Two New CHD2 Mutations Identified, Linked to LGS by Scientists

Two New CHD2 Mutations Identified, Linked to LGS by Scientists
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Researchers have identified a number of previously unknown mutations in the CHD2 gene that are associated with several epileptic conditions, including Lennox-Gastaut syndrome (LGS), in children in China.

The study, “CHD2‐related epilepsy: novel mutations and new phenotypes,” was published in the journal Developmental Medicine & Child Neurology.

Lennox-Gastaut syndrome is a form of epilepsy characterized by multiple types of seizures, cognitive difficulties, extensive changes in the brain’s electric activity (both awake and asleep), and resistance to many types of anti-seizure medications.

An increasing number of epileptic disorders have been associated with mutations in the CHD2 gene — which contains the instructions to produce CHD2, a protein that regulates the activity of other genes.

To date, 51 cases of CHD2-related epilepsy, including three LGS patients (5.9%), have been reported. Seizures were triggered by light in 12 of these patients, and a previous study in zebrafish suggested that partial loss of CHD2 causes sensitivity to light (photosensitivity).

Evidence so far suggests that CHD2-associated epilepsy includes a variety of genetic and clinical features.

A team of researchers at Peking University First Hospital set out to characterize CHD2 mutations and their corresponding clinical symptoms in a group of Chinese children with epilepsy, followed at their hospital.

Of the initial 2,346 children analyzed, 611 were found to carry disease-causing mutations, which in 17 of them (2.8%) were located in the CHD2 gene.

A total of 16 CHD2 mutations were identified: 15 new mutations and one previously reported for a first time in an LGS patient (p.Q1392TfsX17). Thirteen were de novo mutations, meaning they appeared in the individual without being inherited from the parents.

Two of these new de novo mutations — p. K1351fs and p. V882F — were identified in a boy and a girl diagnosed with LGS. The boy started experiencing seizures as a 1 year old, and the girl when she was 3 years old; fever was identified as a seizure-trigger in the boy.

Both children had generalized tonic-clonic seizures, or those starting on both sides of the brain; myoclonic seizures, those causing shock-like jerks of a muscle or a group of muscles; and atonic (drop) seizures.

The boy also had a history of myoclonic-atonic seizures and status epilepticus, a life-threatening condition in which a seizure lasts longer than five minutes or many seizures occur close together without a recovery period.

Both children showed developmental delay. The boy became seizure-free at age 11 when treated with a combination of topiramate and zonisamide. He and the girl had failed to respond to at least three previous medications — valproate sodium (VPA), lamotrigine, and levetiracetam. Her seizures were still not completely controlled, and she was now on a combination of VPA, lamotrigine, and clobazam.

Regarding all 17 patients, age at seizure onset ranged from 3 months to 10 years, and included several types of seizures. Seizures were controlled with anti-seizure medication (mostly VPA and levetiracetam) in nine patients. Three patients were photosensitive.

Abnormal brain electric activity was found in 15 patients, developmental disability in 14, autism features in seven, and epileptic spasms in two. In addition to LGS, other diagnoses included non-specific epileptic encephalopathy, epilepsy with myoclonic–atonic seizures, febrile seizures plus, and West syndrome — which was associated with CHD2 mutations for the first time.

A total of five patients with the Q1392TfsX17 mutation had been identified (one in this study and four in previous reports), suggesting that the CHD2 gene may be more vulnerable to this mutation. The researchers noted, however, that the clinical features of these patients appeared to be similar to those carrying other CHD2 mutations.

Based on these findings, the team noted that disease-causing mutations in the CHD2 gene are associated with mild to severe neurodevelopmental conditions. The scientists suggested that larger studies with long-term follow-up will help to optimize treatment and better understand CHD2-related epilepsy.

These data also highlighted “the importance of considering the involvement of CHD2 in children with [treatment-resistant] epilepsy, intellectual disability, developmental delay, and autistic features at an early age,” the researchers wrote.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Ana de Barros, PhD Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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