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 + Mutations

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT

– Published 30 June 2016
– PubMed Source
– Full Study Source

Salient Points:

    • In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations.
    • 80% of patients had mutations in GLDC.
    • Missense mutations were noted in 52% of all GLDC alleles, most private.
    • The position and frequency of the breakpoint for Intragenic copy-number variations (CNVs) correlated with intron size and presence of Alu elements.
    • Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT.
    • Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects.
    • Based on genotype, 15% of subjects had an attenuated phenotype
    • The 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

– Published 01 August 2016
– PubMed Source

Salient Points:

  • Essentially an example of Variant NKH – where there is no genetic mutation in the GLDC, AMT or GCSH genes (the genes that make up the glycine cleavage system). Instead a mutation is found in a glycine transporter.
  • Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly)
  • This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function
  • In a mouse model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia
  • This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.

Outcome

Prediction of long-term outcome in glycine encephalopathy: a clinical survey

– Published 15 October 2011
– PubMed Source
– Full Study Source

Salient Points:

  • 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

– Published Dec 2019
– biorxiv.org Source

Salient Points:

  • 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

– Published 10 August 2015
– PubMed Source

Salient Points:

  • 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.

Medication

Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia.

– Published March 2016
– Pubmed Source

Salient Points:

  • 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.
  • There was also 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

– Published Jan 2006
– Pubmed Source

Salient Points:

  • Case study of two patients with NKH
  • Both were given Vigabatrin (also known as Sodium Valporate) to disastrous effect.
  • Vigabatrin inhibits the GABA transaminase and elevates the GABA concentration in the brain
  • 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.

 

Other Treatment

The Efficacy of Vagus Nerve Stimulation in Intractable Epilepsy Associated With Nonketotic Hyperglycinemia in Two Children

– Published March 2010
– Pubmed Source

Salient Points:

  • 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

– Published Sept 2019
– Neurology Times Source

Salient Points:

    • 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
    • His neurologic examination was significant for axial (through trunk) and appendicular (in limbs) hypotonia in all limbs. He was nonverbal, and not interactive but tracked his mother and father with his eyes
    • It was unclear whether the decreased responsiveness was a side effect of his recent change in antiepileptic medication, worsening encephalopathy from his underlying metabolic condition, or frequent seizures (more than 20 a day)
    • He was referred to a ketogenic diet clinic and 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

Case Studies

Nonketotic hyperglycinemia case series

– Published Oct 2015
– PubMed Source
Salient Points:

      • 3 children diagnosed with NKH.
      • Discusses intial 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

– Published March 2013
– Research Gate Source

Salient Points:

      • 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

– Published Nov 2006
– NetpubMed Source

Salient Points:

      • 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

https://pubmed.ncbi.nlm.nih.gov/15077252/

Late Onset Nonketotic Hyperglycinemia

Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gen

– Published Feb 2011
– Deep Dyve Source

Salient Points:

      • A 9-year-old boy diagnosed with elevated glycine levels
      • GLDC missense mutation confirmed as (c.605C>T; p.Ala202Val)- the first recorded.
      • This is the first report of late-onset NKH with a confirmed GLDC genetic cause.
      • Presented with learning disabilities and occasional involuntary movements (such as irregular migrating contractions) and twisting/writhing, particularly during illnesses with fevers.

Late-onset Nonketotic Hyperglycinemia – A Case Report

– Published Feb 2011
– Research Gate Source

Salient Points:

      • 66-year-old woman who developed mental deterioration in her school days, and progressive gait disturbance, motor speech issues (dysarthria) and abnormal slowness of movement (bradykinesia) in her 40s.
      • She was short-statured and high-arched palate was observed.
      • Neurological examination revealed dementia, abnormal eye movement, progressive stiffness and contraction in the lower limbs and overactive or overresponsive reflexes (spastic paraparesis with hyperreflexia), bilateral Babinski signs, cerebellar ataxia and painful urination (dysuria).
      • Brain MRI showed marked underdevelopment of the corpus callosum with dilatation of lateral ventricles and cerebral sulci and significant cerebellar atrophy.
      • Amino acid analyses showed significant elevation of glycine without ketosis in serum, cerebrospinal fluid, and urine, which led to the diagnosis

Brain Structures and MRIs

Sequential MR Imaging Changes in Nonketotic Hyperglycinemia

– Published Jan 2006
– American Journal of Neuroradiology Source

Salient Points:

      • Case study of a initial and follow-up MR imaging in a boy with NKH until death at 17 months
      • Interesting case study if you’re interested in exactly what NKH does to the brain structure
      • At 3 Weeks showed increased signal intensity with restricted diffusion of fast myelinating areas
      • There appears to be a high grade of axonal integrity at 3 months, which was subsequently lost as seen upon follow-up at 17 months
      • Pathologic findings in NKH consist mainly of white matter spongiosis with microcysts, with diameters in the order of 15–20 μm, between the myelin sheaths. It is therefore likely that these microcysts are the cause of diffusion restriction in NKH as suggested elsewhere
      • The disappearance of diffusion restriction at 17 months suggests coalescence of microvacuoles to larger cysts, and the decrease of fractional anisotropy suggests axonal degeneration.

Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging

– Published Sept 2017
– Paediatric Neuroradiology Source

Salient Points:

      • 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.
      • One patient had cerebellar vermian hypoplasia and supratentorial hydrocephalus.
      • Another patient had deep grey matter nuclei were affected in one patient.

Abnormalities of the Brain in Nonketotic Hyperglycinemia: MR Manifestations

– Published Sept 1988
– American Journal of Neuroradiology Source

Salient Points:

      • 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.

Magnetic Resonance Findings in an Infant with Nonketotic Hyperglycinemia

– Published Sept 2011
– The Radiological Society Republic of China Source

Salient Points:

      • Case study of a child with NKH with a missense mutation in the GLDC gene (c.2281 G>A ,p.Gly761Arg).
      • MRI at 70 days found a thin corpus collasum and abnormally increased signal intensities
        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./li>
      • 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.

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.

CBD + NKH

– Published Nov 2019
– Royal Holloway University via Wiley.com  Source

Salient Points:

      • This study looked at how CBD (cannabidiol) may be helpful in control of epilepsy, particularly in a condition called Dravet Syndrome.
      • They used a simple organism Dictyostelium (sometimes called a slime mould but it’s an amoeba) to screen for proteins that are needed for CBD to have a functional effect (with cell proliferation as a read-out).
      • This screen identified a ‘CBD-sensitivity gene’ which looked a lot like the GCS-H protein, one of the components of the glycine cleavage system.
      • A number of different experiments confirmed that this protein really does seems to have a similar biochemical function eg, the knockout Dictyostelium has higher glycine and altered folates
      • Overall, in the Dictyostelium model it seemed 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).

Conclusion:

      • It’s unclear whether CBD is beneficial in NKH.