Despite its simple chemical structure, glycine plays a complex role in the body. The glycine cleavage system regulates brain glycine levels and is a key one-carbon donor to folate. Its metabolism is tightly integrated with that of serine. In addition to its biochemical role, glycine functions as a neurotransmitter and neuromodulator. Primary defects in the glycine cleavage system have long been known to cause human disease with a primarily neurological phenotype, and this was labelled as 'nonketotic hyperglycinaemia' in 1968. With increasing availability of molecular testing, many additional genetic conditions became apparent, as well as non-genetic factors that cause hyperglycinaemia. There is now a much greater appreciation of the marked clinical impact of this heterogeneity. The previous terminology of 'classical' and 'atypical' nonketotic hyperglycinaemia does not adequately address these numerous genetic aetiologies, nor does it account for the phenotypic spectrum within individual genetic disorders. We provide here a clinically relevant classification of the glycine encephalopathies, based on the underlying genetic aetiology and its relation to the glycine cleavage system. Characteristic clinical and biochemical features of each condition, as well as non-genetic phenocopies that cause hyperglycinaemia, are discussed in detail. This provides a readily usable framework for clinicians when faced with a patient with elevated glycine levels.

This study aimed to evaluate the application value of amplitude-integrated electroencephalogram (aEEG) findings in a newborn with nonketotic hyperglycinemia (NKH). The clinical data of a neonatal patient with NKH were retrospectively analyzed. In this study, aEEG was first used to assess brain function in NKH due to AMT gene mutations in the Chinese mainland so far. The aEEG assessment was stratified according to its background pattern, sleep-wake cycle (SWC), and seizure activity, which gave more objective and systemic results. Seizures and burst-suppression pattern were detected on the aEEG. The background belonged to discontinuous voltage, and showed discontinuity of cerebral activity in the form of the burst-suppression pattern. The classification of SWC in this record belonged to the "No SWC" category, which meant the child had severe brain damage. A typical neonatal single seizure was found. The seizure activity lasted approximately 30 seconds. However, clinical symptoms were not observed. Patients with NKH often exhibit complicated clinical phenotypes, and there is a lack of specific symptoms, especially the symptoms of encephalopathy are atypical. aEEG is helpful for the early diagnosis and treatment of seizures. It can help the doctor to carry out appropriate treatment in time. The application value of aEEG in patients with NKH was significant.

Glutaredoxin 5 (GLRX5) is a mitochondrial protein encoded by the GLRX5 gene, which is essential for cellular redox homoeostasis, lipoic acid synthesis, and iron-sulfur cluster transfer. Rare cases of pathogenic GLRX5 mutations have been associated with sideroblastic anemia and non-ketotic hyperglycinemia with progressive spasticity and cavitating leukoencephalopathy. We report an 11-month-old child, who died following aspiration, with severe cardiomyocyte mitochondrial abnormalities and cerebral white matter degeneration in the context of a homozygous GLRX5 variant (c.208A>G, p.S70G).

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT, GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3. We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM_016417.3:c.367G>C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH's genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH.