Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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This article includes discussion of pyridoxine-dependent epilepsy, vitamin B6-dependent seizures, pyridoxine-dependent seizures, classic neonatal pyridoxine-dependent seizures, and postneonatal pyridoxine-dependent epilepsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
A newborn with refractory seizures controlled with pyridoxine was first reported in 1954, and for many years, no markers to identify this condition besides the therapeutic response were known. In more recent years, mutations in the ALDH7A1 gene encoding alpha-amino-adipic semialdehyde dehydrogenase (antiquitin) have been identified. In addition to the wide range of differential diagnoses with epileptic and nonepileptic seizures in infants, two other intractable epileptic conditions should be considered that occur in the neonatal and infancy period: pyridoxal phosphate deficiency and folinic acid responsive seizures.
• Pyridoxine dependency should be considered if:
-- Family history shows:
-- The infant shows:
- unusual fetal movements suggestive of intrauterine seizures
• In developing countries, performing genetic studies is difficult; thus, administration of pyridoxine in infants with refractory seizures with unknown etiology is still very useful, not only from a therapeutic but also from a diagnostic point of view. Once a clinical diagnosis of pyridoxine dependency has been established by demonstrating cessation of seizures after the addition of pyridoxine to the treatment, biochemical and molecular studies are recommended.
• In an infant with good response to pyridoxine, the vitamins should be withdrawn to confirm the diagnosis. If the seizures recur, lifelong pyridoxine therapy is required.
• All infants under 2 years of age with drug-resistant seizures of unknown etiology should be given pyridoxine.
• Treatment of pyridoxine-dependent epilepsy is considered to be beneficial, even though prognosis may vary even after early treatment.
Hunt and colleagues first described a girl who began twitching at 3 hours of life; she began experiencing generalized seizures at 5 days of age (45). The seizures were refractory to conventional antiseizure medications. An intramuscular injection of multivitamins controlled the seizures for 48 to 56 hours, whereas subsequent standard doses of oral vitamin supplements did not. Pyridoxine (vitamin B6) was eventually identified as the fraction of the multivitamin preparation responsible for clinical efficacy. Withdrawal of the vitamins led to seizure recurrence within 50 hours. The entity was named “pyridoxine dependency” to distinguish it from pyridoxine deficiency as the patient had no antecedents to suspect pyridoxine deficiency, and high doses of pyridoxine were necessary to control the seizures. A related condition designated as pyridoxine-responsive seizure includes infants and young children with seizures who respond initially to pyridoxine, but who lack seizure recurrence with pyridoxine withdrawal (07; 08). Pyridoxine-dependent epilepsy is considered as a prototypical form of metabolic epilepsy (92).
Classic neonatal form. Infants with pyridoxine dependency may initially present with episodes of restlessness, irritability, and occasionally hypotonia or poor feeding. Abnormal Apgar scores and cord blood gases may also be observed. For this reason, it is not uncommon for these newborns to be diagnosed with hypoxic-ischemic encephalopathy (08). Episodes of encephalopathy may be seen in older infants prior to recurrence of seizures and during intercurrent infection. The seizures typically begin soon after birth and can be of multiple types, such as focal or bilateral motor seizures, epileptic spasms, and myoclonic seizures. The seizures are refractory to standard antiseizure medications but respond well to pyridoxine administration; occasionally, untreated patients have died of status epilepticus. Developmental disabilities are commonly found, which may be independent of the timing of pyridoxine therapy (79). Prolonged seizures as status epilepticus have been associated with pyridoxine dependency in infants (98). Some patients present with intrauterine convulsions (11). There may also be a family history of a sibling who died of status epilepticus in infancy.
Late-onset seizures. Numerous “atypical” presentations of pyridoxine-dependent seizures have been described, mostly involving seizure onset beyond the neonatal period. Cases with seizure onset up to 30 months of age have been observed (41; 23). These late-onset cases are sometimes referred to as “postneonatal pyridoxine-dependent epilepsy.” The seizure types in late-presenting cases are less predictable than in early-onset ones. Generalized tonic or clonic seizures are frequently described. Focal seizures with or without secondary generalization have been reported as well (07; 22; 92). The late-onset form is more frequent than the classic neonatal form.
