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Brain neurotransmitters in glycine encephalopathy.

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corollary, opioid agonists 19-1 11 and adrenergic antagonists 112, 131 both seem to be therapeutically useful
in U S , and we might add that the effect of bromocriptine in decreasing the number of PMS in RI.S patients
is certainly modest compared to that of the opioids
[lo, 111. The relative contribution and sites of central
nervous system action of these neurotransmitter systems might be further elucidated by a positron emission tomographic scan study with receptor-specific
ligands 1151.
This work was funded by a grant from the Sandoz Corporation.
We thank Ms LuAnn Thorne for ryping this manuscript and Donna
Smith, Mitch Rubinstein, and Ramone Ramos for their technical
assistance.
References
1. Walters A, I-iening W, Chokroverry S. Frequent occurrence of
myoclonus while awake and at rest, body rocking .ind marching
in place in a subpopulation of patients with restless legs syndrome. Acta Neurol Scand 1988;77:418-42 1
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sleep (nocturnal myoclonus): relation to sleep disorders. Ann
Neurol 1980;8:4 16-42 1
3. Boghen D, Peyronnard JM. Myoclonus in familial restless legs
syndrome. Arch Neurol 1976;33:368-370
4. Akpinar S. Restless legs syndrome treatment with dopaminergic
drugs. Clin Neuropharmacol 1987;10:69-79
5 . Montplaisirj, Godbout R, Poirier G, Bedard MA. Restless legs
syndrome and periodic movements in sleep: pathophysiology
and treatment with L-dopa. Clin Neuropharniacol 1986;9:456-
Brain Neurotransmitters
in Glycine Encephalopathy
Stephen J. Kish, PhD,"?$ Lori M. Dixon, BSc,"
W. McIntyre Burnham, PhD,f T h o m a s L. Perry, MD!
Lawrence Becker, MD,' Jerome C h e n g , BSc,t
Li-Jan Chang, MSc," and Michelle Rebbetoy, BSc'
We measured neurotransmitter markers in autopsied
brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of
glycine in the frontal cortex of GE patients were three
times higher than control values. No abnormalities were
observed for concentrations of gamma-aminobutyric
acid (and related receptors), other major neurotransmitter amino compounds, or activities of cholineacetyltransferase and aspartate aminotransferase. Mean acetylcholinesterase activity was significantly elevated by
46%. As experimental data suggest, glycine markedly
potentiates the action of the excitatory neurotransmitter
glutamic acid. To the extent that the brain seizures in
patients with GE can be explained by this mechanism,
pharmacotherapy with excitatory amino acid antagonists may represent a new approach to the treatment of
GE.
Kish SJ, D i x o n LM, B u r n h a m WM, Perry TL,
Becker L, Cheng J, C h a n g L-J, Rebbetoy M.
Brain neurotransmitters in glycine encephalopatny.
Ann Neurol 1988;24:358-461
463
6. Guilleminaulr C, ed. Sleeping and waking disorders: indications
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dyskinesia: a review of the literature. J Clin Psychopharmacol
1983;3:343--350
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three patients with restless legs syndrome. Am J Psychiatry
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syndrome related to the endogenous opiates? In: Fahn S, Marsden CD, Van Woert MH, eds. Myoclonus: advances in neurology, Vol 43. New York: Raven, 1986:309-319
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12. Handwerker JV, Palmer RP. Clonidine in the treatment of restless legs syndrome. N Engl J Med 1385;313:122Y-1229
13. Ware JC, Pittard JT, Blumoff RL. Treatment of. sleep-related
myoclonus with an alpha-receptor blocker. Slecp Res 198 1;
10:242
14. Ware JC, Brown F W ,Moorad PJ, et al. Nocturrial myoclonus
and tricyclic antidepressants. Sleep Res 1984; 13:-'2
15. Frost JJ, Dannals RF, Ravert HT, et al. Imaging opiate receptors
with positron emission tomography. J Nucl Med 1984;25:P73
458
Glycine encephalopathy (GE, nonketotic hyperplycinemia) is an autosomal recessive disorcler of infants
characterized biochemically by altered glycine nietabolism and clinically by intractabk seizures, lethargy,
spasticity, severe mental retardation, and carly death
[l]. In GE, marked elevation of glycine is observed in
cerebrospinal fluid and brain [2) consequent t o a a&fect in the glycine cleavage enzyme [ 3 ] .
Apart from biochemical studies of glycine and its
metabolizing enzymes, little information is available
with respect to studies of the behavior of major
nonglycinergic neurotransmitter systems in the brains
From the *Clarke Institute of Psychiatry, Toronto, the Departrnmts
of tpsychiatry, $Pharmacology, and SNeuroparhology, University t ~
Toronto, 'Hospital for Sick Chrldren, Toronto, Ontario, Canada,
and the iiDepartmentof Pharmacology, University of British Columbia, Vancouver, BC, Canada.
