Six-year-old Mallika (name changed) was brought to the Department of Neurosciences, Bai Jerbai Wadia Hospital for Children in Mumbai, to consult regarding her year-long- history with epileptic seizures. Born to non-consanguineous parents, with a normal delivery, Mallika was growing up as a normal child until she was 5 years old. One day, as she was playing, she suddenly developed a seizure and was unresponsive for 10 minutes. Such seizures continued to recur about twice every month since then. In addition, Mallika also started getting focal seizures about 2 months after the first onset of seizures, which gradually progressed to general tonic-clonic seizures, focal seizures during sleep, and myoclonic jerks that resulted in falls. A couple of months earlier, Mallika also started complaining of being unable to balance while walking. Gradually this condition progressed to a point where she needed support while walking. On the whole, her condition was worsening, with an increase in the frequency of epileptic seizures, loss of milestones and cognitive and higher function regression. Her parents were worried as Mallika had already been treated with a wide array of available antiepileptic drugs, which were unable to effectively control the epileptic pseudo ataxia.
Based on this clinical history, a team of doctors including pediatric neurologists Drs. Shilpa Kulkarni, Sonam Kothari, Anaita Hegde and Krishnakumar Shah at Wadia hospital debated on the treatment plan and a course of action for Mallika. Considering that Mallika’s seizures and ataxia were not being adequately controlled with the antiepileptic drugs, and with deteriorating cognitive milestones, it became imperative to understand the disease to provide suitable treatment. Mallika’s test results, including MRI, brainstem evoked response audiometry, ophthalmic evaluation etc, were all normal other than EEG, which was abnormal and showed epileptic discharges.
The history and test results suggested that Mallika was most likely suffering from some form of neurodegenerative disorder or an epileptic encephalopathy. Epileptic encephalopathies are brain disorders that manifest at an early age and display similar symptoms as seen in Mallika. Multiform, intractable seizures, cognitive and neurological deficits and abnormal EEG are all characteristic features of epileptic encephalopathies. While most common causes of epileptic encephalopathies are structural abnormalities, there are rare, but potentially treatable ones caused due to deficiencies in various metabolic pathways. Such treatable epileptic encephalopathies often occur due to gene mutations, and depending on the gene mutation, different treatment options may be available. To determine if Mallika was suffering from such a metabolic disorder associated with epileptic encephalopathies, genetic testing was recommended, and her blood sample was sent for an epilepsy panel. Mallika was discharged from the hospital while awaiting the results from the genetic testing as the seizures were temporarily under control.
Before the genetic test results were out, however, Mallika was admitted back to the hospital due to a decrease in oral intake. In the hospital, she went into refractory status epilepticus. Mallika was started on a ketogenic diet, which was unfortunately unable to control the seizures. Mallika was unable to think clearly or even recognize her parents. She again developed refractory status epilepticus and was moved to the intensive palliative care unit. To make matters worse, she developed Steven Johnsons syndrome, which is often a side effect of many anti-epileptic drugs. Steven Johnsons syndrome was treated via standard intravenous immunoglobulin. She was at her worst cognitive condition when the genetic test results arrived. The results indicated 2 mutations in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene, indicative of early infantile epileptic encephalopathy-50.
Early infantile epileptic encephalopathy-50 is characterized by early-onset seizures and severe developmental regression as seen in Mallika. It is an autosomal recessive progressive neurodegenerative disorder that occurs due to mutations in the CAD gene. The CAD gene encodes an enzyme required for the biosynthesis of pyrimidine nucleotides. Such a condition has been shown to be treatable by oral uridine. Uridine is not available in the Indian market and had to be bought through Amazon. Dr. Kulkarni reminisces that it took over a month to procure the drug, however, the effects were immediate. Within 48 hrs of starting oral uridine, Mallika’s seizures reduced and refractory status epilepticus was aborted.
Today, Mallika is only on 2 antiepileptic drugs in addition to oral uridine, and while she is not yet cognitively normal, she is able to walk, and her speech is slowly recovering.
Dr. Kulkarni would like to stress on the benefits of genetic testing, how this has revolutionized precision medicine for rare disorders, and how it is important to keep pursuing the right diagnosis to identify the right treatment options.