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Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology

Nature Reviews Neurology volume 19, pages 542–555 (2023)Cite this article

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Abstract

Cerebral palsy is a clinical descriptor covering a diverse group of permanent, non-degenerative disorders of motor function. Around one-third of cases have now been shown to have an underlying genetic aetiology, with the genetic landscape overlapping with those of neurodevelopmental disorders including intellectual disability, epilepsy, speech and language disorders and autism. Here we review the current state of genomic testing in cerebral palsy, highlighting the benefits for personalized medicine and the imperative to consider aetiology during clinical diagnosis. With earlier clinical diagnosis now possible, we emphasize the opportunity for comprehensive and early genomic testing as a crucial component of the routine diagnostic work-up in people with cerebral palsy.

Key points

  • Currently, a clinical diagnosis of cerebral palsy (CP) is made on observation of signs and symptoms and does not consider aetiology or pathology.

  • CP encompasses a clinically heterogeneous group of disorders — together referred to as cerebral palsies — with at least one-third of cases having a genetic aetiology.

  • CP has a high degree of genetic overlap with neurodevelopmental disorders, such as intellectual disability, epilepsy and autism, and should itself be considered, at least partly, a genetic neurodevelopmental disorder.

  • The presence of known cerebral palsy risk factors, such as prematurity and growth restriction, and the absence of other comorbid neurodevelopmental phenotypes, including intellectual disability and epilepsy, do not rule out a genetic aetiology.

  • Diagnostic practice has not evolved with the fast-accumulating evidence for a genetic contribution to CP aetiology; the nomenclature for genetic cases and the circumstances under which a genetic diagnosis should negate the CP clinical diagnosis lack consensus.

  • An aetiology-driven diagnosis of CP involving a ‘genotype-first’ approach will bring tangible benefits to individuals with CP through precision medicine and improved clinical management.

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Fig. 1: Timeline of activities by the International Cerebral Palsy Genomics Consortium.
Fig. 2: Genetic investigations in cerebral palsy cohorts.
Fig. 3: Genetic and clinical overlap among cerebral palsy and other disorders.
Fig. 4: Reactome pathway diagrams for three key processes showing significant enrichment for proteins encoded by recurrent cerebral palsy genes.

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Acknowledgements

The authors thank T. Kroes and D. Fornarino for their assistance with the initial curation of cerebral palsy gene lists. J.G. is supported by NHMRC Senior Research Fellowship ID1155224 and C.L.v.E. is supported by The Hospital Research Foundation Fellowship C-MCF-48-2019.

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Authors and Affiliations

  1. Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia

    Clare L. van Eyk & Jozef Gecz

  2. Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia

    Clare L. van Eyk & Jozef Gecz

  3. Department of Paediatrics, Monash University, Melbourne, Victoria, Australia

    Michael C. Fahey

  4. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Jozef Gecz

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  1. Clare L. van Eyk
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  3. Jozef Gecz
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C.L.v.E. and J.G. contributed equally to discussions of the article content. C.L.v.E. researched and drafted the article. All authors reviewed, edited and approved the manuscript.

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Correspondence to Jozef Gecz.

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Related links

Human Phenotype Ontology: https://hpo.jax.org/app/

International Cerebral Palsy Genomics Consortium CP Commons data portal: https://icpgc.org/accessing-the-data/

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van Eyk, C.L., Fahey, M.C. & Gecz, J. Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology. Nat Rev Neurol 19, 542–555 (2023). https://doi.org/10.1038/s41582-023-00847-6

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