Epilepsy patients, especially neonates, may present with antenatal and neonatal seizures, including myoclonic seizures, infantile spasms, and tonic spasms. Motor regression, hypotonia, and movement disorders may also be part of the clinical picture of vitamin-responsive epilepsy among children of different ages. Pyridoxine (B6)-dependent epilepsy (PDE), pyridoxal 5’-phosphate-dependent epilepsy, folinic acid-responsive seizures, cerebral folate deficiency, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, creatine disorders, glucose transporter type 1 (GLUT-1) deficiency, mitochondrial disorders, urea cycle disorders, glutaric aciduria, molybdenum cofactor deficiency, isolated sulfite oxidase deficiency, and tetrahydrobiopetrine deficiency are examples of metabolic and vitamin-responsive epilepsies.5,6

Pyridoxine (B6)-dependent epilepsy (PDE) can present early or later in life. Inheritance of PDE is mainly autosomal recessive manner. ALDH7A1 are the comments pathogenic mutations causing PDE.

The neonatal presentation of PDE typically involves early neonatal seizures that are resistant to conventional AEDs. Once intravenous pyridoxine is administered, clinical and electrographic improvements are usually observed. Pyridoxine is recommended for all neonates with intractable seizures, especially before the age of 18 months. Older age presentation of PDE is also reported in the literature as intractable epilepsy and developmental delay. This presentation may be partially responsive to long-term treatment with B6. The presence of elevated α-amino adipic semialdehyde in urine and plasma supports a diagnosis of PDE. The treatment dose of B6 is usually 15-30 mg/kg/d BID (maximum daily dose 500 mg/d) (Table 1).7,8

Epilepsy due to pyridoxal 5’-phosphate-dependent seizures is similar to that of PDE and should be suspected in neonates in whom seizures are intractable to conventional AEDs. Etiology of pyridoxal 5’-phosphate-dependent epilepsy is a mutation in pyridoxamine 5’-phosphate oxidase. Pattern of inheritance of pyridoxal 5’-phosphate-dependent epilepsy is mainly autosomal recessive manner. Infants with pyridoxal 5’-phosphate-dependent epilepsy respond initially to B6, whereas others respond only to pyridoxal 5’-phosphate. Early initiation of pyridoxal 5’-phosphate (PLP) can result in seizure control. Recommended dosage of PLP is (30–50 mg/kg TID).9

Folinic acid-responsive seizures and PDE share biochemical and genetic characteristics. Elevated CSF α-amino adipic semialdehyde and CSF pipecolic acid have been reported in both conditions, as well as similar ALDH7A1 gene mutations. Neonates with folinic acid-responsive seizures may present with epileptic encephalopathy or later-onset seizures. A trial of pyridoxine and folinic acid should be considered in such cases. Dosage of (3–5 mg/kg/d) is recommended.10

Cerebral folate deficiency usually presents with severe developmental delay, intractable epilepsy, movement disorders, and nonspecific white matter changes. It is mainly inherited in an autosomal recessive pattern. A CSF analysis shows low levels the active folate metabolite “5-methyltetrahydrofolate”. A homozygous mutation in the FOLR1 gene has been reported.11 Similar to folinic acid-responsive seizures, cerebral folate deficiency patients can be treated with pyridoxine and folinic acid. This combination can result in cognitive and seizures improvement.11 Biotinidase deficiency is another form of cofactor-responsive epilepsy that presents with a spectrum of signs and symptoms of intractable epilepsy, developmental delay, ataxia, hearing loss, hypotonia,visual problems, alopecia and skin rash. Patients with later onset biotinidase deficiency may present with focal motor symptoms and visual problems. Deficient biotinidase enzyme activity (<30%) in serum supports a diagnosis of biotinidase deficiency. The diagnosis is confirmed by sequence analysis of the BTD gene. Biotin supplementation in a dose ranging from 10 to 20 mg/d can improve the clinical picture, especially if started early.12 Recurrent subacute encephalopathy is one of the importance early features of biotin-thiamine-responsive basal ganglia disease. It is an increasingly recognized condition and can lead to coma and death if not promptly treated. Patients with biotin-thiamine-responsive basal ganglia disease may also have seizures, dystonia, and ophthalmoplegia, which may be provoked by a fever, minor stress, or surgery. Brain MRI is pathognomonic and shows T₂ increased signal intensity in the putamen, caudate, globi pallidi, thalami, brainstem, brain cortex, and cerebellum. Many reported cases were inherited as an autosomal recessive pattern due to SLC19A3 pathogenic variants.13 Early treatment with biotin and thiamine can result in a dramatic clinical improvement. Biotin is given in dosage of 5–10 mg/kg/d simultaneously with thiamine in dosage range from 300 to 900 mg/d.13

