Existing Research

These are published, peer reviewed studies that hold some significance to NKH.

Unfortunately, because we don’t work in the medical field we only have access to abstracts. However, sometimes even the abstract is enough to take to a consultant meeting to discuss possibilities.

Where possible we have tried to include the Research Gate source, as free accounts are available.

Genetics + Outcome

  • The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT (June 2016)
    • PubMed Source, Full Study Source
    • First large scale study (578 families, 410 unique mutations, 246 novel mutations). 80% of patients had mutations in GLDC, frequency of NKH is estimated at 1:76,000.
  • Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans (August 2016)
    • PubMed Source
    • First demonstration that mutation of the glycine transporter can be associated with NKH in humans. Example of Variant NKH
  • Prediction of long-term outcome in glycine encephalopathy: a clinical survey (October 2011)
    • PubMed Source, Full Study Source
    • Compared 45 NKH children, based on symptoms and outcome. Based on when they presented, the symptoms they had and their outcome, a scale was proposed for severity diagnosis.
  • Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity (Dec 2019)
    • biorxiv.org Source
    • Plasma glycine/CSF glycine is not predictive of clinical severity, NKH is typically characterized as either severe or attenuated type, They developed a multi-parametric mutation scale applicable to all but 4 of 255 missense NKH mutations across the GLDC gene
    • They identified fifty-eight unique symptoms of NKH that were identified and classified into eleven categories: cognitive disorders, seizures, muscle/movement control, brain malformations/injury, respiration, hormonal disorders, hearing, eyesight, immune system and digestion
    • Of those eleven, four major domains emerged:cognitive disorders (81%), seizures (73%), muscle and movement dysfunctions (35%), and brain malformations (32%). They encompassed 46 of 58 (79% of) symptoms. (View symptoms 1 + 2)
    • The four domains were given a severity scale (View)
    • They used the mutations paired with the symptoms taken from the literature to build a model to predict severity outcome
    • It is very different from the previous model, splitting attenuated and severe (rather than severe – no GCS activity, and then four categories of attenuated, based on GCS activity).
  • Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia (August 2015)
    • PubMed Source
    • Compared 124 NKH children, based on symptoms and outcome. Based on when NKH presented, symptoms, medication required, glycine biochemistry, the mutations and the Developmental Quotient score, a scale was proposed for outcome and severity diagnosis.
  • Glycine cleavage system H protein is essential for embryonic viability, implying additional function beyond the glycine cleavage system (2021)>
    • Source
    • Explains why most kids have mutations in AMT or GLDC, as having a mutation in the GCSH gene looks to be fatal.

