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Unfortunately there is not yet a cure for Nonketotic Hyperglycinemia

However, there are medications which some children respond to.

Medication to Avoid

These medications alter glycine levels and can be fatal for NKH children

  • Divalproex Sodium (also known as Depokate)
  • Sodium Valporate (also known as Ofril, Epilim, Episenta, Epival or Convulex)
  • Valproic Acid (also known as Ofril Long or Ofril Retard)
  • Vigabatrin (also known as Sabril)
  • Phenytoin (also known as Dilantin)

Glycine Management

Please note this information does not replace advice from your doctor. Please please please talk to your metabolic consultant/gp/pediatrician if you have any concerns or questions.

Sodium Benzoate

Sodium Benzoate is a sodium salt of benzoic acid, a type of carboxylic acid (such as amino acids which make up proteins, and acetic acids which are part of vinegar and used in metabolism). It’s often used as a food preservative and in NKH it’s used to reduce glycine levels in blood to normal levels(1) by binding to glycine in blood, converting it to hippuric acid(2) which can then be urinated out of the body(3). It also reduces (though does not normalise) the glycine in the cerebrospinal fluid, fluid around the brain and spine(4).

However, not all patients respond to sodium benzoate. Those that do have improved arousal(4), decreased or eliminated seizures(5) and allow some developmental progress(4).

What does it do:

  • Reduce glycine levels in the blood to normal levels
  • Reduce the glycine in the cereborspinal fluid
  • Improve arousal
  • Decreases/eliminates seizures
  • Allow some development progress

Available in:

  • Tablet form
    • Can be mixed with water. This is ideal for older children – as a Sodium Benzoate dose is based on weight, several tablets can be mixed in to 5ml of water. This avoids the volume issue of syrup.
  • Syrup
    • Lasts 30 days.
    • As the syrup is already mixed to a specific strength, as the child’s weight goes up so does the volume of Sodium Benzoate.
  • Powder form
    • The powdered form has a shelf life of a year, and is mixed with water. Once mixed, it has a shelf life of 14 days.

Medication Considerations:

  • Doses are defined by weight. As the weight goes up, so will the dose.
  • Blood/Glycine levels should be checked regularly. When taking bloods to measure glycine levels, blood should be taken 1-2 hours after giving the Sodium Benzoate dose because it will give the lowest level of glycine in the body. This will help avoid Sodium Benzoate toxicity
  • Because Sodium Benzoate also pulls out L-carnitine from plasma, carnitine levels should be checked regularly. Calcium and Potassium levels should also be checked regularly to rule out Sodium Benzoate toxicity.
  • Do not take with Vitamin C. In combination with Ascorbic acid (vitamin C, E300), sodium benzoate and potassium benzoate may form benzene, a known carcinogen (8). Benzene is associated with causing DNA strand breaks, and high levels of exposure have been associated with acute myeloid leukemia (AML), aplastic anemia, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) (9)

Side effects

  • Can be Painful to ingest. Pair with a PPI (Proton pump inhibitors reduce the amount of acid made by your stomach) stomach protectant like ranitidine or omeprazole.
  • Powder form can cause mouth burns.
  • Sodium benzoate can increase the likelyhood of Hyperammonemia, a metabolic issue caused by an excess of ammonia in the blood. L-carnitine can lower blood ammonia to prevent this(6)(7). Ensure that when taking Sodium Benzoate, that both the carnitine and calcium levels are checked regularly.

Sodium Benzoate Toxicity

  • When there is less glycine to bind with there is a risk of Sodium Benzoate Toxicity.
  • The body uses potassium and calcium to regulate sodium levels, so if potassium levels are low it’s likely Sodium Benzoate levels are high, and at risk of toxicity.

Anecdotal effects noted by NKH parents:

  • May cause dental issues to teeth enamel of taken orally
  • Tastes nasty
  • If possible, split SB across 4 – 6 doses a day
  • May cause bowel issues
  • Some children can outgrow the benefits of Sodium Benzoate (anywhere from 4 years onwards) where the negatives outweigh the positives. Others will have an increase in seizures if weaned.
  • If painful to ingest (sidenote: lowering doses may make no difference, even small amounts can be painful). If you skip a dose and there are no symptoms, it’s likely to be Sodium Benzoate.
  • If painful to ingest, may cause upsetting behaviours (tantrums, biting etc)
  • If painful to ingest, may be given with with milk and slippery elm powder (very thick, and lines the stomach. Though this may prevent absorption)
  • When at risk of Sodium Benzoate toxicity, there can be elevated levels in urine (as the body is not breaking it down). This may be shown as whiteness/crystals in urine and/or around the genitals.
  • Some pharmacies may add fillers (such as citric acid as a preservative). These fillers may cause pain, so please ask your pharmacist how they make it up.
  • Because pharmacies use different fillers, some parents find Sodium Benzoate to be less effective towards the end of their expiry period.

