The research team from Kaohsiung Chang Gung Memorial Hospital (KCGMH) and National Yang Ming Chiao Tung University (NYCU) has discovered a new causative gene, NDEL1, for lissencephaly. This follows their 2020 discovery of the CEP85L gene. The team has collectively identified four genes associated with lissencephaly, with this latest finding published in the prestigious neuroscience journal Acta Neuropathologica in January 2024.
Lissencephaly: Rare but Severe, 300 Patients in Taiwan Face Significant Challenges
Lissencephaly is an infrequent brain developmental disorder, with only about 300 patients in Taiwan. In a normal brain, the surface has many folds called ‘gyrus,’ which is crucial for developing higher cognitive functions. However, in patients with lissencephaly, the gyrus is either underdeveloped or absent, resulting in a smoother brain surface.
Dr. Meng-Han Tsai, Director of the Medical Research Department at KCGMH, stated that approximately 12 out of every million newborns are diagnosed with lissencephaly. These patients usually do not survive to adulthood, and those who do have intellectual development comparable to that of an infant. They often suffer from severe developmental delays and intractable epilepsy. In the most severe cases, they cannot speak, swallow, or walk.
About 20 genes are known to cause lissencephaly, but approximately 20% of cases still have unidentified causes. During brain development, nerve cells must migrate to the cortex, which requires regulation by multiple genes. If these genes are abnormal, the nerve cells cannot move to the correct locations, leading to improper development of brain folds and lissencephaly.
NDEL1 Mutation Identified for the First Time, Advancing Brain Development Disorder Research
KCGMH has conducted long-term research on lissencephaly in Taiwan and discovered a patient with refractory epilepsy combined with lissencephaly. The patient exhibited abnormal development of the gyri in the posterior brain region, indicative of lissencephaly. Research revealed that the causative gene for this patient’s lissencephaly is NDEL1, a spontaneous mutation in the patient that was not inherited from either parent. This gene has never been previously associated with any human disease worldwide.
KCGMH collaborated with Professor Jin-Wu Tsai’s team at the Institute of Brain Science of NYCU. They confirmed that this gene affects brain development in mice using advanced genomic sequencing technology. The protein produced by this gene impacts the motor proteins within cells, leading to abnormal brain development.
Prof. Jin-Wu Tsai stated that the discovery of new genes involved in human brain development disorders not only helps to elucidate the fundamental regulatory mechanisms in brain development but also provides further insights into children’s cognitive development and the functioning of the nervous system. This research finding will aid in speeding up the diagnosis of brain development disorders by physicians in the future and offer scientists a deeper understanding of the mechanisms underlying brain development.
This vital research will help accelerate the diagnosis of brain development disorders by physicians and explain why individuals without a family history may develop these conditions. In the future, it may also become a genetic marker for prenatal screening, reducing the incidence of these diseases. Scientifically, this discovery provides a deeper understanding of the mechanisms of human brain development and holds promise for developing drugs or gene therapies in the future.