Treatment + Medication

  • Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia (March 2016)
    • Pubmed Source
    • Four sibling pairs who had attenuated NKH were recruited into the study. It was found that the younger sibling, who was treated with SB and DXM much earlier than their older sibling hit more developmental milestones and had a higher developmental quotient and had a difference in seizure frequency.The adaptive behavior subdomains of socialization and daily living skills improved more than motor skills and communication.
  • Vigabatrin Caused Rapidly Progressive Deterioration in Two Cases With Early Myoclonic Encephalopathy Associated With Nonketotic Hyperglycinemia (Jan 2006)
    • Pubmed Source
    • Case study of two patients with NKH. Both were given Vigabatrin (also known as Sodium Valporate) to disastrous effect. Vigabatrin was given for the treatment of seizures (50mg/kg/day). Rapidly progressive deterioration was noticed after a few days. Acute encephalopathy associated with sleepiness and respiratory failure developed. Vigabatrin produced acute encephalopathy. Once stopped, one patient recovered. The other did not.
  • CBD + NKH (Nov 2019)
    • Royal Holloway University via Wiley.com  Source
    • This study looked at how CBD (cannabidiol) may be helpful in control of epilepsy, particularly in a condition called Dravet Syndrome. The screen identified a ‘CBD-sensitivity gene’ which looked a lot like the GCS-H protein, one of the components of the glycine cleavage system. It seems that CBD alters the amino acid and one-carbon metabolism and that this effect needed GCSH function (though it’s not been tested whether it also needs GLDC or AMT function so it’s hard to predict what this means for NKH). Mostly, it’s unclear whether CBD is beneficial in NKH.
  • Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: Therapeutic implications for neurodegenerative disorders
    • Full Source
    • Mentions after oral administration of cinnamon, they detected sodium benzoate in the brain
  • Can cinnamon spice down autoimmune diseases? (Nov 2020)
    • Full Source
    • Mentions that Sodium Benzoate is a metabolite of Cinnamon, and that cinnamon is FDA approved for NKH other Urea Cycles. Does not go into whether cinnamon is actually helpful for those with NKH
  • The Efficacy of Vagus Nerve Stimulation in Intractable Epilepsy Associated With Nonketotic Hyperglycinemia in Two Children (March 2010)
    • Pubmed Source
    • Two infants suffered from intractable generalized convulsive seizures, despite being on sodium benzoate, dextromethophan, and multiple anticonvulsants (meaning, the seizures were uncontrolled). Both underwent Vagus nerve stimulation – which involves delivering electrical impulses to the vagus nerve. Their intractable generalized seizures were 75% reduced in frequency, the numbers of multiple anticonvulsants were reduced, and the quality of life significantly improved.The efficacy in seizure reduction persists for at least 3 years in both children.
  • Using the Ketogenic Diet to Treat Intractable Epilepsy in a Case of Glycine Encephalopathy (Sept 2019)
    • Neurology Times Source
    • 11 year old boy with NKH was having seizures, which were uncontrolled by dextromethorphan, lamotrigine, clobazam, levetiracetam, and phenobarbital.
    • These drugs made him more lethargic without significant improvement in seizure frequency (more than 20 a day). He started on the ketogenic diet on a 2:1 ratio and titrated by 0.5 daily to a goal of 3:1. Plasma glycine levels decreased following diet initiation and an improvement in both the amino acid profile and seizure frequency were documented. The patient showed a dramatic increase in alertness and wakefulness compared to the day of admission. No seizures were seen after the first day with measurable ketones and for the first 5 months of diet therapy. Since then, the patient has had a greater than 50% seizure reduction
  • The impact of Glycine Reduction
    Therapies on Brain Glycine Levels in Nonketotic Hyperglycinemia (Nov 2021)
    • Source
    • This is an overview poster (!) for a metabolic conference, BUT it has a good overview of where we are currently. Which is, High-dose benzoate and the Keto Diet with low-dose sodium benzoate therapy both normalized plasma glycine levels and improved but did not normalize CSF nor brain glycine levels which remained at 4x the average of normal. KD with low-dose sodium benzoate therapy demonstrates equivalence to standard high-dose sodium benzoate therapy and may be superior at stabilizing plasma glycine levels. The clinical impact of KD remains uncertain and requires further investigation. KD may not improve seizure control. CSF serine levels tended to lower on ketogenic diet. Links to the studies on the poster.

Brain Structures and MRIs

  • Sequential MR Imaging Changes in Nonketotic Hyperglycinemia (Jan 2006)
    • American Journal of Neuroradiology Source
    • Case study of a initial and follow-up MR imaging in a boy with NKH until death at 17 months, showing changes in brain structure over time
  • Magnetic Resonance Findings in an Infant with Nonketotic Hyperglycinemia (Sept 2011)
    • The Radiological Society Republic of China Source
    • Case Study of one child, MRI at 70 days found a thin corpus collasum and abnormally increased signal intensities, and on T2-weighted images were noted symmetrically in the centra semiovales, coronae radiatae, genua, posterior limbs of the internal capsules, cerebellar peduncles, and pyramid tracts. Widespread spongiosis of myelinated white matter is the main histopathological feature of classical NKH of neonates, involving tracts undergoing active myelination during the neonatal period. The ascending and descending tracts in the brain stem, posterior limbs of the internal capsules, the cerebellar peduncles, optic tracts, and optic chiasm are the mostly affected. Electromicroscopic findings of NKH show intramyelinic microvacuoles formation and splitting of myelin lamellae.
  • Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging (Sept 2017)
    • – Paediatric Neuroradiology Source
    • Seven patients with confirmed diagnosis of NKH (8 days–2 years) underwent brain MRI. All seven had different degrees of damage. The affected white matter regions were not predominantly following the expected areas of myelination according to patients’ age. Not an ideal study, as the mutations were not shared amongst patients and only one MRI was done (rather than a study of each patient across time). Did show nonspecific brain atrophy in some children, including Corpus callosum atrophy.
  • Abnormalities of the Brain in Nonketotic Hyperglycinemia: MR Manifestations (Sept 1988)
    • American Journal of Neuroradiology Source
      • MR imaging in seven patients (4 days to 38 months old) with NKH showed age-related findings of progressive atrophy and delayed myelination. Parenchymal volume loss was found as early as 4 days after birth and increased in severity with increasing age to 27 months. Both supratentorial and infratentorial volume loss were present in the most severely affected patients. The corpus callosum was abnormally thin in all patients. Decreased or absent myelination within supratentorial white-matter tracts was detected in all four patients 10 months of age or older. Myelination of the brainstem and cerebellum progressed normally.No correlation was found between the degree of volume loss or abnormality of myelination demonstrated by MR and the concentration of glycine in the CSF or plasma.

