Vitamin and Cofactor Responsive Encephalopathies and Seizures

Ingrid Tein

University of Toronto & The Hospital for Sick Children, Toronto, Canada

[+] Corresponding author:
Dr Ingrid Tein, Director, Neurometabolic Clinic and Research Laboratory, Division of NeurologyDept. of Pediatrics, Laboratory Medicine and Pathobiology, University of Toronto, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8


Early diagnosis and treatment for vitamin and/or cofactor responsive encephalopathies and seizures is critical for both seizure control and cerebral development and to prevent the kindling of intractable seizures with secondary brain injury. Recognition of these specific disorders is key to their management given their essential requirement for specific cofactors and their reduced responsiveness to standard anticonvulsant therapy. The overall goals of this review are: (1) to provide recognition of the clinical phenotypes of selected treatable metabolic etiologies of early-onset encephalopathies with seizures, (2) to highlight the appropriate diagnostic investigations for each, and (3) to outline the effective treatment strategies. Each condition will be described followed by an approach to vitamin-responsive infantile-onset seizure management.

Keywords: vitamin responsive; cofactor responsive; encephalopathies; epilepsy; transporters; energy metabolism

© 2015 Tein I.; licensee JICNA

1. Glucose Transporter Defect – Glut 1

Clinical Features have wide phenotypic variability, including infantile-onset seizures, which may be apneic episodes; episodic eye movements; generalized tonic clonic, clonic, myoclonic, atypical absence; and/or atonic in semiology. There is progressive microcephaly without treatment intervention, developmental delay, and speech delay. Varying degrees of cognitive impairment can occur ranging from learning disabilities to severe cognitive delays. Neurologic features include pyramidal spasticity, extrapyramidal and cerebellar signs, sleep disturbance, and headaches. There are at least three clinical phenotypes. Type I classic GLUT1 deficiency presents with seizures, microcephaly, developmental delay, spasticity, confusion, pyramidal, and extrapyramidal signs. Type 2 presents with developmental delay, dysarthria, dystonia, and ataxia. Type 3 is characterized by choreoathetosis, dystonia, paroxysmal eye and head movements, delay, dysarthria, and hypotonia. Proposed diagnostic criteria for GLUT1 deficiency syndrome includes seizures, developmental delay, complex movement disorder, and fasting EEG changes that improve somewhat postprandially [1].

Biochemical features are characterized by hypoglycorrachia with a CSF glucose-to-blood glucose ratio < 0.4 X 3 (in the absence of infection), low CSF lactate, and reduced RBC glucose transport [2].

Pathology relates to impaired blood-brain barrier glucose transport by GLUT1. It is important to note that glucose serves not only as a key bioenergetic fuel for the brain, but it is also a signaling molecule.

Treatment consists primarily of early institution of the ketogenic diet as fatty acid oxidation becomes competent in the infant and has been initiated as early as 6-28 wks of age [3,4]. Ketogenic diets may contain long-chain or medium- chain triglycerides. Complications may include renal stones; therefore, maintenance of good hydration and monitoring of renal function and regular renal ultrasounds is important. The ketogenic diet has resulted in good control of seizures and motor symptoms [5, 6], although cognition may still be somewhat delayed, which may relate to delay in diagnosis and to the signaling role of glucose. Of note, phenobarb, which is often the first-line therapy in infantile seizures as well as diazepam, inhibits the GLUT1 transporter [7] and may thereby exacerbate the seizure disorder.

Genetics. This condition is autosomal dominant in transmission [8]. Affected individuals may have hemizygous or heterozygous mutations resulting in truncation of the GLUT1 protein. The gene (SLC2A1) is located on chromosome 1p35-p31.3. Rare cases of autosomal recessive inheritance have also been reported [9].


a) X-linked Creatine Transporter Defect

Clinical features include severe developmental delay or regression (or learning disabilities in females) and severe speech delay; seizures; behavioural problems with autistic features; hypotonia; midfacial hypoplasia; and gastrointestinal disturbances, including constipation, megacolon, gastric and duodenal ulcers, and bowel perforations. Failure to thrive and recurrent vomiting and motor delay have also been described [10]. Boys are most severely affected given the X-linked pattern of inheritance. It has a prevalence of 0.3-3.5 % in males. EEG in one patient showed slow, diffuse hypersynchronisms with abnormal multifocal spikes [10]. Carrier females may have borderline to moderate cognitive delays depending on their X-chromosome lyonization pattern [11].

Biochemical features include markedly decreased or absent creatine signal on 1H-MRS brain with severe depletion of creatine/phosphocreatine in the brain [12]. There was increased creatine in the plasma and urine and the guanidinoacetic acid (GAA) was normal in one child [12]. In another child, plasma creatine concentrations were consistently low [10]. There is also an increased urine creatine/creatinine ratio [13]. Creatine uptake can be measured in cultured skin fibroblasts and is decreased.

Treatment consists of creatine supplementation, though this does not correct the cerebral creatine deficiency. Dietary L-arginine, which is the precursor for creatine, was shown in one study to lead to improvement in neurological, language, and behavioral status and increased brain creatine in a 9-year-old boy after one year of therapy [14].

Genetics. This condition is X-linked in inheritance. The gene is SLC6A8 and maps to Xq28.

b) l-Arginine: Glycine Amidinotransferase (AGAT) Deficiency

Clinical features include severe developmental delay with regression, autistic behavior, hypotonia, and severe expressive and cognitive speech delay [15].

Biochemical features include severe depletion of creatine/ phosphocreatine in the brain as demonstrated by a markedly decreased or absent creatine signal on 1H-MRS brain. The AGAT enzyme catalyzes the transfer of a guanido group from arginine to glycine forming guanidinoacetic acid, the precursor of creatine. Blood and urine guanidinoacetate is decreased [16]. Low plasma and urine GAA and creatine at birth are indicative of AGAT deficiency [17].

Treatment consists of oral creatine (e.g. 100-400 mg/kg/ day), which improves cerebral creatine levels and neurological outcomes [18,19]. Early intervention (e.g. creatine supplementation at 2 months of age before onset of symptoms) has been shown to prevent phenotypic expression of the disease [17].

