Background: Nonketotic Hyperglycinemia (NKH) is a rare inborn error of glycine metabolism that causes the accumulation of large amounts of glycine in all body tissues. The buildup primarily occurs in the spinal cord and brain, so initial clinical manifestations and long-term sequelae are often neurological. Classic NKH (biallelic deleterious variants in GLDC or AMT genes) can be categorized into two phenotypes: severe (no developmental progress and intractable epilepsy) and attenuated (variable development and treatable or absent epilepsy) based on age of presentation and outcome. Most children present in the neonatal period, where the severe form is more common. At this age, typical manifestations include progressive lethargy evolving into profound coma and marked hypotonia. A later presentation (at 3 months or older) is rare and usually associated with attenuated enzyme activity. Infants may present with lethargy, hypotonia, seizures, poor feeding, and developmental delay. Case Presentation Summary: A 6-month-old girl, born to healthy, non-consanguineous parents, after an unmonitored, full-term pregnancy, presented with somnolence, seizures (with ocular retroversion), and bilateral arm myoclonus. She had no fever, trauma, infections, or other symptoms. She was hospitalized and started on levetiracetam. Neurological exam at admission showed hypotonia, limited cephalic control, and uncoordinated movements, with no other abnormalities. Due to persistent seizures, zonisamide was introduced, improving both frequency and intensity. Electroencephalogram (EEG) was normal. Brain MRI revealed global moderate ventricular enlargement. Plasma glycine levels were elevated (766 µmol/L), with no other biochemical changes. A lumbar puncture attempt was unsuccessful. Genetic testing showed normal array-CGH and karyotype. Next-generation sequencing for an epileptic encephalopathy gene panel identified two GLDC variants: a likely pathogenic variant (c.1117C>T p.(Arg373Trp)) and a variant of uncertain significance (c.2190T>A p.(Asn730Lys)), both in heterozygosity. Given suspicion of NKH, treatment with sodium benzoate and a glycine-restricted diet was started. Parental testing confirmed compound heterozygosity, allowing for reclassification of the c.2190T>A p.(Asn730Lys) variant as likely pathogenic and confirming the NKH diagnosis. Dextromethorphan was introduced, improving attentiveness and reducing seizures. Eight months later, the EEG revealed multifocal epileptic activity with left temporal predominance. The child has global developmental delay but is steadily acquiring new skills. She is now 29 months old, attends preschool, and receives speech, physical, and occupational therapy. She understands her name, vocalizes, but does not yet speak words. She can sit unsupported. Learning Points Discussion: This case highlights an attenuated presentation of NKH with onset beyond the neonatal period. Although it is a rare condition and the timing of onset is atypical, NKH should be considered in children with lethargy, seizures, hypotonia, and developmental delay. Early recognition, evaluation, and treatment are crucial to achieving the best outcomes. While the child continues to show global delays, her steady developmental progress underscores the importance of early diagnosis and intervention, molecular confirmation, and comprehensive care in improving outcomes for patients with attenuated NKH.
Tavares et al. (Thu,) studied this question.