Received Dec 7, 1987, and in revised fomi Mar 16. 1988. Accepted
for publication Mar 24, 1988.
Address correspondence to D r Kish, Human Brain Laboratory,
Clarke Institute of Psychiatry, 2 5 0 College Sr, Toronto, Ontario
M5T 1R8 Canada.
Copyright 0 1988 by the American Neurological Association
f
of GE patients. Thus, it has yet to be determined
whether the marked accumulation of glycine produces
altered neuronal number or disordered metabolism of
other neurotransmitter systems which could contribute
to the neurological dysfunction. We now report the
results of a biochemical study of markers for the major
amino acid neurotransmitters (gamma-aminobutyric
acid [GABA), glutamic acid, glycine, taurine, aspartic
acid, and the aspartic acid metabolizing enzyme aspartic acid aminotransferase [AAT}), and receptors
(GABAA and associated benzodiazepine receptor,
GABAB) as well as the marker enzymes for the acetylcholine neuronal system (cholineacetyltransferase
[ChAT] and acetylcholinesterase [AChE]) in autopsied brain of 10 infants dying with GE. Because intractable epileptic seizures are a constant and major clinical
feature of this disorder [ 11, we selected for study those
neurotransmitter systems implicated in human epileptic conditions (for extensive review, see [4}).
Patients and Methods
Autopsied frontal cortex was obtained from 10 infants with
GE. All infants showed the classic clinical features of GE
with markedly elevated levels of glycine in cerebrospinal
fluid. Clinical information on 5 of the 10 patients has been
previously described 131. Mean ages of the patients with GE
(3 t 1 months, mean t SE) and 9 control subjects without
neurological disease ( 4 t 1 months) did not differ significantly ( p > 0.05, Student's two-tailed t test). The death-tofreezing interval of the brain at -80°C was less than 24
hours for all cases.
Amino compounds in brain homogenates deproteinized
with perchloric acid were determined as described previously
[ 5 ] . For the amino acid analysis, samples were selected only
from patients having a death-to-freezing interval of less than
8 hours. Benzodiazepine receptor binding was measured in
100 mM TRIS HC1 buffer ( p H 7.4) homogenates according
to the procedure of Kish and coworkers [6]. For the measurement of GABAA and GABAB binding, minor modifications of the procedure of Hill and coworkers [7] were
employed. AAT activity was measured in 0.1 M potassium
phosphate buffer (pH 7.5) homogenates according to the
procedure of Perry and colleagues [8]. ChAT and AChE
activities were determined as described by Fonnum "91 and
Bonham and associates l o ] , respectively.
Results
The mean concentration of glycine in GE frontal cortex was significantly increased by 207% as compared
to the control subjects (Table 1). Levels of the other
amino compounds were not significantly different @ >
0.05) from control brain. As shown in Table 2, mean
levels of benzodiazepine (3H-ffunitrazepam density
[BmaX) and affinity [I&))
and GABAA and GABAB
binding were not significantly different from those of
the control subjects. Activities of the enzymes ChAT
Table 1 . Amino Compounds in Autopsied Frontal Cortex:
Control Subjects Versus Patients with Glycine
Encephalopathy"
Brain Amino
Compound
Glycine
Glycerophosphoethanolamine
Phosphoethanolamine
Taurine
Aspartic acid
Glutamic acid
Glutamine
Cy stathionine
GABA
Control Subjects
Patients with
Glycine
Encephalopathy
1.58
0.34
2
2
0.20
0.09
4.85
0.95h
0.49 t 0.09
3.56
2
0.75
4.02 2 0.67
2.94 ? 0.33
1.03 t 0.41
5.93 ? 1.67
3.25 t 1.22
0.28 ? 0.12
1.55 2 0.29
*
2.91
0.55
4.85
5.24
0.28
2.02
-f-
t
t
t
t
*
0.48
0.20
1.39
0.83
0.07
0.24
"Values are expressed in FmoVgm wet weight and represent the
mean 2 SE of 5 control subjects and 9 patients with glycinc cncephalopathy.
'p < 0.025, Student's two-tailed I rest.
GABA
=
gamma-aminobutyric acid
and AAT were normal, whereas mean AChE activity
was significantly increased by 46%.
Discussion
To our knowledge, this is the first study describing the
behavior of major nonglycinergic neurotransmitter
systems in the brain of patients with GE. Our data
demonstrating markedly elevated levels of glycine in
GE brain confirm and extend the original observation
of Perry and coworkers C2, 31.