Genetics. This is an autosomal recessive condition with GATM gene locus at 15q12.

c) Guanidinoacetate Methyltransferase (GAMT) Deficiency

Clinical features include severe developmental delay with regression; autistic features; severe expressive and cognitive speech delay; intractable seizures (generalized tonic, clonic, and absence); pyramidal signs; and hypotonia and movement disorder, such as ataxia, myoclonus, and/or dystonia [20-22].

Biochemical features are characterized by severe depletion of creatine/phosphocreatine in the brain as demonstrated by a markedly decreased or absent creatine signal on 1H-MRS brain. The GAMT enzyme converts guanidinoacetate to creatine with S-adenosylmethionine (SAM) as the methyl donor. Low CSF creatine and creatinine has been documented [22]. Plasma creatinine is in the low to normal range, and the 24-hour urine creatinine excretion is markedly decreased. The accumulation of guanidinoacetate in the brain and body fluids may be responsible for the intractable seizures and movement disorder. Urine exretion of GAA is markedly increased [22].

Pathology in the brain is characterized by marked myelination delay.

Treatment consists of oral creatine, which is partially successful. In one patient, a diet with arginine restriction and supplementation with ornithine and creatine decreased the formation of GAA and improved clinical outcomes affecting developmental milestones and sensorineural hearing loss [23-25].

Genetics. This is an autosomal recessive disorder [21] with GAMT gene locus at 19p13.3.


Clinical features of this group of disorders include congenital microcephaly, early onset seizures, hypertonia, and moderate to severe developmental delay with symmetric postnatal growth retardation and hypogonadism [26].

The 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency may also include congenital cataracts. An adult man with congenital cataracts, mild psychomotor retardation, slight cerebellar ataxia, and a chronic axonal sensorimotor polyneuropathy with 3-PHGDH deficiency has also been described, which expands the spectrum [27]. A mild form has been described in two siblings with juvenile onset of absence seizures and mild developmental delay with favorable response to serine supplementation with cessation of seizures, normalization of their EEG, and improvement in behavior [28].

3-phosphoserine phosphatase deficiency has been described in a Belgian boy who had pre- and postnatal growth retardation, moderate psychomotor retardation, and facial features suggestive of Williams syndrome with reduced phosphoserine phosphatase activity in lymphoblasts and fi- broblasts to 25 % of normal [29].

Biochemical features are characterized by low fasting plasma and CSF serine and glycine. This group of disorders involve rare defects in the biosynthesis of L-serine. Characterized defects include deficiency of 3-phosphoglycerate dehydrogenase, which can be detected on the basis of decreased enzymatic activity in fibroblasts. The 3-phosphoserine phosphatase deficiency can be detected in lymphoblasts and fibroblasts and is reduced to 25 % of normal values in affected patients.

Pathology arises from the deficiency of L-serine, a precursor for nucleosides, phospholipids, and the neurotransmitters glycine and D-serine. L-serine appears to be essential for normal brain function, as it plays a role in the biosynthetic reactions of brain proteins, glycine, cysteine, serine phospholipids, sphingomyelins, and cerebrosides. Disturbances of serine-glycine metabolism in relation to N-methyl-D-aspartate- receptor activation may also play a role in psychiatric disease.

The 3-phosphoglycerate dehydrogenase deficiency results in dysmyelination of the developing brain and requires antenatal treatment. In one patient with the PHGDH gene defect who was detected prenatally on the basis of a reduction of fetal head circumference between the 20th to 26th week of gestation from the 75 % to the 29 %, L-serine at 190 mg/kg /day in 3 divided doses was given to the mother which led to a fetal head circumference increase to the 76 % percentile at 31 weeks gestation [30]. At birth, the girl's head circumference was normal. Within 12 hours after birth, the serine concentration in plasma dropped to a severely deficient value, and the CSF serine was also depleted. MRI was normal but EEG showed discrete seizure activity. After initiation of L-serine at 400 mg/kg/day, the seizure activity decreased and was replaced by normal cerebral activity. At one year and at 4 years of age, this girl had normal growth and psychomotor development. The follow up MRI brains at 12 and 14 months were normal.

Treatment in 3-PHGDH deficiency consists of administration of oral serine (200 mg/kg/day divided into 3 doses) with or without glycine [26, 31-33], which may improve seizure control and cerebral growth. In phosphoserine phosphatase deficiency, treatment with oral serine led to normalization of serine levels and some improvement in head growth [29].

Genetics. 3-PHGDH deficiency is an autosomal recessive disorder and the PHGDH gene is located at 1p12. 3-phosphoserine phosphatase deficiency is presumed autosomal recessive in inheritance and the gene is at locus 7p11.2.


a) Biotin Deficiency

Biochemistry. Biotin is a cofactor in the metabolism of fatty acids and leucine and in gluconeogenesis. It is responsible for the transfer of CO2 in several carboxylase enzymes, including acetyl-CoA carboxylase alpha and beta, methylcrotonyl- CoA carboxylase, propionyl-CoA carboxylase, and pyruvate carboxylase. Sources of biotin include royal jelly, brewer's yeast, Swiss chard, tomatoes, romaine lettuce, carrots, almonds, eggs, and onions. Deficiency states are rare and relatively mild. Causes of biotin deficiency include excessive consumption of raw egg whites (avidin), gastrectomy, achlorhydria, extensive burns, and epilepsy. Clinical deficiency states are characterized by anorexia, decreased growth, alopecia, perosis, and fatty liver and kidney syndrome.

b) Biotinidase Deficiency (Late-Onset Multiple Carboxylase Deficiency)

Clinical features include variable phenotypes depending upon the degree of residual enzymatic activity and affects ~1/60,000 newborns. There are severe forms (< 10 % residual activity); partial forms (10-30% activity) where symptoms are triggered by metabolic stressors, such as prolonged infection; and asymptomatic cases. Clinical and biochemical consequences of severe biotin deficiency have been documented to occur within 12 days of birth [34]. Early infancy onset seizures are the most frequent initial symptom and may present as Otahara syndrome [35] or infantile spasms [36]. The primary features include hypotonia; cognitive delay; ataxia, which may be intermittent; sensorineural hearing loss; optic atrophy; rash; alopecia; and recurrent infections [38-41]. Older children and adolescents with profound biotinidase deficiency exhibit motor limb weakness, spastic paresis, and decreased visual acuity [42]. Wolf et al [43] reported two unrelated asympomatic adults with biotinidase deficiency only because their affected children were identi- fied by newborn screening.

