Homozygosity for disease‐causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia

Abstract

AbstractNonketotic hyperglycinemia (NKH) is a relatively well‐characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system—GLDC, AMT, and GCSH—are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.3):c.602_603del (p.Lys201Thrfs*75) and the homozygous likely pathogenic variant in GLDC(NM_000170.2):c.2852C>A (p.Ser951Tyr) were both identified. Our patient demonstrates a novel combination of two homozygous disease‐causing variants impacting the glycine cleavage pathway at two different components, and elicits management‐ and genetic counseling‐related challenges for the family.