Nonketotic Hyperglycinemia in a Neonate

Hyperglycinemia represents a group of
disorders characterized by elevated concentrations
of glycine in body fluids. Two
types exist, the ketotic and non ketotic. In
the ketotic type, the most striking feature is
ketoacidosis, which begins early in life and
in which hyperglycinemia is secondarily
associated with organic acidemias.
Nonketotic hyperglycinemia (NKH) is a
disorder of glycine metabolism due to a
molecular defect in the glycine cleavage
system (GCS)(1,2). Though NKH is a well
documented entity, to the best of our
knowledge there are no reports of this disorder
from India, the result of inadequate
diagnostic facilities. We report a case of
NKH in a neonate, with a review of its recent
therapeutics.
Case Report
A male baby weighing 2490 g was born
at term, after an uneventful antenatal period,
to a 25-year-old fifth gravida mother.
He was the product of a non-consanguineous
marriage. There was history of early
neonatal deaths of previous 3 male term infants.
They had no history of birth asphyxia
From the Neonatal Division, Department of
Pediatrics, Maulana Azad Medical College,
New Delhi 110 002
Reprint requests: Dr. S. Ramji, Professor,
Department of Pediatrics, Maulana Azad
Medical College, New Delhi 110 002.
Manuscript Received: April 21,1997;
Initial review completed: June 2,1997;
Revision Accepted: ]uly 21,1997
and followed an identical course of lethargy
and floppiness soon after birth, with inability
to suck on the breast, followed by
seizures, progressive sensorial deterioration
and death. One female sibling, 8 years
old, is alive and apparently healthy.
This neonate presented at 11 hours of
age with lethargy, weak cry and inability to
feed. On examination the baby was normothermic,
pink with a heart rate of 136/min,
respiratory rate of 48/min and normal peripheral
perfusion. There were no gross
congenital anomalies. The sensorium was
depressed with minimal spontaneous eye
opening and limb movements. Response to
painful stimuli was decreased. Neonatal reflexes
were sluggish. There were no focal
neurological deficits. In view of the clinical
presentation and similar history in earlier
siblings, possibility of an inborn error of
metabolism was kept and the baby accordingly
investigated.
Hematological investigations revealed:
TLC 8400 /cumm (polymorphonuclears
70%, lymphocytes 30%, immature to total
neutrophil ratio 0.07) and (μESR 1 mm fall
in 1st hour. Initial and subsequent blood
sugars ranged between 45 to 90 mg/dl.
Arterial blood gas analysis yielded pH
7.34, bicarbonate 18.2 mmol/L, base excess
3.4 mmol/L, paO2 90 mmHg, and paCO2
32 mmHg. Blood ammonia was 56 (μg/dl
(normal : 90-150 mg/dl) and serum creatinine
0.5 mg/dl. Ultrasound of cranium was
within normal limits.
The baby was initially started on expressed
breastmilk by nasogastric tube,
which he tolerated well. By 36 hours of life,
the baby's sensorium was completely
obtunded and respiration became shallow.
At this juncture, enteral feeding was discontinued
and the child provided intravenous
fluids and oxygen by hood. At 70
hours of age, the baby had recurrent
myoclonic seizures, which did not respond
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INDIAN PEDIATRICS VOLUME 35-MARCH 1998
to phenobarbitone and phenytoin. At this
stage, the baby was provided assisted mechanical
ventilation. Inspite of adequate
supportive management, the baby died on
the fifth day of life.
The results of gas chromatographicmass
spectroscopy analysis of urine and
blood for organic and aminoacids revealed
markedly elevated levels of glycine. Glycine
levels in blood were 8.2 mg/dl (normal
: 3.1 ± 0.8 mg/dl) and in urine 18.4
umol/mg creatinine (normal : 2.3 ± 1.4
umol/mg creatinine). The other organic
and aminoacids were within normal limits.
Discussion
NKH is a relatively frequent metabolic
cause of overwhelming illness in infancy(
l). Over 150 cases have been reported^).
The exact prevalence is not known,
though it is estimated to be 1 in 250,000. It
is common in northern Finland, where the
prevalence is 1 in 12,000 (1) and is transmitted
as an autosomal recessive trait. In the
present family, only the male children
manifested clinically, suggesting that a sexlinked
mode of inheritance may also exist.
NKH classically presents as a life
threatening metabolic encephalopathy in
the neonatal period. Most infants appear
normal at birth and remain asymptomatic
for a brief period, seldom longer than 48
hours(2). They present with rapidly progressive
neurological symptoms such as
lethargy, poor feeding, seizures, high
pitched cry and generalized hypotonia.
Hiccups are frequently observed. Most
patients lapse into coma and die within a
few weeks. Survivors usually have severe
psychomotor retardation, spasticity, microcephaly
and uncontrolled seizures(l,2). The
present case had a clinical presentation
consistent with the classical type of NKH
and the history in the earlier siblings also
suggests that they too probably had the
same disorder. During the first few weeks
of life, a characteristic electroencephalogram
(EEG) pattern is seen with
bursts of large amplitude sharp waves,
arising periodically from a hypoactive
background. The so called burst-suppression
pattern changes by the end of the first
month to hypsarrhythmia(l,2). Cortical
atrophy and delayed or deficient rnyelination
may be seen on CT or MRI scan(4).
The late onset or infantile type of NKH
has a variable onset from "infancy to adolescence,
the patient usually remaining
asymptomatic in the neonatal period(2).
The presentations include seizures, delayed
development or mental retardation,
spinocerebeller degeneration and optic atrophy(
5,6). Transient NKH is also reported,
which has a variable prognosis(7).
Diagnosis is based on the findings of
hyperglycinemia and hyperglycinuria in
the absence of an organic acid disorder.
Absence of ketoacidosis and exclusion of
organic acidemias is crucial. During the investigation
of neonatal seizures due to a
suspected inborn error of metabolism,
absence of common biochemical abnormalities
evaluated (hyperammonemia, lactic
acidosis, ketoacidosis) should suggest the
possibility of classical NKH. Glycine levels
in cerebrospinal fluid (CSF) are also elevated,
the ratio of CSF and plasma glycine
characteristically being greater than 0.09,
whereas under normal circumstances and
in ketotic hyperglycinemia, it is below
0.04(1,2). CSF examination was not done in
the present case as neither an infective condition
nor this specific metabolic disorder
was suspected at presentation. Liver biopsy
can be performed for the enzymatic diagnosis
of NKH, as GCS is expressed in the
liver(3). GCS is also induced in B lymphocytes
in the peripheral blood by Epstein
Barr virus (EBV) and enzymatic assay can
be performed. This method is useful for
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CASE REPORTS
differentiating NKH from ketotic hyperglycinemia
and for detection of carriers(8).
Prenatal diagnosis is possible by chorionic
villus sampling to estimate GCS activity between
8th-12th week of gestation(9).
The pathophysiologic effects of hyperglycinemia
are attributed to the inhibitory
property of glycine at post synaptic strychnine
sensitive receptors particularly in the
spinal cord and brain stem, and over stimulation
of the excitatory gluta-minergic NMethyl-
D-aspartate (NMDA) receptors,
particularly in the forebrain(lO). Measures
to lower the glycine concentration in NKH
patients have included protein restriction,
synthetic diet devoid of glycine and it's
precursor serine, promotion of renal excretion
by benzoate, administration of ursodeoxycholic
acid, strychnine and benzodiazepines.
The response has generally remained
unsatisfactory(l,2).
Recently, NMDA receptor antagonists
have been used with modest success. Oral
administration of ketamine (8 mg/kg/day,
in four divided doses)(ll), tryptophan
(100-150 mg/kg/day)(12) and dextromethorphan
(5-35 mg/kg/day in three to
four divided gradually increased doses) in
combination with benzoate (500-750 mg/
kg/day)(10,13) have brought about a partial
improvement of neurological symptoms
and EEG findings. Though aggressive
management employing assisted ventilation,
exchange transfusions and peritoneal
dialysis along with the aforementioned
therapeutic approaches has decreased the
mortality, the long term morbidity due to
NKH has remained unacceptably poor.
Acknowledgment
We wish to acknowledge Sapporo City
Institute of Public Health, Japan for carrying
out the GC-MS analysis for organic and
amino-acids.
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