Biochemical features are characterized by ketoacidosis and lactic acidosis. Urine organic acids demonstrate 3-hydroxy isovaleric acid, ß-methylcrotonylglycine, and 3-hydroxypropionic acids.

Pathology is characterized by cerebellar atrophy and may include basal ganglia calcifications [45]. Imaging also demonstrates low cerebral volume with ventriculomegaly and widened extracerebral CSF spaces [46].

Treatment with oral biotin supplementation (5-10 mg/ day) leads to rapid clinical and biochemical improvement; however, there may be residual CNS injury, including developmental delay, ataxia, sensorineural hearing loss, and visual defects depending in part on the time of treatment intervention. Suormala et al [47] suggested treatment with biotin for all patients with residual activities below 10 %. Wolf [42] suggests that all individuals with profound deficiency should have lifelong treatment with biotin. Annual vision and hearing evaluations should be conducted, and raw eggs should be avoided, as they contain avidin, which binds biotin and decreases the bioavailability of biotin.

Genetics. Inheritance is autosomal recessive due to mutations in the BTD gene, which is located at gene locus 3p25.1. Because of the importance of early treatment intervention and the response to biotin therapy, screening for biotinidase deficiency is now part of many newborn screening programs [48].


a) Folate Deficiency

Biochemistry. Folic acid is important in the synthesis of DNA (thymine and purine bases) and in cell division. Sources of folic acid include leafy green vegetables, such as spinach and lettuce, dried beans, peas, fortified cereals, and sun- flower seeds. Folate deficiency may be seen in individuals taking medications that interfere with folate metabolism such as methotrexate, trimethoprim, sulfonamides, dilantin, primidone, and metformin. It may also occur in malabsorption syndromes, including celiac disease, liver disease, and renal disease.

Clinical manifestations include diarrhea, anorexia, weight loss, palpitations, weakness, headaches, irritability, behavioral disorders, and megaloblastic anemia. Folate de- ficient mothers may bear children with low birth weight, prematurity, and neural tube defects.

Folic acid responsive disorders include hereditary folate malabsorption (SLC46A1), the cerebral folate transporter defect FOLR1, 5,10-methylenetetrahydrofolate reductase defi- ciency, and homocystinuria due to cystathione ß-synthase deficiency.

b) Folic Acid Transport Defect (Hereditary Folate Malabsorption) SLC46A1

Clinical features include early infancy onset with megaloblastic anemia, pancytopenia, diarrhea, vomiting, infections, seizures, cognitive delay, drowsiness, ataxia, athetosis, and peripheral neuropathy.

Biochemical features are characterized by a defect in the intestinal and blood-brain barrier transport of folate [49]. Folate deficiency is demonstrable in RBCs, serum, and the CSF.

Pathology is characterized by basal ganglia calcifications [50, 51].

Treatment involves parenteral administration of folinic acid, which restores normal growth and corrects hematologic abnormalities but has less effect on development and seizures. Corbeel et al [52] also gave methione and Vitamin B12 because of concurrent low plasma methionine, and the seizures were controlled. Peripheral neuropathy improved with intramuscular folinic acid therapy [54].

Genetics. Inheritance is autosomal recessive due to mutations in the SLC46A1 gene at 17q11.2 [54-56].

c) Cerebral Folate Transport Defect FOLR1

Clinical features include late infantile onset of severe developmental regression, seizures, and progressive movement disorder characterized by ataxia and/or athetosis [57].

Biochemical features are characterized by a defect in cerebral folate transport due to mutations in the folate receptor 1 gene coding for folate receptor alpha, which results in severe folate deficiency in the CSF [57].

Neuroimaging is characterized by severe hypomyelination affecting periventricular and subcortical white matter. On brain MRS, there are decreased choline and inositol peaks in the parieto-occipital white matter [57].

Genetics. Inheritance is autosomal recessive due to mutations in the FOLR1 gene at 11q13.4.

Treatment involves oral folinic acid, which leads to clinical improvement in CNS function and in CSF methyltetrahydrofolate (MTHF) and glial choline and inositol [57].

d) 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Deficiency

Clinical features range from severe infantile onset (< 20 % residual activity) with apnea seizures, coma, and progression to death in one year [58] to asymptomatic adults. Symptoms may also include severe cognitive impairment, microcephaly, weakness, gait abnormalities in adolescence and adulthood, incoordination, thrombotic strokes, and psychiatric disorders, such as schizophrenia, catatonia, psychosis with hallucinations and delusions, and depression [59-62].

Biochemical features are characterized by elevated plasma homocysteine, decreased plasma methionine, decreased folate in serum and RBCs, homocystinuria, and decreased MTHFR activity in fibroblasts or leukocytes. Decreased S-adenosylmethionine and demyelination have been documented [63].

Treatment includes folinic acid, methyltetrahydrofolate, betaine, and methionine supplementation [60, 62].

Genetics. Inheritance is autosomal recessive due to mutations in the MTHFR gene at 1p36.22 [64-66].


Functions. Pyridoxine is converted into pyridoxal 5'-phosphate (PLP), its biologically active form. Pyridoxine has a number of important cellular functions. It assists in balancing cellular sodium and potassium, promotes RBC production, decreases the formation of homocysteine, and prevents excema and psoriaris. It is a precursor for pyridoxal 5'-phosphate, a cofactor for aromatic amino acid decarboxylase, which converts 5-hydroxytryptophan into serotonin and L-DOPA into dopamine, noradrenaline, and adrenaline. Dietary sources include dragon fruit, grains, and nuts.

Pyridoxine may be given with isoniazid at 10-50 mg/day to prevent peripheral neuropathy and CNS toxicity during tuberculosis therapy. In high doses, it may lead to sensory neuropathy and ataxia.

a) Pyridoxine Deficiency

Clinical features include chelitis, conjunctivits, sideroblastic anemia, neonatal onset seizures, irritability, and confusion.

