I have been invited to lecture at Bristol tomorrow (June 2019) on my experience of assessing and treating children with dystonia which has given me a chance to reflect on changing practices.
There are two components to clinical management which are not entirely separable:
- the diagnostic perspective – what is the cause of the dystonia, particularly is it a degenerative or a static condition; and
- the treatment perspective – which itself can be split into treating the underlying neurobiological disorder and treating the symptoms and consequences
It has to be said that for really all neurological conditions, we still end up treating the symptoms and consequences rather than the underlying neurobiological disorder. Even advanced molecular therapeutic agents summarised as “effective” or “highly effective” really tend to produce a relative and partial improvement or retard the inevitable deterioration rather than produce a reversal or cure.
From the diagnostic perspective, these days my approach in children with dystonia of unknown cause with a normal MRI brain is to undertake exome sequencing early, rather than undertake too many low-yield biochemical investigations beyond simple screening tests. I will usually these days undertake more advanced biochemical investigations (CSF neurotransmitters, muscle respiratory chain analysis and such-like) after genetic testing.
The genetics tests are usually the most appropriate next generation sequencing gene panels, chromosomal microarray and specific gene tests where there are more specific phenotypical features which may not be picked up on currently available clinical next generation sequencing panels. There are quite a few childhood dystonia conditions which involve exon deletions or nucleotide repeat expansions.
The relevant gene panels in childhood dystonia are often not those labelled “dystonia” such as the one undertaken at Sheffield. Childhood dystonia is often associated with epileptic encephalopathy or global cognitive impairment which may be the dominating feature at one or other point in the child’s life. The dystonia may arise much later than the epileptic encephalopathy and global developmental delay, well after the epilepsy has settled down. I can across a teenager with GLUT1 glucose transporter deficiency with progressive dystonia, where the early history of epilepsy and ataxia had been forgotten because it was no longer present. Conversely, I have seen children with Rett syndrome MECP2 mutation and Angelman syndrome present with infant-onset dystonia rather than the usual “classical” features of Rett syndrome or Angelman syndrome.
What this means is that the molecular diagnosis for a child with dystonia of presumed genetic cause may only be made by testing on exome sequencing panels labelled “epileptic encephalopathy” or “intellectual disability”, or indeed other gene panels for “ataxia” and “spastic paraparesis” rather than the one called “dystonia gene panel”.
Obviously we do need to be pretty sure there is a genetic cause to be found. Acquired in utero brain injury does not always result in MRI brain abnormalities. It’s quite typical for extreme premature-delivered infants to develop dystonic cerebral palsy and yet have normal MRI brain. I have also seen children with dystonic cerebral palsy after newborn hypoxic-ischaemic brain injury with normal late childhood MRI brain, but transient abnormalities (diffusion restriction in the basal ganglia) on neonatal MRI brain.
Whilst this diagnostic odyssey is being undertaken, there is usually a need to intervene therapeutically. I will cover the therapeutic interventions and how this interacts with underlying diagnosis in a later blog article.