Cerebral creatine deficiency syndromes described in the literature include L-arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase (GAMT) deficiency, and creatine transporter deficiency. The presentation of cerebral creatine deficiency syndromes usually includes seizures, intellectual delay, autistic features, speech delay, and movement disorders. Pathogenic variants of GAMT, GATM, and SLC6A8 are diagnostic. Cerebral creatine pool is almost completely depleted on brain MR spectroscopy in males and females with GAMT deficiency and L-arginine:glycine amidinotransferase deficiency and in males with creatine transporter deficiency. Treatment with oral creatine monohydrate (dosage of 100–200 mg/kg in 3 doses) and a special diet can result in improvements in seizures and intellectual improvements (Table 1).14,15

In GLUT-1 deficiency, SLC2A1 gene mutations lead to a defect in glucose transport to brain cells and low CSF glucose. The clinical spectrum of GLUT-1 deficiency ranges from movement disorders to developmental delay, microcephaly and intractable epilepsy. A CSF glucose to serum glucose ratio of < 0.4 supports a diagnosis of GLUT-1 deficiency. A ketogenic diet is the gold standard of care in patients with GLUT-1 deficiency.16

Some mitochondrial disorders can be associated with epilepsy. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fibers (MERRF) are examples of progressive myoclonic epilepsies. A high serum, CSF, and magnetic resonance spectroscopy (MRS) lactate level, along with a muscle biopsy, may provide early clues of mitochondrial disorders.17 Oral administration of riboflavin (dose: 50–400 mg po daily in children and 50–400 mg po daily in adults) or ubiquinone (coenzyme Q10) (dose: 2–8 mg/kg po twice per day in children and 50–600 mg po given daily in adults) can yield improvements in some cases. Trials of cocktails of other mitochondrial supplements can also be considered (e.g., -L-creatine, L-arginine, L-carnitine, vitamin E, vitamin C, and α-lipoic) (Table 2).18

Clinical presentation of urea cycle disorders can occur early in the neonatal period with encephalopathy, hypothermia, cerebral edema, and seizures. Late presentation can be episodic encephalopathy, seizures, vomiting, and ataxia.19 Accumulation of ammonia and other precursor metabolites attributed to specific enzyme deficiency in the urea cycle. High ammonia, absence of metabolic acidosis or ketosis, and abnormal plasma levels of amino acids suggest a diagnosis of urea cycle disorders. The diagnosis is confirmed by molecular genetic testing and abnormal enzyme activity. Treatments for urea cycle disorders include dialysis in cases of hyperammonemic coma, catabolism reversal by glucose infusion and an insulin drip, and arginine and pharmacological scavenging of excess nitrogen.20,21

Glutaric aciduria occurs due to increased glutaric acid urinary excretion. It is usually inherited as an autosomal recessive manner. This leads to 3-hydroxyglutaric and glutaric acid accumulation. Glutaryl-CoA dehydrogenase gene heterogeneous mutations have been described.22 Clinically, glutaric aciduria can present with acute decompensation after a febrile illness or dehydration. Later, macrocephaly, dystonia, and seizures may be observed. In chronic cases, brain MRI shows basal ganglia hyperintensities, cyst-like dilatation of Sylvian fissures, and brain atrophy. The addition of riboflavin (dose: 200 mg/d) and L-carnitine (dose: 100 mg/kg/d) to antiepileptic medications can result in a significant clinical improvement.23

Molybdenum cofactor deficiency is a severe epileptic encephalopathy. It is an inherited condition that usually occurs early in the neonatal period. It is similar to isolated sulfite oxidase deficiency, with the presence of intractable seizures, feeding difficulties, progressive severe intellectual disability, and spasticity.24

Molybdenum cofactor deficiency investigations show low serum uric acid levels and high urinary xanthine and hypoxanthine levels due to loss of function of xanthine dehydrogenase. Isolated sulfite oxidase deficiency is associated with positive urine sulfite on dipstick screening, elevated urinary thiosulfate and S-sulfocysteine, low urinary organic sulfate, normal serum uric acid levels, and low plasma total homocysteine. Molybdenum cofactor deficiency is caused by MOCS1, MOCS2, and GPHN mutations. On the other hand, isolated sulfite oxidase deficiency is caused by pathogenic variants in the SUOX gene.24 Intravenous administration of 80 to 160 µg of purified cyclic pyranopterin monophosphate/kg of body weight can improve seizures in molybdenum cofactor deficiency.25,26 A low-protein diet restricted in cysteine and methionine, betaine, thiamine, cysteamine, and penicillamine (chelating agents used to chelate sulfite) can be used to manage cases of isolated sulfite oxidase deficiency and alleviate seizures with no much benefit.

Tetrahydrobiopetrine (BH4) deficiency is a rare metabolic disease, which is responsible for 2% of hyperphenylalaninemia cases. Typically, infants with (BH4) deficienc are hypotonic and exhibit erratic myoclonus and oculogyric seizures, as well as progressive neurological deterioration, “also named malignant hyperphenylalaninemia”. Hyperphenylalaninemia, abnormalities in pterin metabolites in urine, dihydropteridine reductase in serum, CSF pterins, and neurotransmitters and reduced enzyme activity (red blood cells or fibroblasts) support a diagnosis of BH4 deficiency. Early treatment with a phenylalanine-restricted diet, BH4 (5α10 mg/kg/d), L-dopa, and 5-hydroxytryptophan can lead to improved outcomes.27