It is an inborn error of glycine degradation due to which
large quantities of glycine accumulates in all body
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
After PKU , NKH is the second most common amino
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
It is an inhibitory neurotransmitter in
the CNS , when glycine receptors are
activated chloride enters the neuron
, causing an inhibitory post synaptic
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
In the spinal cord, it is excitatory in
the cortex at the NMDA receptor
Excessive stimulation at this site
explains the intractable seizures and
brain damage in the disorder.
Glycine is catalyzed by glycine synthase (also known
as glycine cleavage enzyme). This conversion is
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
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.
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
GCS is made up of four protein
subunits, each is encoded by a separate
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
Mutation in GLDC subunit results in
about 70-75% of NKH(9p24-
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
3. THIRD TIER TESTING:
a) ENZYME TESTING: In patients with an unresolved suspicion
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
2. NMDA RECEPTOR SITE ANTAGONISTS:
Antagonism of a presumably overstimulated NMDA receptor
channel complex with use of dextromethorphan in severely
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
Felbamate is also been successful in treating difficult to treat
Gastrostomy tube placement is considered early in the
treatment of patients with swallowing dysfunction associated
with severe disease.
1. CARRIER DETECTION:
• It is possible once the mutation have been identified in the
• 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
d) PREIMPLANTATION GENETIC DIAGNAOSIS (PGD): The
disease causing mutations have been identified by this
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
• 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
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
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.
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