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  • Updated 09.15.2022
  • Released 05.14.2004
  • Expires For CME 09.15.2025

Nonketotic hyperglycinemia



Nonketotic hyperglycinemia is an autosomal recessive inborn error of metabolism that commonly presents in the neonatal period with hypotonia, intractable seizures, apneic attacks, and a burst-suppression pattern EEG. Plasma and cerebrospinal fluid glycine concentrations are substantially increased as a result of a deficiency in liver and brain glycine cleavage enzyme activity. Mutations in genes encoding the P and T glycine cleavage enzyme system subunits account for the vast majority of cases, but there is emerging evidence of defects in other pathways, notably lipoic acid synthesis, which can result in defects in the glycine cleavage enzyme system and other enzymes. The rapid onset and often short clinical course mean that many cases may remain undiagnosed. The authors review this disorder, with emphasis on the early diagnosis, management, and options for genetic testing.

Key points

• Nonketotic hyperglycinemia is an important cause of neonatal encephalopathy.

• No effective treatment is available, and diagnosis is essential for prognostication and genetic counseling.

• A diagnosis of nonketotic hyperglycinemia can only be confirmed by enzyme or DNA analysis.

• 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 (16), 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, and severe mental retardation 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 (25). A defect in glycine catabolism was subsequently demonstrated (06; 12; 55). By this time, it became apparent that many patients previously reported as having idiopathic/congenital hyperglycinemia with hyperglycinuria actually represented examples of nonketotic hyperglycinemia (39; 47; 11). The structure of the glycine cleavage system was elucidated in the 1970s (33) and the molecular and genetic basis subsequently defined. Over 150 patients have been described in the literature and the clinical phenotype is now known to include a number of atypical nonketotic hyperglycinemia variants.

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