The observation of enhanced activity of the cholinergic metabolizing enzyme AChE in the brain of those
patients with G E who have an intractable seizure disorder is similar to the findings of elevated AChE levels in
the cerebral cortex of patients with human focal
epilepsy [ l l , 121. In the experimental literature, altered (increased, decreased) activity of brain AChE has
been reported in an animal model of epilepsy El31 and
other seizure conditions [14, IS}. Although the
biological significance of AChE changes in convulsive
states is not understood, recent evidence suggests that
AChE may have important (neuromodulatory?) physiological actions other than the catabolism of acetylcholine 1163.
The general lack of changes in the examined nonglycinergic neurotransmitter systems in this seizure disorder differs from biochemical findings in biopsied brain
of some (adult) patients with focal cerebral cortical
epilepsy, in which altered levels of GABA [17, 181,
glutamic acid [17-191, aspartic acid [lS, 191, GABAA
Brief Communication: Kish et al: Glycine Encephalopathy
459
Table 2. Ne14rotrunsmitter 1ndice.r in Autopsied Frontdl Cortex: Control Subjects z’ersm Patient., with G o h e Eni-ej&alopathy”
Brain Neurotransmitter
Units
Control Subjects
Patients with
GlycintEncephahpathy
GABAA binding
GABAB binding
Benzodiazepine binding
affinity
Benzodiazepine binding
number (Bmax)
Cholineacetyltransfcrase
activity
Acetylcholinesterixse
activity
Aspartate amino transferase
activity
fmol‘mg protein
frnoVmg protein
nM
352
28.0
1.17
304 2 40
25.5 i 2.4
1.27 t 0.16
fmoVnng protein
419 t 67
477
nmoVgm Froreid10 min
0.99 i 0.09
0.99 c 0.22
rnmol’gm proteidhr
0.61 2 0.06
0.89 i 0.1 I h
nmol/grn protein/ 10 min
6.69 -c 0.74
5.92
?
?
?
101
5.9
0.38
rt
rt
52
0.04
aValues represent the mean -t SE of 8 ro 10 infants with glycinr encephalopathy and 8 to 9 control subjects. GABA,, and GAnA13Iinding were
measured at a concentration of 10 nM ’H-GABA
“p < 0.05, Student’s two-tailed t test.
GABA
=
gamma-aminobutyric acid
receptor binding {20), and increased activities of
ChAT [ 11, 191 and AAT [ 2 17 have been reported.
Although the mechanisms underlying the neurological dysfunction in GE are not understood, results of a
recent pharmacological study suggest an important
causal role for glycine in the pathogenesis of the seizures. Thus, high-dosage administration of sodium
benzoate, a substance that promotes the more efficient
urinary excretion of glycine, has been reported to reduce or eliminate the frequency of seizures in 3 patients with GE [22]. In addition, a good correlation
was observed between the magnitude of sodium benzoate-induced reduction in cerebrospinal fluid glycine
and reduction in seizure frequency and severity [227.
Increased glycine concentration has also been demonstrated in the cerebral cortex of some aclult patients
with focal epilepsy [ 17- 19, 231 and therefinre may
contribute to seizure mechanisms in other human
epileptic conditions.
Recent experimental evidence indicates that brain
glycine may fmction in part by acting as an dlosteric
modulator of excitatory amino acid responses. In this
respect, Johnson and Ascher [24} have described a
marked glycine potentiation of responses to the excitatory neurotransmitter glutamic acid and its analogue
N-methyl-D-aspartate in cultured brain neurons. A
question of clinrcal importance is whether the seizures
in GE (and perhaps also in some adult epileptic conditions) can be related to excessive activity of e.xcitatory
neurotransmitter amino acid function consequent to
grossly above-normal potentiation by glycine. Although the actual concentration of glycine at the allosteric N-methyl-D-aspartate receptor site in living GE
brain cannot be determined from postmortem brain
homogenates, the possibility exists that above-normal
glycine potentiation could represent the primary pathogenetic mechanism of seizure production in GE. In
this regard pharmacological measures employing Nmethyl-D-aspartate antagonists [ 2 5 ] or specific glycine antagonists acting at the allosteric N-methyl-Daspartate receptor might offer effective therapeutic
approaches in GE.
This study was supported by the Hospital fi)r Sick Children tS. K.),
the Clarke Institute of Psychiatry (S. K.), and the Medical Rescarch
Council of Canada (W. B. and T. L. F’.). Dr Kish is a Career Scientist
of the Ontario Ministry of Health.
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Brief Communication: Kish et al: Glycine Encephalopathy 461
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