What are the current treatment recommendations for Non-Ketotic Hyperglycinemia (NKH)?

Current Treatment Recommendations for Non-Ketotic Hyperglycinemia (NKH)

Initiate combination therapy with sodium benzoate (500-750 mg/kg/day) plus dextromethorphan (starting at low doses and titrating up to 5-35 mg/kg/day) as early as possible—ideally from the neonatal period—to reduce glycine levels and block NMDA receptor overstimulation, which improves seizure control and developmental outcomes in patients with attenuated NKH. 1, 2

Understanding NKH and Treatment Rationale

Non-ketotic hyperglycinemia is a rare inborn error of glycine metabolism causing toxic accumulation of glycine in the central nervous system, leading to:

• Excessive NMDA receptor stimulation 3, 4
• Muscular hypotonia, seizures, apnea, and lethargy 3
• Poor neurodevelopmental prognosis, particularly in severe forms 5

The current therapeutic approach targets two mechanisms: reducing glycine levels and blocking NMDA receptor activation. 1, 5

First-Line Pharmacologic Treatment

Sodium Benzoate

• Dosing: 500-750 mg/kg/day divided into multiple doses 1, 4
• Mechanism: Conjugates with glycine to form hippuric acid, which is renally excreted 1
• Efficacy: Normalizes plasma glycine levels but only partially reduces cerebrospinal fluid glycine concentrations 3, 1
• Monitoring: Check plasma and CSF glycine levels to ensure adequate reduction 1

Dextromethorphan (NMDA Receptor Antagonist)

• Initial dosing: Start at low doses (0.25 mg/kg/day) and titrate based on response 3
• Therapeutic range: 3.5-35 mg/kg/day, with significant interpatient variability in metabolism 1
• Mechanism: Blocks the NMDA receptor cation channel to prevent glycine-mediated excitotoxicity 4
• Efficacy: Potent anticonvulsant effect in some patients; improves EEG activity, eye contact, and developmental milestones 3, 1

Critical caveat: Dextromethorphan shows remarkable interpatient variability in both metabolism and clinical response—some patients achieve seizure freedom while others show minimal benefit. 1

Treatment Timing and Prognosis

Early vs. Late Treatment

The most important prognostic factor is timing of treatment initiation:

• Siblings with attenuated NKH treated from the neonatal period achieve significantly better developmental outcomes compared to those diagnosed and treated later 2
• Early treatment (from birth) results in higher developmental quotients, earlier milestone achievement, and reduced seizure burden 2
• In 3 of 4 sibling pairs studied, the child treated from birth had no seizures while the later-treated sibling developed seizure disorders 2

Disease Severity Considerations

• Attenuated NKH: Patients with residual enzyme activity respond better to therapy and can achieve meaningful developmental progress 2
• Severe NKH: Treatment is less uniformly effective; outcomes include persistent developmental delay and intractable seizures in some cases 1, 5
• One patient in a case series died at 3 months from intractable seizures despite aggressive treatment 1

Adjunctive Seizure Management

When seizures persist despite benzoate and dextromethorphan:

• Add conventional antiepileptic drugs (benzodiazepines, phenobarbital) as needed 3
• Consider alternative NMDA receptor antagonists (ketamine) in refractory cases 5
• Monitor EEG regularly to assess epileptiform activity even in clinically seizure-free patients 3

Monitoring Protocol

Laboratory Monitoring

• Plasma glycine levels: Target normalization (103-125 μmol/L) with benzoate therapy 3
• CSF glycine levels: Expect partial but not complete reduction (may remain 42-47 μmol/L despite normal plasma levels) 3
• Frequency: Serial measurements to guide dose adjustments 1

Clinical Monitoring

• Serial EEG to assess epileptiform activity 3
• Brain MRI to evaluate myelination (delayed myelination is common) 4
• Standardized neurodevelopmental assessments at regular intervals 2
• Monitor for nystagmus resolution and eye contact improvement as early treatment markers 3

Expected Outcomes with Optimal Treatment

Best-Case Scenario (Attenuated NKH, Early Treatment)

• Seizure freedom or significant seizure reduction 2
• Developmental quotient of approximately 60 at 12 months 4
• Moderate to severe developmental delay but with continued progress 1
• Better improvement in socialization and daily living skills compared to motor and communication domains 2

Realistic Expectations

• No causal treatment exists; therapy is symptomatic and supportive 5
• Even with optimal treatment, most patients remain moderately to severely developmentally delayed 1
• Intractable seizures may persist in some patients despite aggressive therapy 1

Common Pitfalls to Avoid

1. Delayed treatment initiation: Every day counts—start therapy immediately upon diagnosis, even before confirmatory testing is complete 2
2. Inadequate benzoate dosing: Use high-dose benzoate (750 mg/kg/day) to maximize glycine reduction 1, 4
3. Starting dextromethorphan at excessively high doses: Begin low (0.25 mg/kg/day) and titrate to avoid toxicity while assessing individual response 3
4. Stopping treatment prematurely: Continue therapy long-term even if initial response seems limited 1
5. Failing to monitor CSF glycine: Plasma normalization does not guarantee adequate CNS glycine reduction 3