IllnessHyperglycinemia, non-ketotic; differential diagnosis

NGS +

[[Sanger]]

Non-ketotic hyperglycemia (NKH) is a rare metabolic disorder caused by defects in the breakdown of gylcine leading to its accumulation. The classic form ranges from severe to mild symptoms, with the former typically occurring in the first few days of life with reduced muscle tone, lethargy, seizures, coma and apnea. As the disease progresses, developmental delay becomes evident and seizures worsen. Attenuated classic NKH may occur in the neonatal period or later in infancy and developmental delays are highly variable. Hyperactivity and behavioral problems sometimes occur. The clinical picture of NKH variants varies depending on the mutated gene and the specific mutation. The differential diagnosis of NKH is very complex and includes cofactor deficiency and impaired regulation/inhibition of the "glycine cleavage enzyme system" as well as glycine transport defects (see additional genes). The DNA diagnostic yield is about 95%, provided that the function of the glycine cleavage enzyme system is proven. Inconspicuous genetic findings do not imply a definite exclusion of the clinical suspected diagnoses.

References: https://www.ncbi.nlm.nih.gov/books/NBK1357/

https://www.ncbi.nlm.nih.gov/books/NBK92946/

https://www.ncbi.nlm.nih.gov/books/NBK465013/

• Alias: Glyzin-Enzephalopathie; Hyperglycinämie, nicht-ketotische; Glycin-Enzephalopathie
• Allelic: Anemia, sideroblastic, 3, pyridoxine-refractory (GLRX5)
• DD: Epilepsy, pyridoxine-dependent (ALDH7A1)
• DD: Isovaleric acidemia (IVD)
• DD: Mental retardation, XL 3 [methylmalonic acidemia + homocysteinemia, cblX type]
• DD: Methylmalonic aciduria, mut(0) type (MMUT)
• DD: Multiple mitochondrial dysfunctions syndrome 1 (NFU1)
• DD: Multiple mitochondrial dysfunctions syndrome 3 (IBA57)
• DD: Propionicacidemia (PCCA, PCCB)
• DD: Pyridoxamine 5'-phosphate oxidase deficiency (PNPO)
• Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (LIPT2)
• Epilepsy, early-onset, vitamin B6-dependent (PLPBP)
• Glycine encephalopathy (AMT, GLDC)
• Glycine encephalopathy with normal serum glycine (SLC6A9)
• Glycine encephalopathy? (GCSH)
• Hyperglycinemia, lactic acidosis + seizures (LIAS)
• Hyperglycinuria (SLC36A2)
• Hyperglycinuria, benign (SLC6A18)
• Iminoglycinuria, digenic (SLC36A2, SLC6A19/SLC6A20)
• Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (BOLA3)
• Spasticity, childhood-onset, with hyperglycinemia (GLRX5)