Question:
A newborn has seizures, continuous hiccups, and developmental delay. EEG demonstrates a burst-suppression pattern. Which metabolic disorder best explains these findings?
A newborn has seizures, continuous hiccups, and developmental delay. EEG demonstrates a burst-suppression pattern. Which metabolic disorder best explains these findings?
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Diagnosis of NKH is confirmed by analyzing paired CSF and plasma samples. An elevated CSF-to-plasma glycine ratio (typically $>$ 0.08) is highly specific for the disease.
Updated On: Sep 3, 2026
- Holocarboxylase deficiency
- Argininosuccinic aciduria
- Isovaleric acidemia
- Non-ketotic hyperglycinemia
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The Correct Option is D
Solution and Explanation
Concept:
The clinical presentation features a neonate with severe early-onset epileptic encephalopathy (seizures, burst-suppression EEG) and a highly specific, unique clinical sign: continuous, intractable hiccups.
This specific constellation of symptoms strongly points to a neurotransmitter/amino acid metabolic defect.
Explanation:
• Non-ketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the mitochondrial glycine cleavage system.
• This defect leads to a massive accumulation of the amino acid glycine in all body tissues, most notably within the central nervous system (CSF).
• Glycine acts as a dual neurotransmitter: it is an inhibitory neurotransmitter in the spinal cord and brainstem, but functions as a mandatory excitatory co-agonist at NMDA (N-methyl-D-aspartate) glutamate receptors in the cerebral cortex.
• The massive excess of glycine overstimulates NMDA receptors, causing severe neurotoxicity and early-onset, intractable seizures. The EEG classically reflects severe encephalopathy with a burst-suppression pattern.
• A pathognomonic clinical feature of the brainstem inhibitory effect of excess glycine is the presence of severe, continuous, and intractable hiccups in the neonatal period.
• Options (A), (B), and (C) are organic acidemias or urea cycle defects. They typically present with severe metabolic derangements like hyperammonemia, profound anion-gap metabolic acidosis, and unique odors, rather than the classic continuous hiccups and burst-suppression seen in primary NKH.
Final answer:
Non-ketotic hyperglycinemia is uniquely characterized by neonatal encephalopathy, continuous hiccups, and a burst-suppression EEG pattern.
The clinical presentation features a neonate with severe early-onset epileptic encephalopathy (seizures, burst-suppression EEG) and a highly specific, unique clinical sign: continuous, intractable hiccups.
This specific constellation of symptoms strongly points to a neurotransmitter/amino acid metabolic defect.
Explanation:
• Non-ketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the mitochondrial glycine cleavage system.
• This defect leads to a massive accumulation of the amino acid glycine in all body tissues, most notably within the central nervous system (CSF).
• Glycine acts as a dual neurotransmitter: it is an inhibitory neurotransmitter in the spinal cord and brainstem, but functions as a mandatory excitatory co-agonist at NMDA (N-methyl-D-aspartate) glutamate receptors in the cerebral cortex.
• The massive excess of glycine overstimulates NMDA receptors, causing severe neurotoxicity and early-onset, intractable seizures. The EEG classically reflects severe encephalopathy with a burst-suppression pattern.
• A pathognomonic clinical feature of the brainstem inhibitory effect of excess glycine is the presence of severe, continuous, and intractable hiccups in the neonatal period.
• Options (A), (B), and (C) are organic acidemias or urea cycle defects. They typically present with severe metabolic derangements like hyperammonemia, profound anion-gap metabolic acidosis, and unique odors, rather than the classic continuous hiccups and burst-suppression seen in primary NKH.
Final answer:
Non-ketotic hyperglycinemia is uniquely characterized by neonatal encephalopathy, continuous hiccups, and a burst-suppression EEG pattern.
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