dependency is an autosomal-recessive inborn error of metabolism. Pyridoxine
dependency should be suspected in neonates with continuous seizures without
an apparent cause. A history of unusual fetal movements (intrauterine
convulsions) and meconium stained amniotic fluid is often present. An
EEG pattern characterized by generalized bursts of synchronous high-voltage
1- to 4-Hz spike and wave complexes has been described.
seizures in neonates with pyridoxine dependency are probably due to abnormal
glutamate acid decarboxylase (GAD) and are probably caused by low concentrations
of gamma-aminobutyric acid (GABA) and high concentrations of glutamic
acid. Gamma-aminobutyric acid is an inhibitory neurotransmitter in the
central nervous system, whereas glutamic acid is an excitatory neurotransmitter.
The lack of sufficient pyridoxine to fully activate the abnormal GAD leads
to decreased activity of glutamate acid decarboxylase; the low activity
of glutamate decarboxylase decreases the conversion of glutamate to GABA.
Other possible cause of pyridoxine dependent seizures is the failure of
pyridoxine to become pyridoxal phosphate.
Pyridoxal phosphate is the active form of pyridoxine.
The diagnosis of pyridoxine
dependency is made on the basis of the response to intravenous pyridoxine
(pyridoxal phosphate). Low levels of pyridoxal-5-phosphate and high levels
of pipecolic acid in the CSF can occur in patients with pyridoxine dependent
consists of pyridoxine 100 mg intravenously. The convulsions and abnormal
electroencephalographic seizure pattern usually stop immediately.
Neonates should be monitored during, and for about one hour after, the
infusion of pyridoxine because hypotonia and apnea may occur in neonates
with pyridoxine dependency. This first-dose effect of pyridoxine in patients
with pyridoxine dependency is probably due to a burst of GABA synthesis
that results from sudden activation of glutamate decarboxylase.Intravenous
therapy should be followed by oral pyridoxine 5 to 15 mg/kg per day. Patients
taking oral pyridoxine should be evaluated periodically for the possibility
of neuropathy. Pregnant mothers of infants with pyridoxine-dependent seizures
should receive pyridoxine 100 mg/day during the final half of gestation.
Acid Responsive Seizures
with onset of seizures during the first week of life and no explanation
for seizures may have folinic acid responsive seizures. This type of seizure
may be associated with an abnormal peak in the CSF electrophoresis. Treatment
with folinic acid 2.5 to 5 mg twice daily stops the seizures.
is the enzyme that cleaves biotin from biocytin and byotinyl peptides.
Biotin is needed for the activation of mitochondrial carboxylases (propionyl-CoA
carboxylase, pyruvate carboxylase, and beta methylcrotonyl-CoA carboxylase).
No biotinidase leads to no biotin. No biotin leads to no activity of the
previously mentioned carboxylases. Lack of activity of the mitochondrial
carboxylases leads to metabolic derangement and to seizures. Neonates
with seizures due to biotinidase deficiency usually have skin rash, total
or partial alopecia, and persistent conjunctivitis. The diagnosis is suspected
by the specific pattern of urine organic acid reflecting the deficiencies
of propionyl-CoA carboxylase, pyruvate carboxylase, and beta methylcrotonyl-CoA
carboxylase. The diagnosis is confirmed by measuring biotinidase activity
in blood serum. Treatment consists of biotin 5 to 20 mg orally each day.
of glucose transport
is transported across the blood brain barrier by facilitative diffusion.
Glut-1 protein is a major transporter. A defect in this transporter leads
to low cerebrospinal fluid glucose and lactate. The possibility of a disorder
of glucose transport should be considered when the cerebrospinal fluid
glucose concentration is less than about 50% of the serum glucose concentration
and the CSF lactic acid is low.Treatment
with a ketogenic diet controls seizures and prevents neurological deficit.
oxidase deficiency, alone or combined with xanthine oxidase deficiency
(molybdenum cofactor deficiency) may produce neonatal seizures. Urine
uric acid may be low in molybdenum cofactor deficiency. Elevated plasma
or urine S-sulfocysteine is diagnostic. These aminoacids have to be requested
by name since they will not be detected by routine aminoacid or organic
acid determinations. There is no specific therapy.
aminotransferase (GABA-transaminase) is the enzyme that catalyzes the
conversion of GABA to succinic acid. The diagnosis is established by elevated
GABA levels in plasma or CSF (it seems paradoxical that seizures would
be produced by elevated GABA, since GABA is an inhibitory neurotransmitter).
Agenesis of the corpus callosum and cerebellar hypoplasia was reported
in a patient.
methyltransferase (GMAT) deficiency is suspected by the MRI spectroscopy
finding of an absence of creatine/creatine phosphate peak, generalized
elevation of serum amino acids when calculated relative to creatinine,
by low plasma creatinine levels. Guanidinoacetate
methyltransferase (GMAT) deficiency is diagnosed by elevated guanidinoacetate
(assayed by tandem-mass spectroscopy). Treatment with creatinine monohydrate
(400 to 500 mg/kg per day) has proven effective.