Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.

The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh-like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A > G in GCSH.

d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence.

Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C>T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH.

Hyperglycemic Nonketotic Signal Changes of the Striatum: An Unusual Complication in the Setting of Neurosurgical Procedures.

BACKGROUND: Hyperglycemic nonketotic chorea is an uncommon complication of poorly controlled diabetes mellitus. Patients typically develop abnormal signal changes in the striatum on imaging studies. Whereas the condition is well reported in the medical literature, reports on this topic in the surgical literature are lacking. CASE DESCRIPTION: We report the first case of striatal hyperglycemic nonketotic signal changes occurring in the setting of a frontotemporal craniotomy for resection of a sphenoid wing meningioma. Postoperative magnetic resonance imaging (MRI) of the patient demonstrated restricted diffusion within the bilateral caudate nuclei, globus pallidus, putamen, and thalami in response to intraoperative hyperglycemia. Normalization of the patient's serum glucose levels postoperatively was followed by improvement in the radiographic abnormalities and their associated clinical sequelae. At the patient's last follow-up appointment 5 months after surgery, MRI demonstrated complete resolution of the abnormal signal changes to the patient's neurologic baseline. CONCLUSIONS: Although uncommon, striatal signal changes associated with nonketotic hyperglycemia should be recognized as a potential complication of surgery. Knowledge of this rare entity is important so that tight control of perioperative serum glucose can be achieved in diabetic patients to prevent this rare entity.

Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice.

Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. GLDC mutations cause a rare recessive disease non-ketotic hyperglycinemia (NKH). Mutations have also been identified in patients with neural tube defects (NTDs); however, the relationship between NKH and NTDs is unclear. We show that reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of NKH including glycine accumulation, early lethality and hydrocephalus. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates, as well as growth retardation and reduced cellular proliferation. Formate treatment normalizes the folate profile, restores embryonic growth and prevents NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism.

Transient nonketotic hyperglycinemia in an asphyxiated patient with pyridoxine-dependent seizures.

An asphyxiated neonate with pyridoxine-dependent seizures and associated transient nonketotic hyperglycinemia is reported. Frequent seizures and their resultant hypoxic-ischemic insult may have led to the elevation of the cerebrospinal fluid glycine level in this patient. Early diagnosis and treatment of pyridoxine-dependent seizures is essential for an improved neurologic outcome.

[Non-ketonic hyperglycinemia]. / Niekwasicza hiperglicynemia (NKH)

The author presents the possible pathomechanism of brain damage in NKH and the clinical course of severe - newborn and infants - atypical type of the disease. Characteristic for the newborn type EEG patterns has been discussed. Among the detailed presentation of diagnostic methods it was stressed that besides high concentration of glycine in blood and urine, the necessary parameters are high glycine ratio of cerebro-spinal fluid to blood serum, and the detailed differentiation with many transient and persistent hyperglycinemic states, the most important of them being organic acidurias which need the estimation of urinary organic acids. Possibilities of prenatal diagnostic and molecular identification are presented. All the treatment methods used up to now have been presented with special attention to natrium benzoate and dextrametorphan being used together.