Biochemical features are characterized by impairment in the decarboxylation of glutamate to GABA and an impairment of the transamination of glutamate to alpha-ketoglutarate (Kreb's cycle intermediate).

b) Pyridoxine Dependent Epilepsy (Antiquitin Deficiency) - α - Amino Adipic Semialdehyde (αAASA) Dehydrogenase Deficiency

Clinical features include seizure onset, usually on day one of life but may be delayed up to 3 weeks or even later. Seizures may be prolonged with recurrent episodes of status, which is typical but may also be recurrent, self-limited events, including partial seizures, generalized seizures, atonic, and myoclonic seizures. Infantile spasms may also occur. Mothers may complain of intrauterine seizures. In the classic presentation, neonatal or early infantile seizures are clonic, generalized tonic, and/or myoclonic and are resistant to standard anticonvulsants but respond completely with cessation of clinical and electrographic seizures to 50-100 mg of intravenous pyridoxine within minutes. A transient coma concomitant with seizure cessation is characteristic for pyridoxine- dependent epilepsy (PDE) but does not always occur [67,68]. Seizures usually recur when pyridoxine is stopped, either incidentally or for diagnostic withdrawal, for which time intervals between 1 and 51 days have been reported [69,70]. EEG patterns may vary from normal to high voltage delta activity, focal spike wave discharges, burst suppression patterns, and, rarely, hypsarrhythmia [71-73]. Other features may include respiratory distress, acidosis, sleeplessness, irritability, fluctuating tone, abdominal distension, and vomiting. Despite early treatment and good seizure control, many will have mild to severe developmental delay with speech delay. Atypical presentations may include late onset of seizures up to 3 years of age [74,75], autism, and partial response to common anticonvulsants, especially Phenobarbital with delayed response to pyridoxine [75].

Screening should be performed in neonates, infants, and older children with unexplained, intractable, or poorly controlled seizures, especially in combination with encephalopathy, long lasting focal seizures, and status epilepticus. With available biomarkers, patients with later onset and milder and atypical courses should be considered for screening, particularly if parents are consanguineous and there is a history of partial or transient pyridoxine responsiveness.

Biochemical features are characterized by an increase in plasma, urine and CSF αAASA and piperideine-6-carboxylate (P6C), and plasma pipecolic acid due to a defect in α-aminoadipic semialdehyde dehydrogenase in the peroxisomal pipecolic acid pathway of lysine catabolism, which is dominant in the brain [76]. Antiquitin (ATQ) functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway and catalyzes the conversion of α-aminoadipic semialdehyde (αAASA) to α-aminoadipic acid. αAASA is in chemical equilibrium with P6C. Diagnosis is confirmed by mutation analysis of the ATQ gene. Neonatal lactic acidosis, hypoglycemia, profound electrolyte disturbances, hypothyroidism, and diabetes insipidus have been reported along with PDE. Many patients have improved with pyridoxine treatment [69]. Pyridoxal-5’-phosphate (PLP) is a cofactor for liver, muscle, and brain glycogen phosphorylase isozymes and plays an essential role in the mobilization of carbohydrate reserves in a wide variety of tissues [77]. It further acts as a cofactor to serine palmitoyltransferase, which catalyzes the rate-limiting step in the de novo synthesis of sphingolipids [78]. PLP is also essential for sphingosine-1-phosphate (S1P), a bioactive lipid molecule that regulates proliferation, differentiation, migration, and apoptosis [79].

Neuroimaging shows a spectrum of changes, from normal to hypoplasia, of the corpus callosum and megacisterna magna [80] and enlarged ventricles and diffuse cerebral hemispheric gray and white matter atrophy [69, 81]. A few cases have been described with mesial temporal sclerosis [82] and cortical dysplasia [83]. White matter involvement includes pronounced supratentorial white matter changes in newborns with a tendency to resolve with treatment and periventricular dysmyelination in older children [84, 85].

Pathophysiology relates to (i) the accumulation of αAASA and piperideine-6-carboxylate (P6C); (ii) the pyridoxal 5’-phosphate (PLP) deficiency as a consequence of αAASA and P6C accumulation, which inactivates pyridoxal 5’-phosphate through the formation of a P6C-PLP complex; (iii) accumulation of pipecolic acid as a secondary consequence of ATQ deficiency [86]; and (iv) possibly the primary toxicity of pipecolic acid, αAASA, and the P6C/PLP complex. PLP acts as a cofactor in numerous enzyme reactions facilitating transamination and decarboxylation of amino acids and neurotransmitter precursors.

Treatment consists of supplementation with oral pyridoxine 30 mg/kg/day divided in three doses. Oral pyridoxal phosphate (PLP) up to 30 mg/kg/day divided in three doses can be alternatively given as both patients with antiquitin or with PNPO (pyridoxamine 5'-phosphate oxidase) deficiency will respond, whereas PNPO deficient patients will only respond to PLP and not to pyridoxine. An initial trial is given with 100 mg intravenously of pyridoxine, which may result in respiratory arrest in responders. Thus, treatment should be performed with respiratory support if needed. Not all patients with PDE have immediately shown the expected clinical or EEG responses; therefore, Stockler et al [86] suggests that neonates with therapy resistant seizures should receive oral pyridoxine until PDE is fully excluded by biochemical or mutational analysis. Scharer et al [87] has described three different phenotypes in pyridoxine treated patients: (i) complete seizure control and normal developmental outcome, (ii) complete seizure control and developmental delay or intellectual disability, and (iii) incomplete seizure control and developmental delay or intellectual disability. Long-term treatment doses vary between 15-30 mg/kg/day in infants or up to 200 mg/day in neonates and up to 500 mg/day in adults [86]. Folinic acid may have an additional benefit as an add-on treatment. Prenatal treatment with maternal pyridoxine supplementation may possibly improve outcomes [86]. Though there is a good rationale for a lysine-restricted diet, the effect on PDE outcome is yet to be determined and will require multicentre studies. Lysine restricted diets have potential side effects and risks and are a burden for families.

Genetics. Inheritance is autosomal recessive due to mutations in the antiquitin (ALDH7A1) gene at locus 5q31 [88,89].