Other notes

  • Not all children respond to SB, and it may not effect their blood/glycine levels.
  • Cinammon is processed into Sodium Benzoate in the liver. (10)

Sources

  • 1. https://www.ncbi.nlm.nih.gov/pubmed/9580775
  • 2. https://en.wikipedia.org/wiki/Hippuric_acid
  • 3. http://link.springer.com/article/10.1007/BF01805533
  • 4. https://www.ncbi.nlm.nih.gov/pubmed/9580775
  • 5. https://www.ncbi.nlm.nih.gov/pubmed/3706242
  • 6. https://www.ncbi.nlm.nih.gov/pubmed/3593373
  • 7. https://www.ncbi.nlm.nih.gov/pubmed/1863104
  • 8. https://en.wikipedia.org/wiki/Sodium_benzoate
  • 9. http://www.annualreviews.org/doi/abs/10.1146/annurev.publhealth.012809.103646
  • 10. https://www.rush.edu/news/press-releases/cinnamon-may-help-halt-parkinsons-disease-progression

Please note this information does not replace advice from your doctor. Please please please talk to your metabolic consultant/gp/pediatrician if you have any concerns or questions.

 

Dextromethorphan

Dextromethorphan (DXM or DM) is a cough suppressant, and is a common ingredient in more than 125 cough and cold remedies. It works by decreasing activity in the part of the brain that causes coughing.

In NKH, it’s used as an unlicensed neurotransmitter blocker – it blocks the same receptors that glycine uses.

How it works

Once taken orally, DXM is rapidly absorbed through the gastrointestinal tract (the path through the esophagus, stomach, small and large intestine) where it enters the bloodstream and crosses the blood-brain barrier.

In the brain, glycine stimulates the NMDA receptors. To open, the NMDA receptor requires glycine and glutamate (another neurotransmitter). DXM occupies the glutamate binding site, preventing the NMDA receptor from activating. It also works as an ion channel blocker – if the NMDA receptor is open, it will block the channel, preventing molecules from entering or leaving the cell.

Because DXM blocks the glutamate binding site, it’s called an glutamate antagonist of the NMDA receptor – it inhibits the actions of the NMDA receptor.

What this means for NKH

Since glycine stimulates NMDA receptors, inhibitors (like Dextromethorphan) have a significant impact on seizure control and improving neurological function. They can even modify abnormal EEG waves of the brain.(10)

Early treatment with Dextromethorphan, in addition to Sodium Benzoate, has been shown in some NKH patients to:

– Reduce seizures and normalise EEG (2) (3) (8)
– Improve alertness and social interest (2) (8)
– Improve muscle tone (3)
– Prevent death of brain cells (4)
– Can be a potent anticonvulsant in some but not all patients (5)

Unfortunately, NKH studies have shown that the results of treatment with DXM and sodium benzoate are not effective for every child. There is a variability in outcome. (5)

It’s also been shown that in patients with severe NKH, treatment with DXM and sodium benzoate does not improve long term neurodevelopmental outcome, even when started in the early neonatal period (6) (7) (9)

Available in:

  • Natural form: white to slightly yellow, odourless crystalline powder
  • Liquid-filled capsule
  • Chewable tablet
  • Dissolving strip
  • A solution (liquid)
  • An extended-release (long-lasting) suspension (liquid)
  • Lozenge to take by mouth

Medication Considerations:

  • DXM is not shown to be a sedative or have addictive properties when taken at the recommended doses. (1)
  • Doses are defined by weight. As the weight goes up, so will the dose.
  • Dextromethorphan doses range from 5 to 15mg/kg/day but individual variability is substantial (6)
  • Should be used in combination with Sodium Benzoate
  • When temporary stopped during infections with fever, temporary neurological deterioration can occur (12)

Side effects:

  • DXM can have relatively strong side effects, especially after long term and regular use. The side effects are different from child to child and seem to be caused by substantial difference in the body’s metabolism of DXM into dextrophan. (5)
  • Easily apparent and nontoxic side effects include increased drowsiness, with a strong desire for sleep, or sleeping for unusually long periods and random movements; both respond rapidly to decreasing the dose or increasing the dosing interval (5)
  • Irritability, involuntary movements, refusal to eat, troubled sleeping and breathing suppression. (4)

Dextromethorphan toxicity:

  • Overdose of DM causes increased sleepiness and while awake, more movement (6)
  • Cimetidine slows the metabolism of dextromethorphan and should not be used in dextromethorphan slow metabolisers as it may cause toxicity (6)
  • If necessary, blood concentration can be monitored (6)

Brands

  • Delsym. Manufacturer: Reckitt Benckiser
  • Benylin DM by McNeil
  • Triaminic by Novartis
  • Romilar by Bayer
  • Vicks Formula 44 by Procter & Gamble
  • Robitussin by Wyeth

Note: Some brands (like Benylin) have alcohol listed in the ingredients.