Infantile epileptic spasm syndrome with or without hypsarrhythmia is rare but may occur (36; 50). Kalser and colleagues reported a case of infantile spasms without hypsarrhythmia and paroxysmal eye-head movement pyridoxine-dependent epilepsy due to PLPBP/PLPHP deficiency (50). On the other hand, our group studied a patient with infantile epileptic spasm syndrome who responded well to pyridoxine. Pyridoxine withdrawal led to recurrence of the seizures, which stopped again after restarting the vitamin. Unfortunately, genetic studies could not be performed.
Early-onset encephalopathy with burst suppression may also occur (48).
(1) Prolonged seizure-free period (4 weeks to 3 months) on antiseizure medications before administration of pyridoxine.
(2) Prolonged remission (lasting 5.5 months) after discontinuing pyridoxine.
(3) History of fetal distress in labor with seizures incorrectly attributed to intrauterine hypoxia.
There are patients that have folinic acid-responsive seizures associated with α-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene that are identical to the major form of pyridoxine-dependent epilepsy (35). In these patients, treatment with both folinic acid and pyridoxine is recommended (35). These findings indicate folinic acid-responsive seizures are part of the phenotypic continuum of pyridoxine-dependent seizures (39).
Other atypical presentations involve unusual responses to medication. One patient developed pyridoxine-dependent seizures 6 weeks after the successful discontinuation of phenobarbital used to control neonatal seizures (40). Initial pyridoxine treatment failure followed months later by the successful treatment of recurrent seizures with pyridoxine has also been reported (03). Pyridoxine-dependent seizures were genetically confirmed in a 19-year-old patient with a history of neonatal seizures associated with shunted hydrocephalus and drug-resistant status epilepticus (80). Symptoms manifesting in the large phenotypic spectrum of patients with pyridoxine-dependent epilepsy have been described (94).
Juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency was described in a female with homozygosity for the most prevalent ALDH7A1 missense mutation. The patient was diagnosed through family analysis because of an affected offspring that had neonatal pyridoxine-responsive seizures. Although seizures in the mother had been incompletely controlled by levetiracetam, she remained seizure-free on pyridoxine monotherapy 200 mg/day. Her fourth pregnancy resulted in an affected female who was prospectively treated and never developed seizures, with a normal outcome at 2 years of age while on pyridoxine (83).
Hydrocephalus is a very rare manifestation in pyridoxine-dependent epilepsy that may appear at 6 to 7 months of age. A patient with seizure onset at 13 hours of life who developed hydrocephalus was reported. She remained seizure-free on antiseizure medications, vitamins, and cofactors until 5 months of age when seizures reappeared together with hydrocephalus. It was postulated that the pathogenesis of hydrocephalus is related to the high expression of antiquitin in choroid plexus epithelium, which is where cerebrospinal fluid is produced (69).
Neurocognitive function. Neurodevelopment is affected in 75% of the pyridoxine-treated patients (04; 16). Earlier seizure onset has been associated with worse cognitive function and delay in diagnosis and pyridoxine treatment initiation was found to correlate with increased risk for intellectual disability (04; 31).
Individuals in whom seizures are incompletely controlled with pyridoxine require concurrent treatment with one or more antiseizure medications and have significant intellectual disability (04; 94). Some affected individuals with normal intellectual function have been reported (04; 16; 94; 31).
EEG abnormalities. Patients with pyridoxine dependency do not have a characteristic EEG pattern (90). In a retrospective study of patients with pretreatment pyridoxine-dependent epilepsy, Mikati and coworkers identified high-voltage, bilaterally synchronous 1- to 4-Hz EEG activity that occurred in bursts and was associated with intermixed spikes and sharp waves (59). Nabbout and coworkers also found high-voltage rhythmic delta activity in neonates, but the activity was continuous rather than paroxysmal (67). Continuous and discontinuous backgrounds, suppression burst-like patterns, and hypsarrhythmia have been reported (67; 68). However, the features were not found in all patients reviewed. Such activity noted in a neonatal recording may suggest pyridoxine-dependent seizures, but the absence of the finding does not rule out the diagnosis. A normal EEG does not exclude the diagnosis either (59). On the other hand, the EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy (14).
