Nonketotic hyperglycinemia (NKH)
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A newborn presents with severe hypotonia, apnea, and intractable seizures within the first days of life. CSF glycine is markedly elevated with an elevated CSF:plasma glycine ratio.
AR; glycine cleavage system genes
- GLDC (~70%), AMT (~20%), GCSH
- Severe neonatal encephalopathy
- Hypotonia, apnea, hiccups
- Intractable seizures
- Elevated CSF:plasma glycine ratio (>0.08)
- Burst suppression on EEG
- Most severe form: neonatal, lethal
- Attenuated forms exist
- Not on standard newborn screening (glycine is not part of routine acylcarnitine/amino-acid profiles flagged for NKH)
- Elevated plasma and CSF glycine with paired CSF:plasma glycine ratio >0.08 (the key biochemical hallmark)
- Confirm with molecular testing of glycine cleavage system genes (GLDC, AMT, GCSH); exclude secondary causes (e.g., valproate, ketosis)
- Limited options; sodium benzoate, dextromethorphan, ketogenic diet (variable efficacy)
"NKH is BaD": treatment is sodium Benzoate and Dextromethorphan (an NMDA antagonist that prevents glycine from binding its receptor).
Glycine cleavage system has 3 proteins: P protein (GLDC, ~70% of mutations), T protein (AMT, ~20%), and H protein (GCSH, <1%). Glycine builds up in the CSF, causing symptoms.