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Journal of Clinical Medicine May 2022Nonketotic hyperglycinemia (NKH) is a rare inborn error of glycine metabolism that is characterized by the accumulation of glycine in all tissues, especially in the... (Review)
Review
Nonketotic hyperglycinemia (NKH) is a rare inborn error of glycine metabolism that is characterized by the accumulation of glycine in all tissues, especially in the central nervous system (CNS). Based on clinical outcomes, NKH can be divided into two forms, i.e., severe and attenuated NKH. A poor prognosis, including no developmental progress and intractable epilepsy, is typical of severe NKH, whereas patients with the attenuated form present with varied symptoms and neurodevelopmental outcomes. So far, no causal treatment of NKH is known. Currently, the therapy is based on sodium benzoate and NMDA (The N-methyl-D-aspartate receptor) receptor site antagonists (dextromethorphan, ketamine). Different clinical outcomes of the therapy raise doubts about the effectiveness of the treatment. The purpose of this review is to summarize the therapeutic potential, challenges and effectiveness of different NKH therapies.
PubMed: 35683414
DOI: 10.3390/jcm11113027 -
Annals of Neurology Oct 2015Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic...
OBJECTIVE
Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed.
METHODS
We reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay.
RESULTS
Patients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P-protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors.
INTERPRETATION
Accurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity.
Topics: Animals; COS Cells; Chlorocebus aethiops; Female; Glycine; Humans; Hyperglycinemia, Nonketotic; Infant; Infant, Newborn; Male; Mutation, Missense; Predictive Value of Tests; Prognosis; Protein Structure, Secondary
PubMed: 26179960
DOI: 10.1002/ana.24485 -
The Egyptian Journal of Neurology,... 2022Inherited neurotransmitter diseases are a subset of rare neurometabolic disorders characterized by hereditary deficiencies in neurotransmitter metabolism or transport.... (Review)
Review
Inherited neurotransmitter diseases are a subset of rare neurometabolic disorders characterized by hereditary deficiencies in neurotransmitter metabolism or transport. Non-ketotic hyperglycinaemia (NKH), called glycine encephalopathy, is an autosomal recessive glycine metabolism disorder characterized by an abnormal accumulation of glycine in all bodily tissues, including the CNS. The SLC6A9 gene, which codes for the GLYT1 protein, a biochemical abnormality in the GCS, and dihydrolipoamide dehydrogenase enzymes, which function as a GCS component, are responsible for the neonatal form's symptoms, which include progressive encephalopathy, hypotonia, seizures, and occasionally mortality in the first few days of life. By changing the MAPK signalling pathways, glycine deprivation in the brain damages neurons by increasing NMDA receptor activation, increasing intracellular Ca levels, and leading to DNA breakage and cell death in the neuron region. In addition to the previously mentioned clinical diagnosis, NKH or GE would be determined by MLPA and 13C glycine breath tests. Pediatricians, surgeons, neurologists, and geneticists treat NKH and GE at the newborn period; there is no cure for either condition.
PubMed: 36415754
DOI: 10.1186/s41983-022-00567-6 -
Genetics in Medicine : Official Journal... Jan 2017The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH).
PURPOSE
The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH).
METHODS
Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database.
RESULTS
In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for 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.
CONCLUSION
The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.
Topics: Alleles; Aminomethyltransferase; Dihydrolipoamide Dehydrogenase; Exons; Female; Genetic Testing; Genotype; Glycine; Glycine Decarboxylase Complex; Glycine Dehydrogenase (Decarboxylating); Humans; Hyperglycinemia, Nonketotic; Introns; Male; Mutation, Missense
PubMed: 27362913
DOI: 10.1038/gim.2016.74 -
Orphanet Journal of Rare Diseases Dec 2022Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of...
BACKGROUND
Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction.
AIM
We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate.
METHODS
Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS).
RESULTS
Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable.
CONCLUSION
KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.
Topics: Infant; Humans; Hyperglycinemia, Nonketotic; Glycine; Diet, Ketogenic; Brain; Benzoates
PubMed: 36471344
DOI: 10.1186/s13023-022-02581-6 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2017Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they... (Review)
Review
Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications.
Topics: Humans; Iron-Sulfur Proteins; Mitochondria; Mitochondrial Diseases
PubMed: 28064324
DOI: 10.17712/nsj.2017.1.20160542 -
Journal of Clinical & Experimental... 2020Autoimmune diseases are one of the dreadful group of human diseases that have always been of keen interest to researchers. Due to complex and broad-spectrum nature,...
Autoimmune diseases are one of the dreadful group of human diseases that have always been of keen interest to researchers. Due to complex and broad-spectrum nature, scientists are not yet able to pinpoint the pathogenesis of and delineate effective therapy against this group of diseases. However, it is becoming clear that a decrease in number and function of T regulatory cells (Treg), an increase in autoreactive Th1/Th17 cells and associated immunomodulation and inflammation participate in the pathogenesis of many autoimmune diseases. Cinnamon ( or ) is a widely used natural spice and flavoring ingredient and its metabolite sodium benzoate (NaB) is a food-additive and FDA-approved drug against nonketotic hyperglycinemia (NKH) and urea cycle disorders (UCD). Recent studies indicate that cinnamon either in powder or extract form and NaB are capable of modulating different autoimmune pathways as well as protecting animals from different autoimmune disorders. Here, we have made an honest attempt to delineate such pieces of evidence with available anti-autoimmune mechanisms and analyze whether cinnamon supplements could be used to control the fury of autoimmune disorders.
PubMed: 33294884
DOI: 10.33140/jcei.05.06.01 -
Journal of Inherited Metabolic Disease Jul 2022Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected...
Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age-related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross-sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d-serine and l-serine levels were stereoselectively determined in seven NKH patients and compared to 29 age-matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age-adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age-adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d-serine was more reduced than l-serine, with a decreased d/l-serine ratio, indicating a specific impact on d-serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l-serine, d-serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one-carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.
Topics: Amino Acids; Cross-Sectional Studies; Glycine; Humans; Hyperglycinemia, Nonketotic; Infant, Newborn; Serine; Threonine
PubMed: 35357708
DOI: 10.1002/jimd.12500