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Neurogenetic disorders across the lifespan: from aberrant development to degeneration

Nature Reviews Neurology volume 18, pages 117–124 (2022)Cite this article

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Abstract

Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.

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Acknowledgements

R.A.H. was supported by grant funding from the Huntington Disease Society of America and Hereditary Disease Foundation and was a Columbia University Irving Medical Center ADRC Research Education Component trainee (P30 AG066462-01, PI Scott Small, MD). The New York Brain Bank is supported by P50 AG008702 (PI Scott Small, MD). M.F.M. was supported by grants from the NIH (NS125224; OD025320; NS096144). W.K.C. was supported by a grant from SFARI.

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Author notes

  1. These authors contributed equally: Richard A. Hickman, Sarah A. O’Shea.

Authors and Affiliations

  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Richard A. Hickman

  2. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Sarah A. O’Shea

  3. The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA

    Mark F. Mehler

  4. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Mark F. Mehler

  5. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY, USA

    Mark F. Mehler

  6. Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA

    Wendy K. Chung

  7. Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Wendy K. Chung

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W.K.C., R.A.H. and S.A.O'S. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. M.F.M. made a substantial contribution to the discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Wendy K. Chung.

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Nature Reviews Neurology thanks E. Head, who co-reviewed with A. Martini; R. Hagerman; and P. Nopoulos for their contribution to the peer review of this work.

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Glossary

Intrinsically disordered

An intrinsically disordered protein or region that lacks a dominant 3D structure and adopts a range of conformational states.

Liquid–liquid demixing

A process that generates membraneless compartments within the subcellular space, in which certain components are enriched while others are excluded.

Metastable

A kinetically trapped structure (for example, a protein or other molecule) that maintains a local free energy minimum within a dynamic system.

Pleiotropic

When one gene influences two or more seemingly unrelated phenotypic traits.

Population-based cohorts

Epidemiological studies in which a defined population is followed and observed longitudinally.

Super-enhancers

Transcriptional enhancers that drive expression of genes that define cell identity.

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Hickman, R.A., O’Shea, S.A., Mehler, M.F. et al. Neurogenetic disorders across the lifespan: from aberrant development to degeneration. Nat Rev Neurol 18, 117–124 (2022). https://doi.org/10.1038/s41582-021-00595-5

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