Neuroradiological findings. Neuroimaging findings are diverse and range from normal to neonatal intracerebral hemorrhage, subependymal cysts, ventriculomegaly, and significant cortical dysplasia or hydrocephalus (61; 94). In a large study, the most common MRI findings were hypoplasia of the corpus callosum and reduced white matter (61). Other findings may be incomplete or delayed myelination, hypoplasia of the optic chiasm or nerve, and hypoplasia of the cerebellum; rare findings are arachnoidal cysts and hypoplasia of the brainstem and pons (94). Magnetic resonance spectroscopy findings in a patient with pyridoxine-dependent seizures showed a decrease in N-acetyl-aspartate to creatine ratio (32).
Neuropathological findings. In an untreated patient with molecularly confirmed antiquitin deficiency, postautopsy macroscopic and histological examination showed a combination of seizure-related lesions consisting of extensive areas of cortical necrosis, gliosis, and hippocampal sclerosis. Developmental abnormalities including corpus callosum dysgenesis and corticospinal pathfinding anomalies were also seen (56).
Diagnosing pyridoxine-dependent epilepsy is important because early treatment improves outcome. Unfortunately, infants with early-onset seizures initially responsive to routine antiseizure medications have a poor prognosis. A correlation with the delay before treatment has been found. In early-onset pyridoxine-dependent epilepsy, a delay of up to 4 days does not seem to cause additional harm, whereas delays of more than 1 week are associated with an increased risk of learning difficulties and cerebral palsy. Patients with a later onset tolerate much longer delays without apparent harm (07).
Some evidence suggests that antenatal pyridoxine supplementation may be effective in preventing intrauterine seizures, decreasing the risk of complicated birth and improving neurodevelopmental outcome (14).
Additionally, the maintenance dose may have some influence on outcome (07). Nevertheless, even with early treatment, the outcome is poor, and many children show learning difficulties. Neuropsychological assessment shows that children who have been treated early are within the normal range but below average on nonverbal measures. On verbal tasks, their receptive verbal skills also show to be normal, but expressive language functions are impaired. This finding is typical in children with early-onset pyridoxine-dependent seizures but is less evident in children with later-onset forms. Children with the early-onset form may have severe articulatory dyspraxia and may need special schooling (07).
The patient, a 12-month-old girl, was born full-term; she became irritable and began having repetitive, brief, bilateral clonic seizures in the upper limbs at 1.5 months of age. The interictal EEGs as well as neuroradiological imaging and neurometabolic work-up were normal; all failed to identify an etiology. At 2 months of age, a pyridoxine trial was performed with 200 mg per day administered orally. At 5 months of age, withdrawal was attempted; pyridoxine was stopped abruptly, and the seizures recurred 7 days later. Pyridoxine was reintroduced, and the baby remained seizure-free for 7 months.
Her sister with mental retardation and refractory seizures that had started at 2 months of age died during status epilepticus when she was 4 years old; she never received pyridoxine. Her 16-year-old brother had drug-resistant seizures that started at 3 days of life; he developed severe encephalopathy. At 15 years of age, 400 mg/day of pyridoxine was introduced, and he improved significantly, both in regards to seizure frequency and alertness.
In this familial case, pyridoxine could be administered early because of the familial antecedents. However, in an infant under 2 years of age with refractory seizures without known etiology, the treatment with pyridoxine is always indicated.
Alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency has been identified as a major cause of this disorder, causing accumulation of both alpha-aminoadipic semialdehyde dehydrogenase and pipecolic acid in body fluids (18; 87). Elevated urinary concentration of alpha-aminoadipic semialdehyde is a more sensitive biomarker than pipecolic acid for pyridoxine-dependent epilepsy. Elevated plasma concentrations of alpha-aminoadipic semialdehyde are also present (81). Children with pyridoxine-dependent seizures have mutations in the ALDH7A1 gene encoding alpha-AASA dehydrogenase (62; 77; 12; 85).
