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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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