Nonketotic Hyperglycinemia: Clinical Insights and Genetic Mechanisms

Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder arising from defects in the glycine cleavage system, most commonly in the genes encoding glycine decarboxylase (GLDC) and aminomethyltransferase (AMT). This enzyme complex normally catabolises glycine within mitochondria, coupling decarboxylation to folate one-carbon metabolism. In NKH, accumulation of glycine across central nervous system and peripheral tissues disrupts neurotransmission and metabolic homeostasis. Clinically, patients present in the neonatal period with encephalopathy, hypotonia, apnoea and often refractory seizures. Some survive beyond infancy in an attenuated form characterised by developmental delay, behavioural disturbances and varying degrees of motor and cognitive impairment. Hydrocephalus and ventriculomegaly are frequent findings, reflecting altered cerebrospinal fluid dynamics. Current management is symptomatic, employing sodium benzoate to promote glycine conjugation and NMDA-receptor antagonists to temper excitotoxicity, while emerging approaches include dietary modulation and maternal formate supplementation in model systems. Despite these measures, prognosis remains poor and there is a pressing need for targeted therapies. Recent advances in patient-derived cellular models, animal studies and genotype–phenotype correlation tools are shedding light on disease mechanisms and setting the stage for novel interventions targeting metabolic and genetic pathways.

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Nonketotic Hyperglycinemia: Clinical Insights and Genetic Mechanisms publication trend

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Technical terms

Glycine cleavage system: Mitochondrial multienzyme complex that degrades glycine and donates one-carbon units to folate metabolism.

Glycine decarboxylase (GLDC): The P-protein component of the glycine cleavage system responsible for glycine decarboxylation.

Induced pluripotent stem cells (iPSCs): Somatic cells reprogrammed to a pluripotent state, capable of differentiating into diverse cell types.

One-carbon metabolism: Network of biochemical reactions that transfer single-carbon units for nucleotide synthesis and methylation reactions.

Astrocyte: A type of glial cell in the central nervous system involved in neurotransmitter regulation, metabolic support and blood–brain barrier maintenance.

Ventriculomegaly: Enlargement of the brain’s ventricular system, which can precede or accompany hydrocephalus.

References

1. Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient. International Journal of Molecular Sciences (2024).
2. Impaired folate one-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase-deficient mice. Journal of Clinical Investigation (2020).
3. Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non‐ketotic hyperglycinemia. Journal of Inherited Metabolic Disease (2020).
4. Nonketotic Hyperglycinemia: Insight into Current Therapies. Journal of Clinical Medicine (2022).
5. Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity. PLOS Computational Biology (2020).
6. The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype. Orphanet Journal of Rare Diseases (2024).