Pyridoxal-5-phosphate is involved as a cofactor in numerous enzymatic reactions including glutamic acid decarboxylase (GAD), which converts the excitatory neurotransmitter, glutamate, to gamma-amino-butyric acid (GABA), the principal inhibitory neurotransmitter in the mammalian CNS. Both of these neurotransmitters are thought to play important roles in the mechanisms of epileptic phenomena (19; 52; 51; 05; 24). Impaired electron transport chain function, accumulation of glutamate in the CNS, tricarboxylic acid cycle dysfunction in human ALDH7A1 pyridoxine-dependent epilepsy, an abnormal GABA pathway, tricarboxylic acid cycle, and electron transport chain in aldh7a1 knock-out zebrafish were found. It was suggested that CNS glutamate toxicity and impaired energy production may play important roles in the disease neuropathogenesis and severity in human pyridoxine-dependent epilepsy (64).
Abnormal activity of delta-1-piperideine-6-carboxylate (P6C)-α-AASA results in increased levels of P6C, which is the cyclic Schiff base of α-AASA. These two substances are in equilibrium with one another. P6C, in turn, inactivates pyridoxal-phosphate (PLP) by condensing with the cofactor, and this likely results in abnormal metabolism of the neurotransmitter (62).
AASA is formed by the catabolization of lysine through the saccharopine and pipecolate pathways and is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). In a mouse model, the saccharopine pathway was indicated to be primarily responsible for body’s production of AASA/P6C. This finding may lead to the development of new therapies for pyridoxine-dependent epilepsy targeted at inhibiting the saccharopine pathway upstream of AASA/P6C synthesis (74; 29). A study that evaluated the phenotype, biochemical features, genotype, and treatment outcome of pyridoxine-dependent epilepsy found no correlation between severity of the phenotype and the degree of α-AASA elevation in urine or genotype (02).
Mutations in a recombinant human antiquitin cDNA were generated and expressed in Escherichia coli. In the E coli expression system, all the mutants were stably expressed but lacked enzymatic activity. This finding is consistent with the pathogenicity of these mutations in vivo (28).
The presence of Roth spots in a patient with pyridoxine-dependent epilepsy may suggest a pathogenic mechanism of vasogenic damage (17).
Antiquitin is expressed within glial cells in the brain, and its dysfunction in pyridoxine-dependent epilepsy is associated with neuronal migration abnormalities and other structural brain defects. These malformations persist despite postnatal pyridoxine supplementation and likely contribute to neurodevelopmental impairments (46).
In a model of Aldh7a1-knock-out mice, Al-Shekaili and colleagues found evidence of an impaired amino acid profile and increased levels of methionine sulfoxide, an oxidative stress biomarker, in the mouse brains (01). This suggests that increased oxidative stress may be a novel pathobiochemical mechanism in ALDH7A1 deficiency. Previously, it was found that ALDH7A1 protects cells against oxidative stress through different pathways (21). These findings may lead to research into new treatment options using antioxidants as supplements or adjuvant therapy (97).
Knock-out ALDH7A1 zebrafish (75; 100) and mouse models (01) for pyridoxine-dependent epilepsy due to antiquitin deficiency may provide valuable insights into pyridoxine-dependent epilepsy pathophysiology. Further research may offer new opportunities for drug screening and improve neurodevelopmental outcomes for the condition.
Genetic studies and counseling. If ALDH7A1 pathogenic variants have been identified in an affected family member, carrier testing is possible in at-risk relatives for early diagnosis and treatment. Prenatal testing for pregnancies at increased risk may be possible at clinical laboratories that offer either testing of this particular gene or custom prenatal testing. In the case of parenthood planning, couples at risk may opt for preimplantation genetic diagnosis (PGD). Genetic counseling on risks and possibilities should be included in the management of these families (39).
A study in 185 subjects with a diagnosis of pyridoxine-dependent epilepsy has added 47 novel variants to the literature, resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, an incidence of approximately 1 of 64,352 live births was estimated, suggesting that pyridoxine-dependent epilepsy may be more common than initially estimated (25).
