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Disturbance of GABA Metabolism in Pyridoxine-Dependent Seizures By G. Kuriemann, R. Ziegler, Marianne Grüneberg, T Bömelburg, K. Ullrich and D. G. Palm
Abstract In an infant with typical pyridoxine-dependent seizures, CSF GABA level, was determined before treatment with pyridoxine. Before onset of treatment, level of GABA in CSF was highly lowered (16 pmol/ml), pyridoxine level in serum was within normal range. Immediately after application of 80 mg pyridoxine fits stopped and the EEG was without seizure activity. The data substantiate previous findings in brain tissue from a patient with pyridoxinedependent seizures. They are proof of a disturbed GABA metabolism in pyridoxine dependent seizures.
Keywords Pyridoxine-dependent seizures - GABA CSF
Introduction Pyridoxine-dependent seizures are a rare disease; about 100 cases are reported in the literature (6). The main symptom are seizures without specific type especially during the first few days of life, although some cases of intrauterine seizures were reported (3, 9). In atypical cases the onset of seizures was delayed byweeks or even months (1, 2). Seizure activity usually did not respond to standard anticonvulsant therapy. Sometimes a partial respond was observed to anticonvulsant medication (7, 14). Up to now there are only speculations about a postulated disturbed GABA metabolism in pyridoxine-dependent seizures (15, 16).
Case report A 10-week-old boy was admitted to our hospital because of intractable seizures since the second day of life, the main types were myoclonic and grand mal seizures. He was
Received January 29, 1992; accepted May 4, 1992 Neuropediatrics 23 (1992) 257-259 (Q Hippokrates Verlag Stuttgart
treated at another hospital with high doses of phenobarbital, diphenylhydantoin, diazepam with necessity of assisted ventilation, and finally ACTH as weIl. No satisfactory effect on his seizures was achieved. The EEG showed persistent massive epileptic discharges. After admission to our clinic 50 mg pyridoxine was given intravenously with simultaneous EEG control. The fits stopped immediately and the EEG was normal after three minutes (Figs. 1, 2). The boy fell asleep for 18 hours. In an attempt to differentiate between a pyridoxine deficiency or dependency state, the pyridoxine supplementation was stopped. Four days later fits recurred in the same manner as before. Pyridoxine level in serum was 16 J,lg/ml (normal 5 to 30 J,lg/ml), GABA level in CSF was lowered to 16 pmol/ml (in our laboratory, normal values are 54 to 184 pmol/ml in unaffected children). GABA was determined by a quantitative fluorometric method, with an aminioacid analyser, using ophthaldehyde. EEG monitoring showed the same findings compared with the first EEG. Again fits stopped and the EEG returned to normal traces soon after injection of 80 mg pyridoxine. The diagnosis of pyridoxine-dependent seizures was made. With 80 mg pyridoxine daily, anticonvulsant therapy was stopped without any further fits. Currently the boy is seizure-free, but his global development is delayed.
Discussion This is the first report of GABA measurement in the CSF in a living child with pyridoxine-dependent seizures. Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the brain. The rate-limiting step in GABA biosynthesis is the decarboxilation of glutamic acid by glutamate decarboxylase (GAD). GAD has an absolute requirement for pyridoxal phosphate (PLP); the catabolism of GABA by GABA-transaminase requires PLP as weIl. Pyridoxine (vitamin B6 ) is converted in the body to the active form pyridoxal phosphate. Scriver postulated a reduced synthesis of GABA resulting from a decreased activity of GAD that could be responsible for the lowered seizure threshold in patients with pyridoxine dependency seizures (15). It is believed that in pyridoxyine dependency there is a molecular defect in the binding of PLP to its apoenzyme GAD. The genetic defect of pyridoxine dependent seizures has been postulated to involve a gene located on chromosome 2 coding for the GAD apoprotein, resulting in deficient pyridoxine binding (7).
Downloaded by: NYU. Copyrighted material.
University of Münster, Department of Pediatrics, Neuropediatrics, Albert-Schweitzer-Str. 33, D-4400 Münster, Germany
258 Neuropediatrics 23 (1992)
Downloaded by: NYU. Copyrighted material.
Fig. 1
G. Kuriemann et al
EEG before application of pyridoxine.
'ff';t-f:; "'>--F'-~'l'v...~,-"-----",~""\~~,~,~""""""",~~~""-·,-""~,,,,,,,,,,,,,,,,,,~,,,,.,,.r-~-../'-·/'v-....!"~,·,.,-..,..
.../"\I.r-v~~w-~~~~~;~"~.r~~~,./'4~~~~J,"~'..fr~J~'·~ ~~
.
.
