General description

Nonketotic hyperglycinemia is an autosomal recessive disorder caused by a deficiency in the mitochondrial glycine cleavage system (GCS). This enzymatic defect leads to the accumulation of glycine in body tissues and fluids, with particularly high concentrations in the central nervous system. The pathophysiological mechanism of nonketotic hyperglycinemia primarily involves the overstimulation of N-methyl-D-aspartate (NMDA) receptors in the cerebral cortex, hippocampus, and cerebellum due to excessive glycine levels. Glycine plays a dual role in the central nervous system: it functions as an inhibitory neurotransmitter in the spinal cord and as a modulator of excitation at NMDA receptors in higher brain centers. The diagnosis is typically confirmed by elevated glycine levels in plasma and cerebrospinal fluid (CSF), with an abnormally high CSF/plasma glycine ratio exceeding 0.08, which serves as a biochemical marker of nonketotic hyperglycinemia.

The clinical presentation of NKH varies considerably, with several forms recognized based on severity and age of onset. The classical or neonatal form (onset 0-4 weeks) represents the most severe phenotype. Affected neonates typically present with progressive lethargy, profound hypotonia, myoclonic seizures, hiccups, apnea, and abolished Moro reflex within the first few days of life. These symptoms frequently progress to encephalopathy, coma, and even death in early infancy without intervention.

Survivors of the severe form generally develop intractable seizures and profound intellectual disability. Most affected children fail to achieve developmental milestones such as head control, sitting independently, or speech acquisition, and any skills that are acquired may be subsequently lost. Additional manifestations include feeding difficulties, abnormal muscle tone progressing to spasticity, and poor visual tracking.

MR spectroscopy

Magnetic resonance spectroscopy provides additional diagnostic information, with a characteristic elevated glycine peak at 3.55 ppm.

References

1. Mourmans, J., et al. "Sequential MR imaging changes in nonketotic hyperglycinemia." American journal of neuroradiology 27.1 (2006): 208-211.
2. Mohammad, Shaimaa Abdelsattar, and Heba Salah Abdelkhalek. "Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging." Neuroradiology 59 (2017): 1155-1163.