NONKETOTIC HYPERGLYCINEMIA (NKH)
Non-ketotic hyperglycinemia (NKH) is a rare, genetic, metabolic disorder caused by a defect in the GLDC or AMT gene code which affects the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of glycine in the body's tissues and fluids. NKH typically presents in the first week of life with low muscle tone, lethargy, seizures, coma, and apnea requiring ventilator support. NKH is caused by genetic variants (mutations) in the genes that encode the components of the glycine cleavage enzyme system. The incidence of NKH is predicted to be approximately 1:76,000. NKH can occur in individuals of any ancestry. There are approximately 500 children with NKH worldwide.
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Glycine encephalopathy, formerly referred to as nonketotic hyperglycinemia, is a heterogeneous disorder associated with the insufficient activity of various components of the mitochondrial glycine cleavage system. The enzyme system for cleavage of glycine is composed of four protein components: P protein, a pyridoxal phosphate-dependent glycine decarboxylase; H protein, a lipoic acid-containing protein; T protein, a tetrahydrofolate-requiring enzyme; and L protein, a lipoamide dehydrogenase. Nonketotic hyperglycinemia may be caused by a defect in any one of these enzymes. It is an autosomal- recessive disorder with several reported phenotypes, including the classic severe neonatal form, an infantile variant, a mild- episodic childhood variant, a late-onset form, and a benign reversible form.
Most patients described to date have the neonatal and most severe phenotype, likely because it is the most distinctive phenotype. These patients present shortly after birth with lethargy, encephalopathy, hypotonia, myoclonic jerks, and apnea. EEG generally reveals a burst-suppression pattern. Those who survive the neonatal period generally develop intractable seizures and profound mental retardation. Patients with the infantile form have seizures and variable cognitive impairment after a short period of apparently normal development. In the mild, episodic form, patients typically present some time after infancy with mild psychomotor retardation and may manifest episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, children present with progressive spastic diplegia and optic atrophy. They generally do not have seizures, and intellectual function is preserved. Diagnosis is best made by documenting an increased cerebrospinal fluid to plasma glycine ratio. At present, confirmation of the diagnosis requires enzyme analysis in the liver or transformed lymphoblasts. Treatment with dextromethorphan and sodium benzoate has led to a variable improvement in seizure control and behavioral problems in some patients.
The accumulation of glycine in the brain and neuronal tissue is responsible for many of the clinical signs and symptoms of NKH. Glycine is both an excitatory and inhibitory neurotransmitter and has an excitatory effect when bound to the N-methyl-D-aspartate (NMDA) receptor. The excitatory actions cause seizures, while the inhibitory actions cause hypotonia and lethargy. Classical NKH presents most frequently in the neonatal period (less than one week of age) and less often in the infantile stage (over one week of age). Regardless of the age of presentation, disease severity can be severe or attenuated. Neonatal NKH presents with hypotonia, lethargy, myoclonic jerks, and apnea. Without intervention and ventilation, this presentation is generally fatal. Survivors have a profound neurological deficit and intractable seizures. Infantile NKH is hallmarked by hypotonia, seizures, and developmental delay. There are descriptions of mild to severe, atypical forms of NKH that present from late infancy to adulthood.38 A burst suppression pattern on electroencephalogram is commonly seen in NKH.39 Recent studies have shown a predictable relationship between prognosis/response to medical intervention and genotype-phenotype, and central nervous system malformations.