Cerebral Palsy as a Genetic Disorder: A Deeper Investigation
Moving beyond the current causes of Cerebral Palsy, genetic research is providing robust evidence for its cure and prevention
Studying diseases based only on symptoms is like taking a walk through the territory of wild guesses. We must be grateful that the science of genetics has finally steered us to an enlightened ground. Following the truth of the oldest advice that ‘Prevention is Better than Cure’, research is getting to the root cause of diseases: genetic malfunctions.
Genes are like the Supreme Court judges of the human body: their verdict is final and binding. But what if we could prevail on these unrelenting authority figures to review their judgment? What if this could lead to a baseline shift in disease detection and treatment?
Already, genetics dramatically transforms the quality of life through previews of what lies ahead in a range of biological fields. For example, a couple wanting to have a child can undergo genetic screening to determine what diseases may affect their baby.
Cerebral Palsy is among the most critical conditions that can benefit from genetic research. This neuropathological disorder leads to disability in movement, posture, intellect, muscle weakness, blindness, hearing and speech problems, and epileptic seizures.
Research thus far points to the condition being a result of brain malformation or brain injury during birth. Several factors cause cerebral palsy, including premature birth, intrauterine infections, fetal growth restriction, multiple pregnancies, and placental abnormality. They lead to hypoxia or lack of oxygen to the embryonic brain, causing Cerebral Palsy (CP).
Clinicians have adopted two crucial safety measures to prevent CP: fetal heart rate monitoring and early delivery. Yet, CP cases did not decrease and kept the focus away from examining the role of genes, if any.
However, emerging interest in the congenital and consanguineous aspects of Cerebral Palsy directed the quest toward genetics. A study of monozygotic twins (twins born from the same egg or ovum) with CP suggests that the disease may have its origins in their genes.
The International Cerebral Palsy Genomics Consortium revealed that about 14 percent of CP cases might be related to brain wiring genes. Michael Kruer, MD, a neurologist at Phoenix Children’s Hospital and University of Arizona College of Medicine, USA, says that a significant portion of CP can be linked to rare genetic mutations, opening a new diagnosis map.
A detailed genetic study of the cohort found either a family linkage or incongruity of genes in Cerebral Palsy patients leading to two conclusions: genetic causes could be from de novo or spontaneous mutations within the fetus with no parental lineage, and approximately two percent of the cases could be due to autosomal recessive genes, autosomal dominant genes, or X-linked genes with parental origin. In autosomal recessive inheritance, a child inherits one mutated gene copy from both parents. In an autosomal dominant case, a child inherits the abnormal gene from only one parent, and in X-linked genes, the child inherits the X (male) chromosome characteristics. These two findings are central to the discussion in this article to explain the role of genes in cerebral palsy.
Modern tools to detect the genetic causalities
The three clinical approaches to studying the genetic relation with any disease, especially Cerebral Palsy, are:
- Whole Exome Sequencing (WES).
- Copy number variants.
- Gene expression studies.
A brief insight into each will help understand the authenticity of the scientific findings.
WES: It reads out the exact codes of the patient’s genes and parents to compare and pinpoint the new mutation. These mutations have proved to be post-fertilization and bear no genetic linkage. They occur in the genes which show tremendous response to the slightest changes in the DNA letter code.
Copy number variation: It is another tool to understand any duplication or deletion that has taken place in the genome. A particular section of the genome is repeated several times, and the number of repetitions varies with individuals, which may suggest mutation.
Gene expression: Genes translate into proteins as the final product to maintain life, and any change in the protein will bring multiple changes in the entirety. Therefore, gene expression studies in the lower animals give a clear idea of the effects of mutations.
The concept of de novo mutations
De novo mutations are an extreme form that occurs in a child despite the mutation not being present in parental lineage. They are spontaneous mutations likely to happen in the splice, missense, or frameshifts, all types of gene mutations, in genetic codons and are termed variants.
What is a codon? A codon is a DNA or RNA sequence that forms a single unit of genomic information that encodes a specific amino acid or announces the cessation of protein synthesis. The end of protein synthesis in DNA is a terminal tragedy leading to a cell’s death. A slight change in the letter of a codon can either stop protein production or change its type. This mutation can disrupt normal functions, worsen protein formation, or cause RNA disruption in the brain, contributing to neuropathological conditions. Accidental mistakes during DNA replication and cell division open the possibilities for these rare mutations.
Genes directly involved in Cerebral Palsy
Cerebral Palsy manifests abnormal neural circuitry due to either weak protein coverings or poor growth of the neural processes or neurotransmitters, all of which have been revealed in gene expression studies. The gene mutation types mentioned have shown signs of Cerebral Palsy or similar neuropathology in organisms.
Four of the eight genes accountable for Cerebral Palsy discovered recently are RHOB, FBXO31, DHX32, and ALK. Six of the eight genes controlling the neural circuit wiring are either involved in making the protein framework that lines the perimeters of neural circuits or in the growth of extensions of neural processes that begin during the early stages of the embryo.
Drosophila melanogaster, a species of fly, showed signs of Cerebral Palsy with problems in walking, turning, and balancing, when mutated in these genes.
Research at Washington University, University of Arizona and Yale University identified two genes, FBXO31 and RHOB, either of which, when mutated, can cause CP.
WES studies of a cohort with a history of intellectual disabilities found the zinc-finger gene ZC4H2 responsible for CP. This gene, when mutated in Zebrafish, resulted in impaired swimming. The absence of the same ZC4H2 gene protein in hippocampal neurons of mice showed a reduced density of the dendritic processes at the synapse and a lack of central and spinal plasticity, which impacted their ability to adapt to their habitat.
Autosomal and X-linked genes in the development of Cerebral Palsy
Remember we mentioned autosomal recessive genes earlier in this article? Autosomal recessive or rare autosomal dominant genes are more likely to fail or overproduce protein in most hereditary diseases. The other evidence to support gene mutation as a cause of Cerebral Palsy is that males are more likely to get it. Recessive X-linked genes are insufficient to cater to the functions required by the body and eventually give rise to Cerebral Palsy in males.
“Cerebral Palsy is not one narrow disease but a spectrum of overlapping neurodevelopmental problems,” says Dr. Lewis of Washington University School of Medicine. CP is a complex condition encompassing multiple neuropathological issues such as intellectual disability, autism, epilepsy, and visual impairment. Severe metabolic acidosis or intrapartum hypoxia (low oxygen levels) during labor are presently considered secondary causes of CP because the pathways to CP are created in early pregnancy.
However, the argument about hypoxia needs greater scrutiny as the neural arch and neural canal in an embryo only start to shape at the gastrulation stage, which subsequently leads to the development of the brain. Gastrulation is an early process in embryo growth. It helps the embryo change from a one-dimensional epithelial layer of cells (blastula) into a multilayered and multidimensional formation called the gastrula. Therefore, hypoxia is arguably an unlikely cause as its presence comes in later in the pregnancy.
Therefore, an in-depth study of the role of genetic mutations is a more promising route to finding the answers to diagnose Cerebral Palsy and prevent it. A complete genetic examination of the family history and the fetus in its early stage might lead us to eliminate the disease from humanity.