Michael C. Kruer, MD

Cerebral palsy (CP) is the principal neurodevelopmental disorder impacting movement. CP affects about 1:250 children worldwide. Recognized CP subtypes include spastic, dyskinetic (dominated by dystonia and/or chorea) and hypotonic/ataxic forms. In addition to the variety of movement disorders with which individuals with CP can present, the severity of symptoms can vary significantly from mild to severe. Not surprisingly, one of the biggest challenges for clinicians caring for patients with CP is the variability seen from patient to patient. This variability may often mean that responses to medical, procedural or surgical interventions also vary widely. This heterogeneity may be partially addressed by detailed clinical measures coupled with quality improvement initiatives (reliably identifying when dystonia is present, for example). However, in many instances, patient to patient differences are anticipated to continue to challenge the field’s attempts to build a strong evidence base for effective treatments.

Cutting through Variability in Cerebral Palsy to Improve Patient Outcomes

At the Barrow Neurological Institute at Phoenix Children’s, the research group of pediatric movement disorders neurologist, Dr. Michael Kruer, is leading efforts to better capture individual differences in CP through multi-dimensional phenotyping. This approach combines detailed assessments of clinical symptoms, function, quality of life, neuroimaging and genomic analysis to uniquely characterize each individual. Working in collaboration with colleagues within the Cerebral Palsy Research Network, a national consortium whose goal is to establish gold standards of care for CP, it is anticipated that multidimensional phenotyping, combined with innovative clinical trial designs for outcomes research, may allow the field to move beyond current bottlenecks.

Building on Genetic Insights into Cerebral Palsy

Large population–based studies have shown that birth asphyxia accounts for less than 10% of CP cases. In addition, there has been a growing recognition that genetic causes of CP may be substantial, accounting for nearly 30% of cases.¹ Dr. Kruer’s research has been delving into the rich complexity of cerebral palsy for several years. The team’s research, led by neuroscientist Sara Lewis, PhD, was the first to conclusively show that cerebral palsy was often caused by single gene mutations.² Dr. Kruer was the founding chair of the International Cerebral Palsy Genomic Consortium and now leads the CP Research Network’s NIH R01-supported genomic discovery research program. Currently, CP associated genes are being discovered and characterized at a rapid pace. Work by the Kruer lab has led to the discovery of a dozen novel disease genes in the last two years alone.

An Evolution in Cerebral Palsy Diagnosis and Care

The explosion of genetic findings in children with CP has also led to a rapid evolution in clinical care. Child neurologists are increasingly incorporating genetic testing in the diagnostic workup of children with CP, prompting reconsideration of current practice parameters guiding clinical care. The impact of genetics on the diagnosis of CP has spurred vigorous discussion at seminars presented by Dr. Kruer and colleagues at the International Child Neurology Association (ICNA 2020) and Child Neurology Society (CNS 2022) meetings. Remarkably, our most recent findings, presented at the 2022 American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) annual meeting by Dr. Lewis, indicate that the detection of a genetic cause for an individual’s CP is anticipated to prompt a change in clinical care 26.7% of the time.³ Despite these intriguing findings regarding “actionable” genetic causes of CP, the quality of evidence for such actionable CP genes is relatively sparse, indicating a clear need for additional research. Nevertheless, such insights may allow treating clinicians to avoid complications, to reach for the best treatments first or to use “non-CP” medications for an individual’s CP care right now.

REFERENCES

1. Srivastava S, Lewis SA, Cohen JS, Zhang B, Aravamuthan BR, Chopra M, Sahin M, Kruer MC, Poduri A. Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy: A Systematic Review and Meta-analysis. JAMA Neurol. 2022 Oct 24. doi: 10.1001/jamaneurol.2022.3549. Epub ahead of print. PMID: 36279113.
2. Jin SC, Lewis SA, Bakhtiari S, Zeng X, Sierant MC, Shetty S, Nordlie SM, Elie A, Corbett MA, Norton BY, van Eyk CL, Haider S, Guida BS, Magee H, Liu J, Pastore S, Vincent JB, Brunstrom-Hernandez J, Papavasileiou A, Fahey MC, Berry JG, Harper K, Zhou C, Zhang J, Li B, Zhao H, Heim J, Webber DL, Frank MSB, Xia L, Xu Y, Zhu D, Zhang B, Sheth AH, Knight JR, Castaldi C, Tikhonova IR, López-Giráldez F, Keren B, Whalen S, Buratti J, Doummar D, Cho M, Retterer K, Millan F, Wang Y, Waugh JL, Rodan L, Cohen JS, Fatemi A, Lin AE, Phillips JP, Feyma T, MacLennan SC, Vaughan S, Crompton KE, Reid SM, Reddihough DS, Shang Q, Gao C, Novak I, Badawi N, Wilson YA, McIntyre SJ, Mane SM, Wang X, Amor DJ, Zarnescu DC, Lu Q, Xing Q, Zhu C, Bilguvar K, Padilla-Lopez S, Lifton RP, Gecz J, MacLennan AH, Kruer MC. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nat Genet. 2020 Oct;52(10):1046-1056. doi: 10.1038/s41588-020-0695-1. Epub 2020 Sep 28. PMID: 32989326; PMCID: PMC9148538.
3. Lewis SA, Chopra M, Aravamuthan BR, Hacque N, May HJ, Bain JM, Cohen JS, Zech M, Fehlings D, Wintle RF, Segel R, Carmel J, Srivastava S, Fahey MC, Kruer MC. Clinical actionability of genetic findings in cerebral palsy. Presented at the 76th annual meeting of the American Academy of Cerebral Palsy & Developmental Medicine, Las Vegas, NV, September 2022.