Cerebral palsy: causes, pathways, and the role of genetic variants

Abstract

Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.

Genomic analysis identifies masqueraders of full‐term cerebral palsy

“…Both genetic and environmental factors contribute to the etiology of CP. Recent studies have suggested that a larger number of rare pathogenic genetic variants2 or pathogenic copy number variations (CNVs)3 contribute to CP than previously expected 4. This suggests that “masquerading” genetic diseases can be misdiagnosed as CP 5.…”

Cerebral Palsy and Electronic Fetal Monitoring: Rearranging The Titanic’s Deck Chairs

“…EFM is not a monitor; it merely records data and that data requires interpretation [4,9,10,[26][27][28]51]. Interpretation is an art.…”

“…It is no better than a coin toss as a test for absence of injury [3]. But EFM today remains the most common obstetrical procedure [4,21,24,25], even as evidence against its efficacy continues to mount [2,4,10,21,[26][27][28].…”

Motor Recovery in Children With Cerebral Palsy; Sensory Motor Approaches of Treatments

“…Brain is highly sensitive tissue that cannot tolerate oxygen deprivation for seconds (Larson, Drew, Folkow, Milton, & Park, 2014). Oxygen deficiency and prematurity are considered leading cause in cerebral palsy (MacLennan, Thompson, & Gecz, 2015). Pregnancy disorders, home delivery, traumatic brain injury and neonatal infections are also contributing factors (MacLennan et al, 2015).…”