JENIFER RASEETHA

M.Sc. PART-I

PSBT-201

NON KETOTIC

HYPERGLYCINEMIA

(NKH)

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.

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.

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.

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.

DEGRADATION OF GLYCINE IN OUR

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.

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.

GLYCINE CLEVAGE SYSTEM AND THE REACTION :

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-

135kb), whereas AMT subunit (3q21.1-

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

of NKH consists of measurement of the GCS enzyme activity

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.

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.

PREVENTIVE MEASURES FOR THE

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.

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.

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.

REFERENCE:

www.ghr.nlm.nih.gov/condition/glycine-encephalopathy www.nkh-network.org www.ncbi.nlm.nih.gov www.omim.org www.ajnr.org www.children.webmd.com www.jcn.sagepub.com

http://www.ncbi.nlm.nih.gov (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])