Abstract
Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
Highlights
The cerebral palsies are defined as a group of permanent disorders of movement and posture that are attributed to non-progressive disturbances that occurred in the developing foetal or infant brain (Rosenbaum et al, 2007)
Cases 1–4 were diagnosed with ataxic cerebral palsy based on standard criteria (Smithers-Sheedy et al, 2014), which included the presence of an early ataxic motor disorder with no clinical evidence of a neurodegenerative disorder
Having identified four cases with de novo mutations we reviewed all the ataxia cases in our cohort and identified six additional children who had congenital cerebellar ataxia and who had been analysed using exome sequencing, but who did not have a specific diagnostic label of ataxic cerebral palsy
Summary
The cerebral palsies are defined as a group of permanent disorders of movement and posture that are attributed to non-progressive disturbances that occurred in the developing foetal or infant brain (Rosenbaum et al, 2007). They are classified into clinical subtypes including spastic, dyskinetic, dystonic and ataxic groups, but there may be additional disturbances of cognition, communication and behaviour. An internet search for the term ‘cerebral palsy’ provides dozens of legal services for claims of negligence and as a result of this climate of litigation in developed countries the Caesarian section rate (and its complications) has soared in the last 40 years (Nelson, 2003)
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