Case Studies

  • Nonketotic hyperglycinemia case series (Oct 2015)
    • PubMed Source
    • 3 children diagnosed with NKH. Discusses initial diagnosis. Care was withdrawn within the first week for two children. Third child was given dextromethorphan and ketogenic diet, and at age three had a global developmental delay and poorly controlled epilepsy.
  • Neonatal Nonketotic Hyperglycinemia: A Case Study and Review of Management for the Advanced Practice Nurse (March 2013)
    • Research Gate Source
    • >Baby S. presented with typical neonatal onset NKH. Rest of paper discusses Nonketotic Hyperglycinemia overview, Pathophysiology, Diagnosis, Symptoms and Treatments
  • Adult Nonketotic Hyperglycinemia (NKH) Crisis Presenting as Severe Chorea and Encephalopathy (Nov 2006)
    • NetpubMed Source
    • Adult, previously undiagnosed presented with NKH (attenuated). Given valporate (not ideal). Developed episodes of encephalopathy and chorea provoked by a fever and protein loading. After treatment with sodium benzoate and dextromethorphan, the patient’s encephalopathy resolved and her chorea improved
  • Genotypic and phenotypic features in Turkish patients with classic nonketotic hyperglycinemia (2021)
    • Source
    • Overview of ten Turkish patients who were diagnosed with classic NKH in a single center from 2013 to 2019
  • Nonketotic Hyperglycinemia: Two Case Reports and Review
        • Source
        • Looks at the progression of two neonates with classic NKH
    Natural history of nonketotic hyperglycinemia in 65 patients
    • Source
    • Data for 65 patients (36 boys, 29 girls) were collected from 58 families. Median age of death for boys was 2.6 years vs <1 month for girls. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living ≥3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. Overall, there appears to be a significant gender difference in mortality and developmental progress.
    • Nonketotic Hyperglycinemia of Infants in Taiwan
      • Source
      • A look at 12 cases reported in Taiwan between 2000 – 2013.
    • Nonketotic hyperglycinemia case series (2015)
      • Source
      • A case studying following three cases who presented with neonatal hiccups and who were later diagnosed with (NKH)

NKH Models

  • Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non-ketotic hyperglycinemia (2020)
    • Source
    • Looked at glycine metabolism in tissues in mice, and what happened with treatment (SB and Cinnmate, and what happened when rescued (ie, GLDC function was restored). Showed the toxicity of other amino acids, not just glycine.
  • Glycine decarboxylase deficiency causes
    neural tube defects and features of non-ketotic hyperglycinemia in mice
    • Source
    • Shows that a mutation in the GLDC gene also causes Neural Tube Defects. They show a reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of
      NKHs. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates. Formate treatment normalizes the folate profile, restores embryonic growth and prevents
      NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism.
  • Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice (2019)
    • Source
    • Ventriculomegaly (where the ventricles – fluid-filled spaces in the brain – are larger than usual) is associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans with NKH. Showed mutations in the glycine cleavage system causes a toxic level of glycine AND a diminished supply of glycine-derived 1-carbon units to the folate cycle. It turns out its the inadequate 1-carbon supply, as opposed to excess glycine, is the cause of ventriculomegaly. Maternal supplementation with formate in mice prevented both ventriculomegaly, as assessed at prenatal stages, and postnatal development of hydrocephalus in Gldc-deficient mice. Furthermore, ventriculomegaly was rescued by genetic ablation of 5,10-methylene tetrahydrofolate reductase (Mthfr), which results in retention of 1-carbon groups in the folate cycle at the expense of transfer to the methylation cycle.

Other Resources

These are semi-interesting posts/articles that have some relation to glycine/NKH or NMDA receptors. These are not published or peer reviewed. Please ask more questions, or delve into the resources of each article before believing what you see here.

Glycine + Mitochondria

– Published Feb 2017
– Josh Mitteldorf on Science Blog Source

Salient Points:

      • As we age we have less mitochondria (the power factories of a cell – they power everything in the body), and they work less efficiently.
      • When you add a glycine culture to the cells, the mitochondria become like new.
      • Glycine does not stop the detrimental epigenetic changes in mitochondria that come with age, but one of the changes results in a glycine shortage in the mitochondria. Therefore, glycine supplementation can help at an intermediate stage.
      • Mthionine is the “start codon”; every gene begins with a methionine, and a severe shortage of methionine can slow down all protein synthesis
      • Glycine plays a role in breaking down methionine in the liver, and if the glycine level is jacked up super-high, it is (theoretically) possible to force this reaction so far as to create a methionine shortage.
      • Exercise is the best thing we know for promoting replication of mitochondria. This has been substantiated in humans and in rodents
      • PGC-1a is a circulating hormone that promotes mitochondria creation. PGC-1a does not survive digestion. PQQ is a small molecule, more bioavailable when ingested, that increases circulating PGC-1a. The two-step process has been documented in rodents (!), where oral PQQ leads to more mitochondria.