Patients at Risk for PDE. As recommended by Goutieres and Aicardi [90], pyridoxine dependency should be considered as the cause of intractable seizures in the following situations:

  1. Seizures of unknown etiology in a previously normal infant without an abnormal gestational or perinatal history
  2. The occurrence of long-lasting focal or unilateral seizures
  3. Signs of encephalopathy, such as irritability, restlessness, crying, and vomiting preceding the actual seizures
  4. A history of severe epilepsy in a sibling, often leading to death during status epilepticus
  5. Parental consanguinity

In order NOT to miss milder and atypical presentations, Stockler et al [86] recommends that the following patients should also be considered for screening:

  1. Infants and children with seizures that are partially responsive to pharmacological anticonvulsive drugs (e.g. phenobarbital), particularly if associated with developmental delay and intellectual disability
  2. Neonates with hypoxic ischemic encephalopathy and difficult to control seizures
  3. Patients with a history of transient or unclear response to pyridoxine
  4. Patients with a history of response to folinic acid and/or with the characteristic unidentified peak ‘X' on CSF monoamine analysis
  5. Seizures in any child under the age of one year without an apparent CNS malformation.

Other Pyridoxine-responsive Disorders that Include Seizures Responsive to Pyridoxine or its Vitamers are (i) Pyridoxal phosphate response encephalopathy due to de- ficiency of pyridoxamine 5' phosphate oxidase deficiency (PNPO), which responds only to pyridoxal 5-phosphate; (ii) hypophosphatasia due to tissue non-specific alkaline phosphatase (TNSALP) deficiency with seizures and lethal bone disease; (iii) familial hyperphosphatasia with mental retardation, seizures, and neurological deficits (Mabry syndrome) due to a defect in phosphatidylinositol glycan anchor biosynthesis class V (PIGV) [91-94]; and (iv) hyperprolinemia type 2 due to P5CD deficiency with non-progressive developmental delay with intellectual disability, mild ataxia, and occasional seizures.

c) Folinic Acid Responsive Seizures (FARS) are Genetically Identical to Antiquitin Deficiency

Clinical features include intractable seizures and encephalopathy.

Biochemical features are characterized by two characteristic yet unidentified peaks (peak X) in the HPLC chromatogram for CSF monoamine neurotransmitter analysis. Two patients with the FARS peak had increased levels of alpha-AASA and pipecolic acid in CSF and known or, presumably, pathogenic mutations in the ATQ gene.

Treatment. Patients have shown an improvement of seizures upon administration of folinic acid (3-5 mg/kg/day). Two patients with the CSF marker of FARS responded clinically to pyridoxine. Improved outcomes have been seen with pyridoxine and folinic acid together.

Genetics. FARS has been shown to be genetically identical to ATQ deficiency [95].

d) Pyridoxamine 5'-Phosphate Oxidase (PNPO) Deficiency

Clinical features include neonatal onset seizures that may be clonic, myoclonic, and frequently status epilepticus. Birth is often premature with seizure onset on day 1 or in utero. There may be rotatory eye movements, orobuccal rhythmic movements, myoclonus, hyperexcitability, and hypersalivation. EEG reveals a severe burst suppression pattern or myoclonic epilepsy [96-99]. Without treatment with pyridoxal- 5'-phosphate (PLP), there is severe developmental delay, intractable seizures, and dystonia.

Biochemical features are characterized by hypoglycemia, early lactic acidosis, pancytopenia, and coagulopathy. PLP-responsive epileptic encephalopathy is caused by de- ficiency of pyridoxamine 5'-phosphate oxidase (PNPO). The CSF and urine biochemical profiles are consistent with a reduction of PLP-dependent enzyme aromatic L-amino acid decarboxylase (AADC) activity characterized by (1) build up of metabolites of L-DOPA, including markedly elevated CSF 3-methoxytyrosine and increased urinary excretion of vanillactic acid (VLA) and (2) markedly decreased concentration of dopamine metabolite, homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. The CSF amino acid profile demonstrates elevated glycine, threonine, taurine, and histidine and low arginine [98].

Pathophysiology relates to the disturbance in neurotransmitter metabolism.

Neuroimaging demonstrates progressive hypomyelination and global cerebral atrophy.

Treatment consists of pyridoxal-5'-phosphate(PLP), which brings about a rapid clinical response.

Genetics. Inheritance is autosomal recessive with mutations in the PNPO gene at locus 17q21.32.


The classic approach has been to try each of the vitamers in sequence and to ascertain the clinical and EEG response.

  1. Pyridoxine 100 mg bolus IV with EEG Then 10 mg/kg q8h po X 24 hrs If no definite response (EEG normalization or Sz control)
  2. Folinic acid 5 mg/kg q 24 hrs po X 3 days If no definite response
  3. PLP 10 mg/kg q 8h po X 3 days

However, if seizures are frequent and intractable, or there is epileptic encephalopathy with status, a more immediate and preferable therapeutic approach would be to initiate treatment with a combination of oral PLP with folinic acid in order to achieve earlier seizure control and to thereby avoid further ongoing kindling of seizures. The PLP would treat both the antiquitin defect as well as PNPO deficiency. Serum, urine, and CSF biomarkers should be sent followed by specific gene testing for the suspected disorder. Therapy with PLP and folinic acid should be continued until the specific defect is identified, at which time the treatment could be modified according to the identified disorder. As both urine and plasma αAASA and plasma pipecolic acid are informative in both the untreated and treated states of antiquitin deficiency [86], initiation of therapy with pyridoxine should NOT be delayed for diagnostic purposes, and diagnostic samples can be taken any time before and after treatment. In this way, there would be no delays in initiating treatment, as PLP would treat both the antiquitin defect as well as PNPO deficiency.


Serum glucose, lactate, NH3, quantitative amino acids, acylcarnitines, biotinidase assay,
α-amino adipic semialdehyde (αAASA)*, P6C*, pipecolic acid**
Urine amino acids, organic acids, αAASA*, sulfocysteine
CSF glucose, lactate, amino acids (glycine), neurotransmitters + Peak X (Keith Hyland’s lab) αAASA*, pipecolic acid

Gene testing as indicated by screens - > e.g. antiquitin sequencing

* Because αAASA and P6C are unstable, samples should be frozen immediately after collection.
** Elevated pipecolic acid may also be seen in other inborn errors of metabolism, e.g. generalized peroxisomal dysfunction, hyperlysinemia, and defects of proline metabolism and in liver disease.


