• AMT
• GLDC
• genotype
• glycine encephalopathy
• nonketotic hyperglycinemia

Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive genetic disorder of abnormal glycine metabolism caused by insufficient activity of the glycine cleavage enzyme system. Glycine is believed to function mainly as an inhibitory neurotransmitter, but it can also act as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor. The accumulation of a large amount of glycine in the brain leads to neuronal and axonal injury via overactivation of NMDA receptors located in the hippocampus, cerebral cortex, olfactory bulb, and cerebellum and to stimulation of the inhibitory function of glycine receptors located in the spinal cord and brain stem, resulting in central apnea, hiccups, and hypotonia in the early stage of the disease.

The child described in this report had typical clinical manifestations of NKH, such as hiccups, disturbance of consciousness, hypotonia, and convulsions, within the first week after birth. Whole-exome genetic testing revealed that the child had a compound heterozygous mutation, namely, c.395C>A (p.S132X) and c.2182G>A (p.G728R), in the GLDC gene, and he was diagnosed with NKH. For treatment, we administered an oral levetiracetam solution and added topiramate and prednisone for epilepsy control, but the epilepsy remained uncontrollable. Ketogenic diet therapy was started at 6 mo of age, his seizures were significantly reduced, and there were no obvious adverse reactions during ketogenic treatment. Furthermore, we found that with the development of the disease, high levels of serum glycine decreased or even disappeared without intervention, and as the disease progressed, the corpus callosum became dysplastic.

This case shows that plasma glycine levels cannot be used to evaluate the prognosis of NKH, that the development of the corpus callosum can be affected by NKH, and that a ketogenic diet may be effective for seizure control in NKH patients.

• Nonketotic hyperglycinemia
• Compound heterozygosity
• GLDC gene
• Case report

• GLDC variation
• compound heterozygous variant
• glycine cleavage enzyme system
• inherited metabolic disease
• nonketotic hyperglycinemia

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.

Neurodegenerative disorders frequently have diverse, severe symptoms and health outcomes that can be difficult to predict. The rare disease non-ketotic hyperglycinemia (NKH) additionally has a wide range of disease-causing mutations in glycine decarboxylase (GLDC), a protein that breaks down glycine. But measuring glycine is not sufficient to foretell disease outcome. A method to predict whether a mutation will cause severe or more mild forms of NKH would be very helpful to both understanding the disease as well as developing treatments for it. We used computation-based approaches to develop a mutation score that comprehensively predicts how mutations decrease GLDC function. After training against clinical data, the score was able to predict whether a mutation will cause severe or attenuated disease. This study utilizes the power of computational and multidisciplinary analyses to advance understanding and treatment of genetically caused neurodegenerative diseases.

• Early onset seizures
• Epileptic encephalopathies
• Infantile epilepsy
• Seizures

• Age Factors
• Humans
• Infant
• Infant, Newborn
• Seizures/diagnosis
• Seizures/etiology
• Seizures/therapy