In 1996, Baxter and colleagues reported an estimated point prevalence of pyridoxine-dependent seizures of 1:100,000 in children younger than 16 years of age in the United Kingdom (09). Subsequently, the same group reported an incidence of 1:350,000 live births per year in the United Kingdom and Ireland, based on definite, probable, and possible cases of pyridoxine dependency (33). Birth incidence in the Netherlands was found to be 1:396,000 (10). However, according to the main reports we may consider an estimated prevalence of between one per 276,000 and one per 700,000 births (07; 13; 38; 18).
In familial cases ALDH7A1 gene analysis provides a means for prenatal diagnosis, and pyridoxine treatment should be started to avoid neurologic damage in the fetus (15).
Epileptic syndromes should be considered in the differential diagnosis, particularly familial types such as benign familial neonatal seizures and benign familial infantile seizures.
In symptomatic focal epilepsies, etiologic considerations include structural abnormalities (congenital malformations), infections (meningitis, encephalitis), neoplasms, hemorrhage, and cardiovascular causes (arteriovenous malformations, embolic stroke). Seizures secondary to common metabolic disturbances should also be considered. Epileptic syndromes as differential diagnoses of pyridoxine dependency are listed in Table 1.
• Self-limited familial and nonfamilial neonatal epilepsy
The list of differential diagnoses of pyridoxine-dependency and paroxysmal nonepileptic events in infancy is long. Table 2 lists the nonepileptic episodic events in infancy.
• Benign neonatal sleep myoclonus
Pyridoxine dependency should be suspected if:
• Family history shows:
• The infant shows:
- unusual fetal movements suggestive of intrauterine convulsions
In neonates and infants without demonstrable brain lesions, metabolic causes (eg, hypocalcemia, hypoglycemia, hyponatremia) and inborn errors of metabolism (eg, urea cycle disorders, nonketotic hyperglycinemia, organic acidurias, biotin disorders, and pyruvate dehydrogenase deficiency) should be ruled out, as well as molybdenum cofactor deficiency and isolated sulfite oxidase deficiency, in which levels of α-AASA are also high (60).
Two pyridoxine-dependent epilepsies should be considered in the differential diagnosis in certain pyridoxine-dependent epilepsy patients with no mutation of the ALDH7A1 gene:
PNPO-associated pyridoxine-dependent epilepsy is caused by biallelic pathogenic variants in the pyridoxine-5′-phosphateoxidase (PNPO) gene. In these patients, pyridoxine is ineffective, whereas administration of pyridoxal phosphate results in a clinical response (63; 38; 44; 71). A study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5′-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiseizure medication-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis (73).
Partial responsiveness to pyridoxine in patients with PNPO deficiency and a mutation in the 3:c.352G > A p.Gly118R gene is known (66). A child with this mutation, riboflavin dependence, and transient worsening of seizures off pyridoxine has been described. This case highlights the importance of identifying the precise gene mutation sequence to properly identify variants relative to individual phenotypic expression, treatment responsiveness, and need for added vitamin supplementation (66).
PLPBP-associated pyridoxine-dependent epilepsy or PLP binding protein deficiency is caused by biallelic pathogenic variants in the PLPBP gene (previously named PROSC) encoding a pyridoxal-phosphate-binding protein (30; 47; 49). The early-onset intractable seizures in PLPHP deficiency are responsive to pyridoxine and/or PLP. Patients show developmental delay and structural brain abnormalities, most notably simplified gyral pattern and cyst-like structures adjacent to the anterior horns (30; 78; 49). PLPBP-associated pyridoxine-dependent epilepsy is rare and only a few patients are reported (49).
A founder mutation in the PLPBP gene was identified in a French Canadian region by whole exome sequencing of three unrelated families showing a homozygous pathogenic mutation c.370_373del, p.Asp124fs in five persons (72).
Finally, the diagnosis of pyridoxine deficiency should be considered as well. The deficiency can be due to insufficient dietary intake, gastrointestinal malabsorptive states, liver diseases, and leukemia. Relative depletion states due to increased metabolic demands are also possible (eg, hyperthyroidism). Isoniazid therapy causes a decrease in vitamin B6 levels. The clinical manifestations are similar in both the pyridoxine-deficiency and pyridoxine-dependency state, but peripheral neuritis, dermatitis, and anemia are only associated with the deficiency state. Increased concentration of α-aminoadipic semialdehyde (α-AASA) in urine and/or plasma identifies the pyridoxine-dependent state.