AADC L-amino acid decarboxylase
AASA amino adipic semialdehyde
AGAT l-arginine:glycine amidinotransferase
ATQ antiquitin
CO2 carbon dioxide
CNS central nervous system
CSF cerebrospinal fluid
DNA deoxyribonucleic acid
EEG electroencephalogram
FARS folinic acid responsive seizures
FOLR1 cerebral folate transporter I
GAA guanidinoacetic acid
GABA gamma aminobutyric acid
GAMT guanidinoacetate methyltransferase
GLUT1 glucose transporter I
5-HIAA 5-hydroxyindoleacetic acid
HVA homovanillic acid
MTHF methyltetrahydrofolate
MTHFR 5,10-methylenetetrahydrofolate reductase
MRS magnetic resonance spectroscopy
NH3 ammonia
PDE pyridoxine dependent epilepsy
3-PHGDH 3-phosphoglycerate dehydrogenase
P6C piperideine-6-carboxylate
PLP pyridoxal 5'-phosphate
PNPO pyridoxamine 5'-phosphate oxidase
RBC red blood cells
SAM S-adenosylmethionine
VLA vanillactic acid


The author reviewed the literature and organized the content of the paper, wrote the chapter, and has given approval of the final version.

Competing interests

The author has declared that no competing interest exists.

Author contributions

The author acknowledges the important experience gained from caring for the children with these diseases and their families.

Supplementary material

Supplementary material is available at JICNA online.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.


1. Klepper J, Leiendecker B (2007) GLUT1 deficiency syndrome--2007 update. Dev Med Child Neurol 49 (9):707-16. crossref pubmed

2. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI (1991) Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 325 (10):703-9. crossref pubmed

3. Klepper J, Leiendecker B, Bredahl R, Athanassopoulos S, Heinen F, Gertsen E et al. (2002) Introduction of a ketogenic diet in young infants. J Inherit Metab Dis 25 (6):449-60. pubmed

4. Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M et al. (2005) Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 36 (5):302-8. crossref pubmed

5. Pascual JM, Wang D, Lecumberri B, Yang H, Mao X, Yang R et al. (2004) GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinol 150 (5):627-33. pubmed

6. Brockmann K (2009) The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 31 (7):545-52. crossref pubmed

7. Klepper J, Flörcken A, Fischbarg J, Voit T (2003) Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro. Eur J Pediatr 162 (2):84-9. crossref pubmed

8. Klepper J, Willemsen M, Verrips A, Guertsen E, Herrmann R, Kutzick C et al. (2001) Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet 10 (1):63-8. pubmed

9. Klepper J, Scheffer H, Elsaid MF, Kamsteeg EJ, Leferink M, Ben-Omran T (2009) Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 40 (5):207-10. crossref pubmed

10. Schiaffino MC, Bellini C, Costabello L, Caruso U, Jakobs C, Salomons GS et al. (2005) X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation. Neurogenetics 6 (3):165-8. crossref pubmed

11. van de Kamp JM, Mancini GM, Pouwels PJ, Betsalel OT, van Dooren SJ, de Koning I et al. (2011) Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79 (3):264-72. crossref pubmed

12. Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ et al. (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68 (6):1497-500. crossref pubmed

13. Battini R, Chilosi AM, Casarano M, Moro F, Comparini A, Alessandrì MG et al. (2011) Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene. Mol Genet Metab 102 (2):153-6. crossref pubmed

14. Chilosi A, Leuzzi V, Battini R, Tosetti M, Ferretti G, Comparini A et al. (2008) Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect. Neurocase 14 (2):151-61. crossref pubmed

15. Chilosi A, Leuzzi V, Battini R, Tosetti M, Ferretti G, Comparini A et al. (2008) Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect. Neurocase 14 (2):151-61. crossref pubmed

16. Bianchi MC, Tosetti M, Fornai F, Alessandri' MG, Cipriani P, De Vito G et al. (2000) Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol 47 (4):511-3. pubmed

17. Battini R, Alessandrì MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC et al. (2006) Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 148 (6):828-30. crossref pubmed

18. Schulze A, Battini R (2007) Pre-symptomatic treatment of creatine biosynthesis defects. Subcell Biochem 46 ():167-81. pubmed

19. Edvardson S, Korman SH, Livne A, Shaag A, Saada A, Nalbandian R et al. (2010) l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab 101 (2-3):228-32. crossref pubmed

20. Stöckler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M et al. (1994) Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 36 (3):409-13. crossref pubmed

21. Stöckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K (1996) Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 58 (5):914-22. pubmed

22. Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B et al. (1997) Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 131 (4):626-31. pubmed

23. Schulze A, Ebinger F, Rating D, Mayatepek E (2001) Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 74 (4):413-9. crossref pubmed

24. Mercimek-Mahmutoglu S, Dunbar M, Friesen A, Garret S, Hartnett C, Huh L et al. (2012) Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency. Mol Genet Metab 105 (1):155-8. crossref pubmed

25. Verbruggen KT, Sijens PE, Schulze A, Lunsing RJ, Jakobs C, Salomons GS et al. (2007) Successful treatment of a guanidinoacetate methyltransferase deficient patient: findings with relevance to treatment strategy and pathophysiology. Mol Genet Metab 91 (3):294-6. crossref pubmed

26. Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E (1996) 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 74 (6):542-5. pubmed

27. Méneret A, Wiame E, Marelli C, Lenglet T, Van Schaftingen E, Sedel F (2012) A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy. Arch Neurol 69 (7):908-11. crossref pubmed

28. Tabatabaie L, Klomp LW, Rubio-Gozalbo ME, Spaapen LJ, Haagen AA, Dorland L et al. (2011) Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis 34 (1):181-4. crossref pubmed

29. Jaeken J, Detheux M, Fryns JP, Collet JF, Alliet P, Van Schaftingen E (1997) Phosphoserine phosphatase deficiency in a patient with Williams syndrome. J Med Genet 34 (7):594-6. pubmed

30. de Koning TJ, Klomp LW (2004) Serine-deficiency syndromes. Curr Opin Neurol 17 (2):197-204. pubmed

