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Hidden Etiology of Cerebral Palsy: Shifting Paradigms In An Era of Molecular Genetics

Administrator: Erdem Simsek

Prompt use of clinical phenomenology and radiological investigations for evaluation for an underlying etiology in cerebral palsy
Shaheen Akhter

Cerebral palsy (CP) is the most common motor disability in childhood. The prevalence of cerebral palsy (CP) is about 2 to 3.4 cases per 1000 children.The etiology of CP is multifactorial. In most cases, CP is thought to be due to prenatal factors. Genetic causes may be responsible for one-third of all CP cases. Many genetic disorders may present with findings consistent with CP. Some inborn errors of metabolism and other progressive disorders may initially mimic CP.The diagnosis of CP is based on a history of non-progressive abnormal motor development with an examination finding. If there are atypical features in the history or examination, metabolic and genetic studies should be performed. Conventional magnetic resonance imaging (MRI) of the brain is often of great benefit in determining the presence of a brain abnormality that may suggest an etiology and prognosis in children with CP. Seventy to ninety percent of children with CP have abnormalities on MRI. Detection or absence of a brain anomaly in a child with CP may indicate an underlying genetic or metabolic etiology. However, there is currently insufficient evidence conclusively about which studies should be ordered. The purpose of this talk is to highlight the time-honored approach of using examination and clinical history tools to focus on further etiological research with neuroimaging modalities to diagnose the possible underlying genetic etiology in cerebral palsy.

 

Practical aspects of doing genetic testing in CP - Tests available and when to do which one for efficient diagnosis
Pratibha Singhi

An ongoing challenge in children presenting with cerebral palsy (CP) phenotype is identifying CP mimicking neurogenetic disorders. To help distinguish patients in these two groups, clinical findings and magnetic resonance imaging (MRI) of the brain are often first step for "unmasking" many of these disorders with genetic etiologies. However, in daily practice, many of these features are nonspecific or outside the defined clinical phenotype impairing the ability to establish a diagnosis without genetic testing.
Recent advances in genetic testing enabled wider use of next generation sequencing (NGS) techniques and chromosomal microarray in clinical practice. Also, NGS has the potential of discovering atypical presentations of established disorders, or enabling diagnosis when a patient has not yet developed classical findings. The diagnostic power of genomic evaluation in children with CP is of growing interest as neurogenetic masqueraders can be identified using next-generation sequencing technology. This talk will focus on the practical aspects of genetic testing in CP, the tests available and how to choose from them.

 

In-depth analysis of genetic testing in CP with illustrative case studies and a glimpse at the future anticipated developments
Erdem Şimşek

Genetic etiology contributes significantly to the development of cerebral palsy (CP), both through impaired brain development and dysregulated responses to risk factors. Several recurrent genes with strong evidence of pathogenicity have been identified. However, there are probably hundreds more genes waiting to be discovered and/or confirmed. The pediatric neurologist and geneticist should collaborate to decide on the genetic algorithm, validate the variants with clinical findings, and regularly reanalyze previous studies if inconclusive.

Another aspect of CP genomics is the multifactorial identification of risk genes rather than strictly a single gene pathway. By processing high-throughput data from population studies or methylation studies with artificial intelligence, we can identify risk genes and even predict CP. With the help of artificial intelligence, reverse phenotyping may become increasingly relevant in patients undergoing neurodevelopmental evaluation as NGS data may already be available.

The purpose of this talk is to discuss with representative case examples what can be done in cases where primary care genetic testing is insufficient, to talk about genetic testing that can be put into clinical practice in the near future, and to discuss the possible contributions of artificial intelligence and big data.

 

Genetic insights into the classification and treatment modalities of the cerebral palsies
Biju Hameed

Cerebral palsy (CP) is the most common motor disability in childhood, but its association with single gene disorders has not been adequately characterized. A genetic contribution to CP risk was identified by the observation of higher CP risk in groups with higher consanguinity and increased familial risk for CP. Historically, neurogenetic disorders were thought to be rare causes of CP, but with the spread of new generation genetic testing techniques, it is increasingly recognized that they play an important role in the etiology of CP. Genetic factors have been identified in approximately one-third of people with CP.
Recent advances in molecular genetics, such as chromosomal microarray and next-generation sequencing, have revolutionized the understanding of etiology by classifying these disorders more precisely with a molecular cause. In this era of genomic medicine, remarkable tools offer clinicians and researchers exciting opportunities for detailed characterization of neurodevelopmental disabilities. Updating practice parameters to include indications for genetic testing and interpretation should be considered to provide clarity and guidance on how to classify CP given the evolving genetic landscape.
This talk aims to explore the genetic landscape of CP and how the genomic revolution has translated into classification and treatment modalities of CP.