Cerebral Palsy Linked to Genetic Abnormalities

Yael Waknine

February 22, 2012

February 22, 2012 — Genetic abnormalities rather than perinatal factors may be the leading cause of cerebral palsy (CP), according to a new review.

"[T]he cerebral palsies should be considered as a group of developmental brain disorders in which genetic abnormalities are likely to play a substantial role, similar to autism spectrum disorders, intellectual disabilities, and epilepsies," said lead author Andres Moreno De Luca, MD, from the Genomic Medicine Institute of the Geisinger Health System, Danville, Pennsylvania, in an interview with Medscape Medical News.

Clinicians are therefore advised to consider genetic testing of children who present with CP or CP-like symptoms, he said.

"We have to consider the genetic causes contributing to the motor impairment of the children we care for as having cerebral palsy," said Barbara M. Weissman, MD, in an interview with Medscape Medical News, noting the importance of genetic testing for patients with conditions of unknown or not readily apparent etiology.

Dr. Weissman, a pediatric neurologist at Emory-Children’s Center and associate professor of pediatrics at the Emory University School of Medicine in Atlanta, Georgia, was not involved in the research.

"I think that more and more we need these studies and so I’m very happy that we have an ongoing search for more genetic causes," she noted.

The article is published in the March issue of Lancet Neurology.

CP Rates Constant

Known as the most common childhood physical disability, CP represents a spectrum of permanent, nonprogressive disorders that affect movement, posture, sensation, perception, cognition, communication, and behavior.

Although the condition has long been attributed to a wide range of perinatal factors, particularly birth asphyxia, detection and early intervention in episodes of acute birth asphyxia have not been effective for improving neurologic outcomes. However, a growing body of evidence supports the role of genetic abnormalities in CP that may also be the original cause for some difficult births, the researchers note.

"It has been clearly shown by multiple, well-designed studies that birth asphyxia accounts for less than 10% of [CP] cases...and there are 6 known cerebral palsy genes and many more that when mutated result in genetic syndromes that present with clinical features that resemble cerebral palsy, which we refer to as cerebral palsy spectrum disorders," said Dr. Moreno De Luca.

Such evidence is supported by the fact that the global prevalence of CP has remained steady over 40 years (0.2 to 0.3 of live births), despite the introduction of electronic fetal monitoring and a 5-fold increase in the rate of cesarean deliveries performed to avoid difficult deliveries.

This is good news for the 76% of US obstetricians who have faced malpractice litigation between 1999 and 2003, primarily for alleged birth mismanagement resulting in CP.

"[E]normous efforts, time, and economic resources are currently spent in litigation processes against obstetricians for having allegedly caused cerebral palsy and very limited resources and funding are allocated to research projects studying the genetic component of this disorder," said Dr. Moreno De Luca.

"If more people start to consider cerebral palsy as a group of neurogenetic disorders, it is likely that the tables will turn leading to an increase in our understanding of this condition and hopefully to novel therapeutic interventions for cerebral palsy," he added.

Evidence for Genetic Factors

According to the authors, a growing body of evidence supports the contribution of genetic abnormalities to CP.

Mutations in multiple genes result in mendelian disorders that present with CP-like features, increasing the risk for congenital abnormalities relative to the general population (11% to 32% vs 2% to 3%). These include cerebral malformations (72%), microcephaly (26%), hydrocephaly (19%), cardiac malformations (29%), musculoskeletal disorders (14%), urinary disorders (9%), and facial clefts (18%).

Six single-gene mutations have thus far been identified in idiopathic CP pedigrees: glutamate decarboxylase 1 (GAD1); KN motif and ankyrin repeat domains 1 (KANK1); and adaptor-related protein complex 4 (AP4) subunits μ1, ε1, β1, and ð1 (AP4M1, AP4E1, AP4B1, and AP4S1). All are autosomal recessive except for KANK1.

In addition, register-based studies have reported a significantly increased CP rate among monozygotic vs dizygotic twin pairs (P = .0026), and the risk for CP is about 2.5 times higher in consanguineous families than outbred families. Links to familial aggregation of cases and paternal age have also been suggested.

Moreover, recent advances in next-generation sequencing technologies have allowed rapid and cost-effective sequencing of the entire human genome and a subset of all coding genes (exomes). As a result, a causative gene has been uncovered in a range of mendelian disorders, including MLL2 in Kabuki syndrome, DHODH in Miller syndrome, and KIF1A in hereditary spastic paraparesis.

"These findings support the notion that developmental brain disorders such as cerebral palsy are probably caused by hundreds of genes, and that systematic family-based exome or genome sequencing has the power to uncover them," the authors write.

Although only 6 genes have been identified thus far, many more will probably be identified.

"The list of monogenic causes of [CP] will probably grow exponentially because of the increasing use of cutting-edge genomic technologies to assess individuals with undiagnosed disorders of brain development," the authors write, noting that the paradigm shift will likely effect a change in diagnostic approach and eventually novel therapies for the condition.

"This exciting new era of cerebral palsy genomics will unquestionably benefit this patient population," they note.

Dr. Weissman concurred, saying, "At least 10% if not more of the children I care for have an underlying genetic cause [for their condition]. With more genes identified, we should be able to identify the problem in even more children and families."

Is Prenatal Testing Warranted?

According to Dr. Moreno De Luca, though, the data supporting prenatal testing are not quite "there" yet.

"At this point, we don’t recommend prenatal testing," Dr. Moreno De Luca told Medscape Medical News. "We need to conduct genetic testing in a research setting in a large number of individuals with cerebral palsy to establish the diagnostic yield of different technologies such as chromosomal microarray analysis and whole genome sequencing.

"We estimate that the yield in cerebral palsy would be similar to that of other neurodevelopmental disorders such as autism and intellectual disabilities, in which chromosomal microarray analysis is considered the standard of care," he added. "Once the usefulness of genetic testing for cerebral palsy is proven, these technologies should be implemented in routine clinical practice."

Dr. Weissman notes that the identification of at-risk populations and related genetic link would be a boon for prospective parents.

"[Although] prenatal testing is a decision for parents to make, knowing that you’re at risk before you become pregnant is probably the best outcome. Then people could be tested to know their at-risk factor — it would be a real blessing to have that information."

The study was funded in part by grants from the US National Institutes of Health. The authors and interviewees have disclosed no relevant financial relationships.

Lancet Neurol. 2012;11:283-292. Abstract

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