WHAT’S THE VERDICT?
The jury returns a verdict for the defense.
Should anything have been done differently in this trial?
Medical considerations
Cerebral palsy is a neurodevelopmental disorder affecting 1 in 500 children.1 Other prevalence data (from a European study) indicate an incidence of 1.3–1.9 cases per 1,000 livebirths.1 The controversy continues with respect to the disorder’s etiology, especially when the infant’s magnetic resonance imaging (MRI) does not identify specific pathology. The finger is then pointed at HIE and thus the fault of the obstetrician and labor and delivery staff. In reality, HIE accounts for less than 10% of all cases of CP.2 Overall, CP is a condition focused on progressive motor impairments, many times associated with specific MRI findings.3 In addition, “MRI-negative” CP is a more vague diagnosis as discussed among neurologists.
The International Consensus Definition of CP is “a group of permanent disorders of the development of movement and posture, causing activity limitations, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain.”4 The International Cerebral Palsy Genomics Consortium have provided a consensus statement that defines CP based upon clinical type as opposed to etiology.5 Many times, however, ascribing an HIE cause to CP is “barking up the wrong tree,” in that we now know there are clear cut genetic causes of CP, and etiology attributed to perinatal causes, in reality, are genetic in up to 80% of cases.3 Types of CP are addressed in FIGURE 1. Overall, the pathophysiology of the disorder remains unknown. Some affected children have intellectual disabilities, as well as visual, hearing, and/or speech impairment.
A number of risk factors have been associated with CP (TABLE 1),3,6 which contribute to cell death in the brain or altered maturation of neurons and glia, resulting in abnormal white matter tracts and smaller central nervous system (CNS) volume or cerebellar hypoxia.6 One very important aspect of assessment for CP is specific gene mutations, which may vary in part dependent upon the presence or absence of environmental factors (insults).1 Mutations can lead to profound adverse effects with resultant CNS ischemia and neuromotor disability. In fact, genetics play a major role in determining the etiology of CP.1 Of interest, animal models who are subject to HIE induction have CNS effects resulting in permanent motor impairment.7
DNA sequencing
The DNA story continues to unfold with the concept that DNA variants alter susceptibility to environmental influences. These insults are, for example, thrombosis or hemorrhage, all of which affect motor function.1 Duplications or deletions of portions of a chromosome, related to copy number variants (CNVs) as well as advances in human-genome sequencing, can identify a single gene mutation leading to CP.1 Microdeletions, microduplications, and single nucleotide variants (SNVs) are to be included in genetic-related problems causing CP.3
A number of candidate genes have been considered and include “de novo heterozygous mutations in known Online Mendelian Inheritance (OMIM).” TIBA1A and SCN8A genes are highly associated with CP.8 Genetic assessment, as it evolves and more recently with the advent of exome sequencing, appears to provide a new and unprecedented level of understanding of CP. Specifically, exome sequencing provides a diagnostic tool with which to identify the prevalence of pathogenic and pathogenic variants (the latter encompassing genomic variants) with CP.9 A retrospective study assessed a cohort of patients with CP and noted that 32.7% of the pediatric-aged patients who underwent exome sequencing had pathogenic and pathogenic variants in the sequencing.9 Thus, we have a tool to identify underlying genetic pathogenesis with CP. This theoretically can change the outcome of lawsuits initiated for CP that ascribe an HIE etiology. Clinicians need to stay tuned as the genetic repertoire continues to unfold.
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