Glycine Encephalopathy via the GCSH Gene

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism caused by defects in the glycine cleavage multi-enzyme system (GCS) (Hamosh et al. 2002. PubMed ID: 20301531). Affected children have a large accumulation of glycine in the body resulting in various neurological symptoms. The majority of patients with glycine encephalopathy present in the neonatal period, while some patients can develop the disease in infancy. Regardless of age at onset, 20% of all affected children present with atypical, less severe phenotypes.

Affected neonates develop severe symptoms including progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have hypotonia, profound intellectual disability, developmental delay and intractable seizures. The atypical form has disease onset from late infancy to adulthood and the clinical outcomes range from milder features to rapidly progressive severe disease.

Glycine encephalopathy is an autosomal recessive disorder. GLDC, AMT and GCSH are the three known genes associated with the disease (Kure et al. 2006. PubMed ID: 16450403). These three genes encode the P, T and H proteins of the glycine cleavage multi-enzyme system (GCS), respectively.

Genetic defects of GCSH (5 coding exons) are an extremely rare cause of glycine encephalopathy. To date, only one conclusively pathogenic GCSH variant affecting splicing has been documented for a transient form of glycine encephalopathy (Human Gene Mutation Database).

Genetic defects of GCSH are an extremely rare cause of glycine encephalopathy. In a study of 69 families with glycine encephalopathy, no pathogenic GCSH variants were found (Kure et al. 2006. PubMed ID: 16450403).

This test provides full coverage of all coding exons of the GCSH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.