31. de Koning TJ (2006) Treatment with amino acids in serine deficiency disorders. J Inherit Metab Dis 29 (2-3):347-51. crossref pubmed

32. de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I et al. (2004) Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet 364 (9452):2221-2. crossref pubmed

33. Fuchs SA, Dorland L, de Sain-van der Velden MG, Hendriks M, Klomp LW, Berger R et al. (2006) D-serine in the developing human central nervous system. Ann Neurol 60 (4):476-80. crossref pubmed

34. Baumgartner ER, Suormala T, Wick H, Bausch J, Bonjour JP (1985) Biotinidase deficiency: factors responsible for the increased biotin requirement. J Inherit Metab Dis 8 Suppl 1 ():59-64. pubmed

35. Singhi P, Ray M (2011) Ohtahara syndrome with biotinidase deficiency. J Child Neurol 26 (4):507-9. crossref pubmed

36. Kalayci O, Coskun T, Tokatli A, Demir E, Erdem G, Güngör C et al. (1994) Infantile spasms as the initial symptom of biotinidase deficiency. J Pediatr 124 (1):103-4. pubmed

37. (1983) Hearing loss in biotinidase deficiency. Lancet 2 (8363):1365-6. pubmed

38. Wolf B, Grier RE, Parker WD, Goodman SI, Allen RJ (1983) Deficient biotinidase activity in late-onset multiple carboxylase deficiency. N Engl J Med 308 (3):161. crossref pubmed

39. Wolf B, Grier RE, Secor McVoy JR, Heard GS (1985) Biotinidase deficiency: a novel vitamin recycling defect. J Inherit Metab Dis 8 Suppl 1 ():53-8. pubmed

40. Wolf B, Heard GS, Jefferson LG, Proud VK, Nance WE, Weissbecker KA (1985) Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program. N Engl J Med 313 (1):16-9. crossref pubmed

41. Wolf B, Heard GS, Weissbecker KA, McVoy JR, Grier RE, Leshner RT (1985) Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol 18 (5):614-7. crossref pubmed

42. Wolf B: Biotinidase Deficiency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ Seattle (WA): University of Washington, Seattle; 1993-. 2000 Mar 24 [updated 2011 Mar 15].

43. Wolf B, Norrgard K, Pomponio RJ, Mock DM, McVoy JR, Fleischhauer K et al. (1997) Profound biotinidase deficiency in two asymptomatic adults. Am J Med Genet 73 (1):5-9. pubmed

44. Schulz PE, Weiner SP, Belmont JW, Fishman MA (1988) Basal ganglia calcifications in a case of biotinidase deficiency. Neurology 38 (8):1326-8. pubmed

45. Schulz PE, Weiner SP, Belmont JW, Fishman MA (1988) Basal ganglia calcifications in a case of biotinidase deficiency. Neurology 38 (8):1326-8. pubmed

46. Desai S, Ganesan K, Hegde A (2008) Biotinidase deficiency: a reversible metabolic encephalopathy. Neuroimaging and MR spectroscopic findings in a series of four patients. Pediatr Radiol 38 (8):848-56. crossref pubmed

47. Suormala TM, Baumgartner ER, Wick H, Scheibenreiter S, Schweitzer S (1990) Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J Inherit Metab Dis 13 (1):76-92. pubmed

48. Wolf B (2012) Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med 14 (6):565-75. crossref pubmed

49. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E et al. (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127 (5):917-28. crossref pubmed

50. Lanzkowsky P (1970) Congenital malabsorption of folate. Am J Med 48 (5):580-3. pubmed

51. Lanzkowsky P, Erlandson ME, Bezan AI (1969) Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification. Blood 34 (4):452-65. pubmed

52. Corbeel L, Van den Berghe G, Jaeken J, Van Tornout J, Eeckels R (1985) Congenital folate malabsorption. Eur J Pediatr 143 (4):284-90. pubmed

53. Steinschneider M, Sherbany A, Pavlakis S, Emerson R, Lovelace R, De Vivo DC (1990) Congenital folate malabsorption: reversible clinical and neurophysiologic abnormalities. Neurology 40 (8):1315. pubmed

54. Zhao R, Min SH, Qiu A, Sakaris A, Goldberg GL, Sandoval C et al. (2007) The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110 (4):1147-52. crossref pubmed

55. Lasry I, Berman B, Straussberg R, Sofer Y, Bessler H, Sharkia M et al. (2008) A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood 112 (5):2055-61. crossref pubmed

56. Shin DS, Mahadeo K, Min SH, Diop-Bove N, Clayton P, Zhao R et al. (2011) Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Mol Genet Metab 103 (1):33-7. crossref pubmed

57. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P et al. (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85 (3):354-63. crossref pubmed

58. Narisawa K, Wada Y, Saito T, Suzuki H, Kudo M (1977) Infantile type of homocystinuria with N5,10-methylenetetrahydrofolate reductase defect. Tohoku J Exp Med 121 (2):185-94. pubmed/p>

59. Freeman JM, Finkelstein JD, Mudd SH (1975) Folate-responsive homocystinuria and "schizophrenia". A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med 292 (10):491-6. crossref pubmed

60. Shih VE, Salem MZ, Mudd SH, Uhlendorf BW, Adams RD: A new form of homocystinuria due to N(5,10) methylenetetrahydrofolate reductase deficiency. (Abstract) Pediat Res 1972, 6: 395

61. Visy JM, Le Coz P, Chadefaux B, Fressinaud C, Woimant F, Marquet J et al. (1991) Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurology 41 (8):1313-5. pubmed

62. Haworth JC, Dilling LA, Surtees RA, Seargeant LE, Lue-Shing H, Cooper BA et al. (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45 (5):572-6. crossref pubmed

63. Hyland K, Smith I, Bottiglieri T, Perry J, Wendel U, Clayton PT et al. (1988) Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology 38 (3):459-62. pubmed

64. Goyette P, Frosst P, Rosenblatt DS, Rozen R (1995) Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 56 (5):1052-9. pubmed

65. Goyette P, Rozen R (2000) The thermolabile variant 677C-->T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 16 (2):132-8. crossref pubmed

66. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG et al. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 7 (4):551. pubmed

