A new study has identified the molecular defects underlying a complex developmental brain condition in children.

The team, led by UCL and including Imperial College London researchers, investigated the role of a specific regulatory protein in the brain known as acyl-CoA-binding domain-containing protein 6, or ACBD6. Up until now, the implication of defects in this protein have been unknown but the new research uncovered evidence that ACBD6 plays an essential part in maintaining a healthy nervous system.

The new study, published in the journal Brain, revealed the role of malfunctioning ACBD6 in an ultra-rare condition in children, known as Autosomal Recessive ACBD6-related disorder. This is characterised by delays in the development of cognitive and motor skills, and is associated with dystonia and parkinsonism.

The discovery was made possible through the use of advanced genomic technologies and extensive global data sharing, with 89 clinicians and scientists from 72 institutes involved worldwide.

Multifaceted approach

The understanding of this rare disorder began with the study of a complex neurological disorder affecting three siblings from a single family, who had mutations in the ACBD6 gene. Thanks to extensive international collaboration over the following years, more affected families with similar genetic disorders were identified, and gradually a resemblance began to emerge among the distinct clinical and radiological features of those affected.

The researchers took a multifaceted approach, investigating 45 affected individuals from 28 unrelated families and extending their study to include animal models. The Imperial team, led by Professor Ed Tate from the Department of Chemistry at Imperial, were responsible for studying the effect of ACBD6 deficiency on N-myristoylation, a specific type of protein modification.

Dr Wouter Kallemeijn, from The Francis Crick Institute and the Department of Chemistry at Imperial, said: “We were able to corroborate our patient findings in ACBD6-deficient frog and zebrafish models – which suffer from remarkably similar disease symptoms as human ACBD6-deficient patients – indicating ACBD6 plays a significant role in N-myristoylation, including that of proteins crucial for and during neurodevelopment.”

International endeavour

Co-lead author Dr Reza Maroofian, from the UCL Institute of Neurology, said: “This study underscores the untapped power of systematically investigating a relatively large number of well-defined individuals affected by ultra-rare disorders and highlights how much we can learn about human biology and pathology from these studies which are currently severely neglected and underfunded.

"This international endeavour stands as a testament to the relentless dedication and collective expertise of the global scientific community and highlights the critical importance of not marginalizing ultra-rare conditions.”

Co-lead author Dr Rauan Kaiyrzhanov, also from the UCL Institute of Neurology, said: “The direct and immediate impact of this study is that introducing these genetic disorders to the medical community will help to diagnose the families affected by this condition worldwide.

"However, the long-term and wider effect of this study is that this ultra-rare condition, which often manifests with abnormal movements such as dystonia and parkinsonism, can help us better understand the biology of these conditions in humans and advance our knowledge of biological mechanisms linked to much more common neurodegenerative movement disorders like Parkinson’s disease and dystonia.”

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‘Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders’ by Rauan Kaiyrzhanov et al. is published in Brain.

Based on materials provided by UCL.