Nonketotic Hyperglycinemia

Clinical characteristics: Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. Based on ultimate outcome NKH is categorized into severe NKH (no developmental progress and intractable epilepsy) and attenuated NKH (variable developmental progress and treatable or no epilepsy). The majority of children with NKH have onset in the neonatal period manifest as progressive lethargy evolving into profound coma and marked hypotonia; 85% have severe NKH and 15% attenuated NKH. Those with onset between two weeks and three months typically present with hypotonia; 50% have severe NKH and 50% attenuated NKH. Those with onset after age three months have attenuated NKH. Severe versus attenuated NKH is consistent within families, but the degree of developmental progress in those with attenuated NKH can vary.

Diagnosis/testing: The diagnosis of NKH is established in a proband with elevated glycine in plasma and CSF, a compatible pattern on brain imaging, and either biallelic pathogenic variants in one of the genes encoding the protein subunits of the GCS identified on molecular genetic testing or deficient activity of the GCS (without deficiency of cofactors such as enzyme-bound lipoate or pyridoxal phosphate).

Management: Treatment of manifestations:

1. Severe NKH. No treatment is effective in changing the natural history of developmental delays, spasticity, and intractable epilepsy, but treatment with benzoate to lower glycine improves attentiveness and facilitates seizure management.

2. Attenuated NKH. Current treatment is reduction of plasma concentration of glycine by administration of sodium benzoate and blockade of overstimulated NMDA receptors.

Surveillance: In the first years of life: routine developmental assessments and neurologic evaluations. Monitoring for scoliosis and hip dysplasia in severely affected individuals; gastrointestinal issues; and pulmonary function particularly in children who develop recurrent respiratory infections.

Agents/circumstances to avoid: Valproate, which raises blood and CSF glycine concentrations and may increase seizure frequency; vigabatrin, which has resulted in rapid loss of function when used to treat seizures, particularly in those with attenuated NKH who have West syndrome.

Genetic counseling: NKH is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant); however, de novo pathogenic variants occur in approximately 1% of individuals with NKH. If both parents are heterozygous for one pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants in an NKH-related gene have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.