Nikhil (name changed) had been visiting Dr K N Shah for the past 20 years. He first consulted Dr Shah, Senior Paediatric Neurologist, at Lilavati Hospital and Research Center in Mumbai at the age of 5 years, when he had his first epileptic seizure.
His family history and birth history were completely normal and without any evidence of neurological disorders. All his milestones were normal until the age of 2, when he started developing speech and language regression (neuro regression). He lost eye contact, but his hearing and vision were normal. He was diagnosed with autistic spectrum disorder and was treated by an occupational therapist for autism and a speech therapist for regression in speech. When he came to Dr Shah at the age of 5 years for this epileptic attack, he underwent a series of tests. While his brain MRI was normal, EEG results showed generalized epileptiform discharges, and Nikhil was diagnosed with idiopathic generalized epilepsy, a comorbidity of autistic spectrum disorder.
Upon further probing into the details of the onset of his generalized tonic-clonic seizures, Dr Shah realized that Nikhil’s epileptic episodes were precipitated while watching television and also upon sudden exposure to sunlight. Such a condition is known as photosensitive epilepsy and repeated EEGs confirmed the diagnosis of his photosensitive epilepsy. His epilepsy was reasonably well controlled by avoiding TV and administration of the anti-epileptic drug valproate. There were a few breakthrough seizures when he watched TV or was exposed to light.
Around age 10, Nikhil also developed obsessive-compulsive disorder – he insisted on listening to audio cassettes and was so obsessed with them that he would be enraged if the audio tapes were taken away. At follow-ups, Dr Shah observed that he did not improve much with occupational therapy and speech therapy, and his cognitive functions regressed. He was able to utter only a few words, although the epilepsy was well controlled. Based on all his symptoms, the clinical impression was ASD, language and speech disorder, OCD, regression in the cognitive functions and photosentitive epilepsy. There was no appropriate treatment other than controlling the epileptic attacks.
To make matters worse, at the age of 23, Nikhil developed tuberculosis of the cervical lymph glands, for which he was treated with anti-tubercular drugs including rifampin, isoniazid, ethambutol, and pyrazinamide. Suddenly, he had 3-4 episodes of epilepsy. He was able to recover only after discontinuing isoniazid.
Although Nikhil’s condition was back under control, there seemed to be no cure in store. With recent leaps in medical technology and the advent of genomic sequencing and progress in understanding the role of genetic mutations, Dr Shah considered trying new-generation sequencing to identify any gene mutation that could lead to such an epileptic syndrome. New generation sequencing showed a mutation in gene CHD2. The CHD2 gene encodes for the chromodomain-helicase-DNA-binding protein 2, which is a chromatin remodeling protein. This gene is associated with epileptic encephalopathy, childhood-onset. Mutations in this gene are known to cause epileptic encephalopathies such as myoclonic jerks, and/or photosensitized, generalized tonic-clonic epilepsy and similar to that of Nikhil’s. They are also associated with ASD, cognitive regression and OCD. Several drugs are currently being tested for treating epileptic encephalopathy, childhood-onset. Drugs like memantine, used to treat dementia in Alzheimer’s disease, and dopamine, used to treat Parkinson’s disease, are being investigated for epileptic encephalopathy, childhood-onset as well. Several clinical trials have already been completed and have reached phase 4.
Nikhil’s parents also underwent genetic counseling, followed by testing. Their results were negative, and did not carry the same mutation. He was therefore diagnosed with a de novo gene mutation. Interestingly, all known cases of CHD2 mutation are de novo.
Nikhil and his family are still in discussion on the next steps of treatment. However, with this diagnosis, Dr Shah was able to inform the parents about the future of their child and also provide possible treatment options. He says, “This case highlights the importance of next-generation sequencing to prognosticate various genetic mutations underlying a myriad of disorders.’’