'
'
t·v-~""""'--.l~/,t;/'~.r~~v~~""-" ..~«~;"Y-'-~"~~~'"~~''''''--'~'''''·'''''"'''~
Disturbance of GABA Metabolism in Pyridoxine-Dependent Seizures By G. Kuriemann, R. Ziegler, Marianne Grüneberg, T Bömelburg, K. Ullrich and D. G. Palm
Abstract In an infant with typical pyridoxine-dependent seizures, CSF GABA level, was determined before treatment with pyridoxine. Before onset of treatment, level of GABA in CSF was highly lowered (16 pmol/ml), pyridoxine level in serum was within normal range. Immediately after application of 80 mg pyridoxine fits stopped and the EEG was without seizure activity. The data substantiate previous findings in brain tissue from a patient with pyridoxinedependent seizures. They are proof of a disturbed GABA metabolism in pyridoxine dependent seizures.
Keywords Pyridoxine-dependent seizures - GABA CSF
Introduction Pyridoxine-dependent seizures are a rare disease; about 100 cases are reported in the literature (6). The main symptom are seizures without specific type especially during the first few days of life, although some cases of intrauterine seizures were reported (3, 9). In atypical cases the onset of seizures was delayed byweeks or even months (1, 2). Seizure activity usually did not respond to standard anticonvulsant therapy. Sometimes a partial respond was observed to anticonvulsant medication (7, 14). Up to now there are only speculations about a postulated disturbed GABA metabolism in pyridoxine-dependent seizures (15, 16).
Case report A 10-week-old boy was admitted to our hospital because of intractable seizures since the second day of life, the main types were myoclonic and grand mal seizures. He was
Received January 29, 1992; accepted May 4, 1992 Neuropediatrics 23 (1992) 257-259 (Q Hippokrates Verlag Stuttgart
treated at another hospital with high doses of phenobarbital, diphenylhydantoin, diazepam with necessity of assisted ventilation, and finally ACTH as weIl. No satisfactory effect on his seizures was achieved. The EEG showed persistent massive epileptic discharges. After admission to our clinic 50 mg pyridoxine was given intravenously with simultaneous EEG control. The fits stopped immediately and the EEG was normal after three minutes (Figs. 1, 2). The boy fell asleep for 18 hours. In an attempt to differentiate between a pyridoxine deficiency or dependency state, the pyridoxine supplementation was stopped. Four days later fits recurred in the same manner as before. Pyridoxine level in serum was 16 J,lg/ml (normal 5 to 30 J,lg/ml), GABA level in CSF was lowered to 16 pmol/ml (in our laboratory, normal values are 54 to 184 pmol/ml in unaffected children). GABA was determined by a quantitative fluorometric method, with an aminioacid analyser, using ophthaldehyde. EEG monitoring showed the same findings compared with the first EEG. Again fits stopped and the EEG returned to normal traces soon after injection of 80 mg pyridoxine. The diagnosis of pyridoxine-dependent seizures was made. With 80 mg pyridoxine daily, anticonvulsant therapy was stopped without any further fits. Currently the boy is seizure-free, but his global development is delayed.
Discussion This is the first report of GABA measurement in the CSF in a living child with pyridoxine-dependent seizures. Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the brain. The rate-limiting step in GABA biosynthesis is the decarboxilation of glutamic acid by glutamate decarboxylase (GAD). GAD has an absolute requirement for pyridoxal phosphate (PLP); the catabolism of GABA by GABA-transaminase requires PLP as weIl. Pyridoxine (vitamin B6 ) is converted in the body to the active form pyridoxal phosphate. Scriver postulated a reduced synthesis of GABA resulting from a decreased activity of GAD that could be responsible for the lowered seizure threshold in patients with pyridoxine dependency seizures (15). It is believed that in pyridoxyine dependency there is a molecular defect in the binding of PLP to its apoenzyme GAD. The genetic defect of pyridoxine dependent seizures has been postulated to involve a gene located on chromosome 2 coding for the GAD apoprotein, resulting in deficient pyridoxine binding (7).
Downloaded by: NYU. Copyrighted material.
University of Münster, Department of Pediatrics, Neuropediatrics, Albert-Schweitzer-Str. 33, D-4400 Münster, Germany
258 Neuropediatrics 23 (1992)
Downloaded by: NYU. Copyrighted material.
Fig. 1
G. Kuriemann et al
EEG before application of pyridoxine.
'ff';t-f:; "'>--F'-~'l'v...~,-"-----",~""\~~,~,~""""""",~~~""-·,-""~,,,,,,,,,,,,,,,,,,~,,,,.,,.r-~-../'-·/'v-....!"~,·,.,-..,..
.../"\I.r-v~~w-~~~~~;~"~.r~~~,./'4~~~~J,"~'..fr~J~'·~ ~~
.
.
'
'
t·v-~""""'--.l~/,t;/'~.r~~v~~""-" ..~«~;"Y-'-~"~~~'"~~''''''--'~'''''·'''''"'''~