67. Bass NE, Wyllie E, Cohen B, Joseph SA (1996) Pyridoxine-dependent epilepsy: the need for repeated pyridoxine trials and the risk of severe electrocerebral suppression with intravenous pyridoxine infusion. J Child Neurol 11 (5):422-4. pubmed

68. Kroll JS (1985) Pyridoxine for neonatal seizures: an unexpected danger. Dev Med Child Neurol 27 (3):377-9. pubmed

69. Mills PB, Footitt EJ, Mills KA, Tuschl K, Aylett S, Varadkar S et al. (2010) Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 133 (Pt 7):2148-59. crossref pubmed

70. Plecko B, Hikel C, Korenke GC, Schmitt B, Baumgartner M, Baumeister F et al. (2005) Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics 36 (3):200-5. crossref pubmed

71. Nabbout R, Soufflet C, Plouin P, Dulac O (1999) Pyridoxine dependent epilepsy: a suggestive electroclinical pattern. Arch Dis Child Fetal Neonatal Ed 81 (2):F125-9. pubmed

72. Hellström-Westas L, Blennow G, Rosén I (2002) Amplitude-integrated encephalography in pyridoxine-dependent seizures and pyridoxine-responsive seizures. Acta Paediatr 91 (8):977-80. pubmed

73. Mikati MA, Trevathan E, Krishnamoorthy KS, Lombroso CT (1991) Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol 78 (3):215-21. pubmed

74. Bankier A, Turner M, Hopkins IJ (1983) Pyridoxine dependent seizures--a wider clinical spectrum. Arch Dis Child 58 (6):415-8. pubmed

75. Coker SB (1992) Postneonatal vitamin B6-dependent epilepsy. Pediatrics 90 (2 Pt 1):221-3. pubmed

76. Cox R: Errors of lysine metabolism, in MD Valle, AL Beaudet, B Vogelstein, KW Kinzler, SE Antonarakis, AB Ballabio, CR Scriver, B Childs, WS Sly (Eds). The Online Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001

77. Newgard CB, Hwang PK, Fletterick RJ (1989) The family of glycogen phosphorylases: structure and function. Crit Rev Biochem Mol Biol 24 (1):69-99. crossref pubmed

78. Hanada K (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632 (1-3):16-30. pubmed

79. Ikeda M, Kihara A, Igarashi Y (2004) Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5'-phosphate binding domain exposed to the cytosol. Biochem Biophys Res Commun 325 (1):338-43. crossref pubmed

80. Ulvi H, Müngen B, Yakinci C, Yoldaş T (2002) Pyridoxine-dependent seizures: long-term follow-up of two cases with clinical and MRI findings, and pyridoxine treatment. J Trop Pediatr 48 (5):303-6. pubmed

81. Gospe SM, Hecht ST (1998) Longitudinal MRI findings in pyridoxine-dependent seizures. Neurology 51 (1):74-8. pubmed

82. Lott IT, Coulombe T, Di Paolo RV, Richardson EP, Levy HL (1978) Vitamin B6-dependent seizures: pathology and chemical findings in brain. Neurology 28 (1):47-54. pubmed

83. Baxter P (2001) Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol 43 (6):416-20. pubmed

84. Tanaka R, Okumura M, Arima J, Yamakura S, Momoi T (1992) Pyridoxine-dependent seizures: report of a case with atypical clinical features and abnormal MRI scans. J Child Neurol 7 (1):24-8. pubmed

85. Jardim LB, Pires RF, Martins CE, Vargas CR, Vizioli J, Kliemann FA et al. (1994) Pyridoxine-dependent seizures associated with white matter abnormalities. Neuropediatrics 25 (5):259-61. crossref pubmed

86. Stockler S, Plecko B, Gospe SM, Coulter-Mackie M, Connolly M, van Karnebeek C et al. (2011) Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 104 (1-2):48-60. crossref pubmed

87. Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E et al. (2010) The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis 33 (5):571-81. crossref pubmed

88. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M et al. (2006) Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 12 (3):307-9. crossref pubmed

89. Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys E, Jakobs C et al. (2007) Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat 28 (1):19-26. crossref pubmed

90. Goutières F, Aicardi J (1985) Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 17 (2):117-20. crossref pubmed

91. Mabry CC, Bautista A, Kirk RF, Dubilier LD, Braunstein H, Koepke JA (1970) Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits. J Pediatr 77 (1):74-85. pubmed

92. Horn D, Schottmann G, Meinecke P (2010) Hyperphosphatasia with mental retardation, brachytelephalangy, and a distinct facial gestalt: Delineation of a recognizable syndrome. Eur J Med Genet 53 (2):85-8. crossref pubmed

93. Thompson MD, Nezarati MM, Gillessen-Kaesbach G, Meinecke P, Mendoza-Londono R, Mendoza R et al. (2010) Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: Five new patients with Mabry syndrome. Am J Med Genet A 152A (7):1661-9. crossref pubmed

94. Krawitz PM, Schweiger MR, Rödelsperger C, Marcelis C, Kölsch U, Meisel C et al. (2010) Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet 42 (10):827-9. crossref pubmed

95. Gallagher RC, Van Hove JL, Scharer G, Hyland K, Plecko B, Waters PJ et al. (2009) Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol 65 (5):550-6. crossref pubmed

96. Bräutigam C, Hyland K, Wevers R, Sharma R, Wagner L, Stock GJ et al. (2002) Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33 (3):113-7. crossref pubmed

97. Clayton PT, Surtees RA, DeVile C, Hyland K, Heales SJ (2003) Neonatal epileptic encephalopathy. Lancet 361 (9369):1614. pubmed

98. Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ et al. (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum Mol Genet 14 (8):1077-86. crossref pubmed

99. Ruiz A, García-Villoria J, Ormazabal A, Zschocke J, Fiol M, Navarro-Sastre A et al. (2008) A new fatal case of pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency. Mol Genet Metab 93 (2):216-8. crossref pubmed

Cite this article as: Tein I.: Vitamin and cofactor responsive encephalopathies and seizures. JICNA 2015 15:105.


  • There are currently no refbacks.

Copyright (c) 2015 Tein I

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Creative Commons License
Published by the International Child Neurology Association Estd. 1971 © 2004-2017