Failure of Early Dextromethorphan and Sodium Benzoate Therapy in an Infant with Nonketotic Hyperglycinemia

Abstract

We report an infant with neonatal nonketotic hyperglycinemia (NKH), diagnosed early and treated with dextromethorphan (DM) and sodium benzoate therapy from the 65th hour of life. Initially the patient responded to treatment showing clinical and electroencephalographic improvement: myoclonic jerks disappeared, muscular tone, reactivity to stimuli and spontaneous movements increased, assisted ventilation was no longer necessary and bottle feeding was initiated successfully; on EEG the suppression-burst pattern disappeared and the background activity was well-organized. At three months of age he developed flexor spasms and hypsarrhythmia. In spite of increasing doses of DM as high as 40 mg/kg/day and persistent therapy with sodium benzoate the child progressively deteriorated and died at the age of 5 months and 7 days. We stress that the adverse clinical course occurred in our patient even though DM and sodium benzoate therapy was started much earlier than in other reported cases. It is possible that prenatal brain damage and probable genetic variants (i.e. absent or minimal residual enzymatic activity and interindividual variations in DM metabolism) affect the response to therapy.

Nonketotic Hyperglycinemia: A Life-Threatening Disorder in Saudi Newborns

“…Two patients had myoclonic jerks, whereas the EEG in all of them showed the burst-suppression pattern, a classic abnormality in NKH. [16][17][18] The disease could be finally documented in Cases 1 and 2 by the presence of an elevated CSF/plasma glycine ratio with normal urinary organic acids. 19 Case 3, a sibling of Case 2, had a clinical course similar to his sister's and other reported cases of NKH.…”

“…30 On the other hand, Ohya and associates 12 reported partial improvement of neurological symptoms and EEG findings following the administration of ketamine (an NMDA receptor antagonist), similar to our observation in Case 1 of this series. Conversely, Zammarchi et al 18 reported failure of dextromethorphan and Na benzoate treatment in a newborn with NKH. Despite initiation of therapy from the 65th hour of life and initial seizure control associated with EEG improvement, the baby developed flexor spasms and hypsarrhythmia at three months.…”

“…Thereafter, he deteriorated and died at the age of five months and seven days. They accounted for this failure of therapy by a possible genetic variant of the glycine defect in this baby 18 (i.e., absent or minimal residual enzymatic activity) or drug pharmacokinetics variability. 7 Similarly, one of our cases (Case 2) died despite therapy with dextromethorphan.…”

Neonatal seizures

“…Levels of glycine in blood, urine and cerebrospinal fluid are very high. In one case dextromethorphan monotherapy (35 mg/kg/day) was associated with cessation of seizures and normalisation of the EEG [39], but this regimen was not successful in another infant [47].…”

Valproic Acid Exacerbated Infantile Spasms and Induced Novel Complex Partial Seizures in an Infant with Non-ketotic Hyperglycinemia

“…In some patients who present with only hypotonia, infantile spasms [7], chorea [8] or attention deficit/hyperactivity disorder [9,10], the diagnosis of NKH may be delayed, and the disease is often not detected until adulthood.…”