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  • Updated 11.29.2023
  • Released 05.14.2004
  • Expires For CME 11.29.2026

Nonketotic hyperglycinemia



Nonketotic hyperglycinemia is an autosomal recessive inborn error of glycine metabolism that commonly presents in the neonatal period with hypotonia, intractable seizures, apneic attacks, and a burst-suppression pattern on EEG. It is a genetically heterogenous condition caused by pathogenic variants in genes encoding the P and T enzyme subunits of the glycine cleavage system, leading to substantially increased plasma and cerebrospinal fluid glycine concentrations. Defects in lipoic acid or pyridoxal phosphate synthesis may lead to a similar phenotype, known as variant nonketotic hyperglycinemia, as both serve as cofactors for the glycine cleavage system. The rapid onset and often short clinical course may pose a diagnostic challenge in many cases. The authors review this disorder, with emphasis on the early diagnosis, management, and options for genetic testing.

Key points

• Nonketotic hyperglycinemia is a cause of neonatal encephalopathy and refractory seizures that may mimic hypoxic ischemic encephalopathy or sepsis. A high index of suspicion is required to recognize and diagnose this disorder.

• There are currently no treatments that alter the course of the disease; however, disease-specific interventions exist in the form of sodium benzoate and dextromethorphan, which serve to lower glycine levels and may improve symptoms.

• A diagnosis of nonketotic hyperglycinemia can be made by biochemical analysis looking at the CSF to plasma glycine ratio as well as molecular genetic testing of implicated genes. Diagnosis is essential for prognostication and genetic counseling.

• Late-onset variants present with a very broad range of neurologic signs and symptoms.

Historical note and terminology

“Idiopathic hyperglycinemia” or “hereditary hyperglycinemia” historically referred to a group of metabolic disorders associated with an elevation of glycine concentrations in body fluids. Soon after the first patient was described in 1961 (15), it became apparent that there were two different forms of hyperglycinemia, each representing a distinct condition. “Ketotic hyperglycinemia,” the originally described condition, was characterized by acute ketoacidosis, neutropenia, thrombocytopenia, and vomiting precipitated by infections or the intake of protein leading to coma and early death. These patients have subsequently been recognized as having organic acidemias such as methylmalonic and propionic acidemia. “Nonketotic hyperglycinemia,” or “glycine encephalopathy,” on the other hand, was characterized by lethargy, hypotonia, unresponsiveness, seizures, severe intellectual disability, and developmental delays without ketoacidosis, neutropenia, or thrombocytopenia. The biochemical basis of nonketotic hyperglycinemia was defined in the late 1960s. Gerritsen and colleagues demonstrated hypo-oxaluria and postulated a defect in glycine oxidase (22). A defect in glycine catabolism was subsequently demonstrated (05; 11; 48). By this time, it became apparent that many patients previously reported as having idiopathic/congenital hyperglycinemia with hyperglycinuria actually represented examples of nonketotic hyperglycinemia (32; 41; 10). The structure of the glycine cleavage system was elucidated in the 1970s with the description of the four enzyme subunits (28). The genes encoding for the T and P subunits, AMT and GLDC, respectively, were discovered in the following decades; AMT in 1994 (36) and GLDC in 2000 (49). Pathogenic variants in these genes were subsequently identified in patients with nonketotic hyperglycinemia. The prevalence of nonketotic hyperglycinemia is currently estimated to be 1 in 76,000, with the clinical phenotype now including a number of atypical nonketotic hyperglycinemia variants.

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