

At the National Ataxia Clinic in Tallaght Hospital, we care for many patients and families with rare inherited ataxias who do not have a genetically confirmed diagnosis. Inherited ataxias affect individuals of all age groups with symptoms that often overlap and it is difficult to distinguish between various types of familial ataxias based only on their clinical presentation. Genetic testing is very important in these cases, but sometimes a genetic diagnosis cannot be achieved by testing for common gene mutations using traditional methods.

At the Ataxia clinic, we are particularly interested in individuals and families with rare inherited undiagnosed ataxias. When a patient with chronic progressive cerebellar ataxia first visits the clinic, we take a detailed history of symptoms and complete family history. Accurate clinical assessment includes a comprehensive neurological examination, performed by an ataxia specialist. Initial diagnostic tests, such as various blood tests and Magnetic resonance imaging of the brain, are performed to rule out acquired causes of ataxia, because these are more common than genetic causes and often treatable. Further investigations are performed if needed (e.g. nerve conduction studies, lumbar puncture, electrocardiogram, eye tests, etc).

Once acquired conditions are ruled out, a formal genetic evaluation of the most common genetic causes (e.g. Friedreich’s ataxia, SCA1, SCA2, SCA3, SCA6, SCA7) is carried out.  If these tests come back with a negative result, then more detailed commercially-available genetic testing is performed. The ataxia gene panel involves analysis of a pre-defined set of nearly 100 genes associated with ataxia and assembled by research and clinical experts in the field. These include genes known to be associated with ataxia as the predominant feature and genes associated with ataxia as part of the phenotype.

Over the last 12 months, we have tested a number of patients with the extensive gene panel and have received positive results for some of the individuals, which have been confirmed later in their affected siblings. As a result, a few Irish families have been diagnosed with rarer forms of ataxias that are being found worldwide, such as SCA21, SCAR10, SPG7-related ataxia, spastic paraplegia type 54.

The gene panel uses a recently described genetic technology, Next Generation Exome Sequencing (NGS) methods, to try to identify the genetic cause of the inherited condition. NGS methods use DNA from individuals involved. The traditional approach has been a piecemeal, ‘pin in map’ approach to genetic testing, which is costly and inefficient. In comparison, NGS allows testing even when we do not know the causative gene. This technology is much more efficient and faster than the traditional gene testing, where we were only able to test one gene at a time. NGS has the ability to detect unexpected novel gene variants. Very rare and unknown genetic variants are only present in a tiny number of individuals and NGS is an efficient way to identify a rare genetic cause of an individual’s disease. The NGS approach is much less expensive and  is becoming cheaper, which is a hugely exciting development for selected patients and families who have eluded diagnosis. NGS is successful in establishing molecular diagnosis in both early- and adult-onset ataxia, with or without a family history.  The key factor, however, for successful results from the gene panel testing is detailed clinical assessment and identifying which patients would most benefit from such testing and this is a priority in the Ataxia clinic.

If all of the above tests are non-diagnostic, then patients with inherited ataxia might be considered suitable to take part in a research study of rare inherited neurological disorders. We also consider other affected and unaffected family members of a patient with inherited ataxia as suitable to participate. This study is performed in collaboration with geneticists and scientists in the University College of Dublin.

Obtaining a genetic diagnosis almost always brings huge relief to patients and their families, and this could be a particularly emotional moment for those who have experienced many years of disappointing negative genetic results.   The achievement of a genetic diagnosis can significantly impact upon the clinical management of patients with rare inherited ataxia and allow genetic counselling for them and genetic screening for their families. In the future, achieving a genetic diagnosis may allow targeted treatment, although such treatments are not currently available in the majority of rare inherited neurological disorders.

If a novel mutation has been detected, this may benefit other people with similar health issues, now or in the future. As new genes are identified, a greater understanding of the mechanisms for inherited ataxias is expected to be gained and, in the long-term, these findings may lead to the development of novel therapeutics. If a genetic diagnosis is made, further unnecessary investigations will be avoided.

If you or a member of your family has been diagnosed with an ataxia and would like to be seen in the Ataxia clinic, in the first place a referral letter should be forwarded by your GP to the National Ataxia Clinic, Tallaght Hospital.

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