Anecdotal effects noted by NKH parents:

  • Typically Delsym is used. Its a cough syrup, and comes in grape and orange. Where possible, get the orange flavour. It will be easier to draw up.
  • DXM and CBD oil are metabolized through the same liver enzyme (CYP2D6), so be sure to get a baseline dextromethorphan plasma level before starting CBD oil. Ideally you should decrease DXM slowly as you increase CBD oil. You should also alternate weeks that you increase CBD and decrease DXM.
  • Some DXM syrups aren’t compatible with the keto diet, and so the powdered form is used in it’s place. Check with the pharmacist to ensure the powdered form doesn’t contain a filler like lactose.
  • It’s also possible with syrups to have the pharmacy make up the active ingredient dxm and purified water.
  • Please be aware of sodium poisoning. Some DMX medications (like delsym) contains 5mg of sodium per 5ml – as the child’s dose increases with weight this could become an issue.
  • At higher doses, DXM can cause problems with coordination and balance. If you’re concerned, toxicity levels can be checked with a blood test.
  • DXM is a weak opiate, and at a higher dose than recommended can cause a dissociative hallucenogenic state (teens call this “Robotripping”, derived from the common cough syrup brand Robitussin)
  • Some parents have found that weaning too quickly can produce withdrawal symptoms. Ideally step down 0.1ml at least every 7 days, ideally every two weeks.
  • Some children do better at a lower dose, rather than the recommended higher dose.

Other notes:

  • Other NMDA receptor site antagonists are ketamine and felbamate. Ketamine has a similar effect to DXM and can improve neurological function, particularly in swallowing and sucking (10)

Sources:

  1.  Bem J.L., Peck R. (1992). “Dextromethorphan. An overview of safety issues”
  2.  National Organisation for Rare Disorders
  3.  Journal of Inherited Metabolic Diseases (2005) “Benzoate treatment and the glycine index in NKH”
  4.  Connecticut Department of Public Health (2005) “Genetics newborn screening program”
  5.  Various (1998) “Long-term use of high-dose benzoate and dextromethorphan for the treatment of NKH”
  6.  Van Hove J. and others (2013) “Glycine Encephalopathy”
  7.  Various (2014) “Physicians guide to the diagnosis, treatment and follow-up of inherited metabolic diseases”
  8.  Shaw V. (2014) “Clinical Paediatric Dietetics”
  9. Van Hove J. and others (2016) “Neurodevelopment outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated Nonketotic Hyperglycinemia”
  10. Danaei N., Nooripour S. (2015) “An infant with Nonketotic Hyperglycinemia: a case report
  11. Hennermann J. (2006) “Clinical variability in glycine encephalopathy”
  12. Van der Knaap M., Valk J. (2006) “Magnetic resonance of myelination and myelin disorders”
  13. Kenner C., Wright Lott J. (2007) “Comprehensive neonatal care: An interdisciplinary approach”

Seizure Management

Please note this information does not replace advice from your doctor. Please please please talk to your Neurologist/GP/Pediatrician if you have any concerns or questions.

Prednisone/prednisolone

Prednisone is a steroid used to treat infantile spasms: a severe form of epilepsy that appears in the first year of life and is associated with severe neurodevelopmental impairment.

Typically given when an eeg shows hypsarrhythmia, which is a disorganized, chaotic pattern of brain waves that occurs in children with infantile spasms (IS) but not in other seizure disorders.

EEG with normal activity

EEG with Hypsarrhythmia

What it does:
Available in:
Medication Considerations:
Side effects:
Toxicity:
Anecdotal effects noted by NKH parents:
Other notes:
Sources:

 

Phenobarb
– through a subcut (could possibly be infected) – its a horrid syrupy medication.
– Orally is horrid and causes vomitting if not given on a full stomach.

Supplements
– Folinic Acid
– L-Carnitine

Stomach Protectants
– Baby Gaviscon (Reflux)
– Raditine
– Omeprazole

Seizure Management
– Keppra