Non ketotic hyperglycinemia


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Non ketotic hyperglycinemia

  2. 2. INTRODUCTION:  It is an inborn error of glycine degradation due to which large quantities of glycine accumulates in all body tissues.  This results from absence of one of the components of glycine cleavage system.  Hence it is also known as Glycine encephalopathy  It is an inherited disease, characterized by mental retardation.  After PKU , NKH is the second most common amino acid disorder.  NKH should not be confused with other metabolic disorders which produce elevated glycine level.
  3. 3. CLASSIFICATION OF THE DISEASE :  NKH can be distinguished by the age of onset and by the severity of symptoms.  All forms of NKH represent neurological symptoms. 1. Neonatal form :-  The form presenting in first few days of life with lethargy, myoclonic jerks, progressing to apnea and often to death. 2. Infantile form:-  This form presents seizures and various mental retardation after symptom- free interval and normal development for upto 6 months.
  4. 4. 3. Mild- episodic form:-  This form presents in childhood with mild mental retardation , episodes of delirium, chorea and vertical gaze palsy during febrile illness. 4. Late- onset form :-  In this form patients present childhood with progressive spatic diplegia and optic atrophy but intellectual function is preserved.
  5. 5. ROLE OF GLYCINE IN OUR BODY:  Glycine is not essential to the human diet as it is biosynthesized from serine, which in turn is derived from 3-Phosphoglycerate.  It is an inhibitory neurotransmitter in the CNS , when glycine receptors are activated chloride enters the neuron , causing an inhibitory post synaptic potential.  This effect is responsible for the apnea and hiccuping seen in the early stage of these disease.  Glycine is a required co-agonist along with glutamate for NMDA receptors.  In the spinal cord, it is excitatory in the cortex at the NMDA receptor channel complex.  Excessive stimulation at this site explains the intractable seizures and brain damage in the disorder.
  6. 6. BODY :-  Glycine is catalyzed by glycine synthase (also known as glycine cleavage enzyme). This conversion is reversible:  CO2 + NH4 + + N5,N10-Methylene tetrahydrofolate + NADH + H+ → Glycine + tetrahydrofolate + NAD+  Glycine is degraded in the body in 3 different ways but the predominant pathway for glycine catabolism involves the glycine cleavage system.
  7. 7. THE GLYCINE CLEAVAGE SYSTEM :-  The glycine cleavage system is widely distributed in animals, plants and bacteria.  In animals, the system is loosely bound to the mitochondrial inner membrane.  It consists of four proteins- Three enzymes and a carrier protein. 1. The enzymes are:- I. P-protein or glycine dehydrogenase. II. T-protein or aminomethyl transferase. III. L-protein or dihydrolipoamide dehydrogenase. 2. The carrier protein :-  H-protein , that carries amino methyl intermediate.
  9. 9. GENETICS :  NKH is an inherited autosomal disease.  Both parents are carriers of the gene.  It is caused by mutation in 1 of the 2 genes, which contribute to the formation of GCS.  GCS is made up of four protein subunits, each is encoded by a separate gene.  Defects in 3 of these 4 subunits have been linked to NKH.  Mutation cause a change in the genetic sequence, thus enzyme no longer works properly.  Mutation in GLDC subunit results in about 70-75% of NKH(9p24-
  10. 10. DIAGNOSIS OF THE DISEASE:  NKH when clinically suspected, the following diagnostic testing is recommended: 1. FIRST TIER TESTING: a) QUANTATIVE AMINOACID ANALYSIS: Consists of biochemical screening including measurement of glycine levels in both plasma and CSF. b) URINE ORGANIC ACID ANALYSIS: It should also be performed to exclude ketotic hyperglycinemia. 2. SECOND TIER TESTING: a) MOLECULAR GENETIC TESTING: It consists of molecular genetic testing of the constituent genes GLDC, AMT, and GCSH. 3. THIRD TIER TESTING: a) ENZYME TESTING: In patients with an unresolved suspicion
  11. 11. TREATMENT OF THE DISEASE:  No effective treatment for severe NKH exists.  Current treatment of NKH consists of reduction of plama concentration glycine through treating with benzoate and blocking NMDA receptor site. 1. SODIUM BENZOATE:  Oral administration of sodium benzoate at doses of 250-750 mg/kg/day can reduce the plasma glycine concentration into the normal range, but not the CSF glycine concentration.  In mildly affected patients, it may even improve behaviour.  In patients with severe phenotype, even the high doses administrated early in the disease do not affect the natural progression.
  12. 12. 2. NMDA RECEPTOR SITE ANTAGONISTS:  Antagonism of a presumably overstimulated NMDA receptor channel complex with use of dextromethorphan in severely affected children.  Dextromethorphan doses commonly range from 15 mg/kg/day, but individual variability is substantial. 3. SEIZURE CONTROL:  Drugs like benzodiazepines are benefial to newborns and infants in control of the seizures.  Phenobarbital is useful in treating seizures in older affected children.  Felbamate is also been successful in treating difficult to treat seizures. 4. OTHERS:  Gastrostomy tube placement is considered early in the treatment of patients with swallowing dysfunction associated with severe disease.
  13. 13. DISEASE: 1. CARRIER DETECTION: • It is possible once the mutation have been identified in the family. • Carrier testing using biochemical methodologies is not reliable. 2. PRENATAL TESTING: a) MOLECULAR GENETIC TESTING: For identification of disease causing mutation. b) BIOCHEMICAL TESTING: It is the measurement of amniotic fluid glycine concentration. c) ENZYMATIC TESTING: It is possible by assay of GCS enzyme activity. d) PREIMPLANTATION GENETIC DIAGNAOSIS (PGD): The disease causing mutations have been identified by this method.
  14. 14. RECENT RESEARCH : • Paracetamol prevents hyperglycinemia in vervet monkeys treated with valproate :- • Valproate administration increases the level of the inhibitory transmitter, glycine , in the urine and plasma of patients and experimental animals. • The relationship between the hyperglycinemic effect of valproate and induced pyroglutamic aciduria via paracetamol in the vervet monkey were investigated. • The first aim was to determined if valproate could induce hyperglycinemia in the monkey. • The second aim was to increase glutamic acid (oxoproline) urine excretion using paracetamol as a pre-treatment and to assess whether valproate has an influence on the γ-glutamyl cycle.
  15. 15.  RESULT :  Hyperglycinemia was induced in healthy vervet monkeys when treated with a single oral dose of 50 mg/kg valproate.  An acute dose of 50 mg/kg paracetamol increased oxoproline in the urine.  Pre-treatment with paracetamol opposed the hyperglycinemic effect of valproate.  The CSF:serum glycine ratio in a nonketotic monkey increased markedly after paracetamol treatment and remained high following valproate treatment.  CONCLUSION:  The γ-glutamyl cycle does indeed play a role in the hyperglycinemic effect of valproate treatment.  Thus paracetamol may have value in preventing and/or treating valproate-induced NKH.
  16. 16. REFERENCE:         (Paracetamol prevents hyperglycinemia in vervet monkeys treated with valproate: Viljoen J, Bergh JJ, Mienie LJ, Kotze HF, Terre'Blanche G.Metab Brain Dis. 2012 Sep;27(3):327-35. doi: 10.1007/s11011012- 9285-y. Epub 2012 Feb 17.PMID: 22350964 [PubMed - indexed for MEDLINE])