The rare occurrence of this disease, its heterogeneous presentation, and variable response to treatment make the diagnosis difficult. However, measurement of urinary alpha-AASA is a simple way of confirming the diagnosis of pyridoxine-dependent seizures, and ALDH7A1 gene analysis provides a means for prenatal diagnosis.
Beyond the laboratory tests, neuroimaging, and other supportive studies warranted by the history and physical exam, a pyridoxine challenge may be part of the diagnostic work-up for a pediatric patient with medically refractory seizures of unknown etiology. In practice, pyridoxine challenges are usually associated with antiseizure medications. As such, cessation of seizure activity in response to pyridoxine would be suggestive, but not conclusive, of pyridoxine dependency. To confirm the diagnosis, pyridoxine therapy would have to be discontinued, followed by seizures that again respond to pyridoxine. Pipecolic acid in plasma and cerebral spinal fluid may serve as a nonspecific diagnostic marker for this disorder (76). Pyridoxine challenge is especially valid in countries where measurement of urinary alpha-AASA and ALDH7A1 gene analysis is not possible (22; 92). In pyridoxine-dependent epilepsy, simultaneous quantification of multiple lysine metabolites, including α-aminoadipic semialdehyde, piperideine-6-carboxylate, pipecolic acid, and α-aminoadipic acid in plasma, serum, dried blood spots, urine, and dried urine spots might play an important role not only in the diagnosis but also in the management of the disorder (96).
Intravenous pyridoxine should be given with concurrent clinical and EEG monitoring. The classic response is a dramatic cessation of ongoing seizures, usually within 10 minutes of injection. The EEG usually normalizes a few minutes later. In some cases, seizures take up to 1 hour to stop, and the EEG may take several hours to normalize (84).
Sometimes, however, the response to pyridoxine may not be immediate and total (61). An adequate trial of pyridoxine (minimum 72 hours) with careful clinical and EEG monitoring is necessary, and if there is any sign of improvement, pyridoxine should be continued. A repeat trial should be considered if seizures remain poorly controlled.
There is a tendency to regard structural brain abnormalities as a sufficient cause of epilepsy; hence, alternative diagnoses, such as pyridoxine deficiency, may be missed (61). The diagnosis of pyridoxine deficiency may also be difficult due to the possibility of multisystem pathology in neonates and infants. Thus, Mills and colleagues consider it useful to perform a biochemical and DNA test for antiquitin deficiency in a wide range of infants with epilepsy (61).
Different groups have identified novel biomarkers for pyridoxine-dependent epilepsy that may be used in current newborn screening programs in a cost-effective manner (57; 95). 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) was identified and suggested as a potential newborn screening biomarker for pyridoxine-dependent seizures in dried bloodspots (34).
Patients need lifelong supplements of pyridoxine. Currently, there are no controlled studies to define the optimal dose due to the rarity of the disorder (39). The International PDE Consortium has published clinical practice guidelines for pyridoxine-dependent epilepsy (26). The doses of pyridoxine recommended by age are in newborns 100 mg/day, in infants 30 mg/kg/day with a maximum of 300 mg/day, and in children, adolescents, and adults 30 mg/kg/day with a maximum of 500 mg/day. In times of seizure exacerbation during an acute illness, the dose of pyridoxine may be doubled up to a maximum of 60 mg/kg/day (in children) or 500 mg/day (adolescents and adults) for up to 3 days. In addition, in times of illness adequate caloric intake should be ensured to prevent catabolism of endogenous protein and protein intake should be reduced (26; 34).
In patients with folinic acid-responsive seizures associated with α-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene the recommended dose of folinic acid is 2.5 to 5 mg twice daily. If seizures recur, an increase in folinic acid up to 8 mg/kg/day can be used, together with ASM if necessary (88). Treatment with both pyridoxine and folinic acid as well as a lysine-restricted diet to reduce α-AASA levels may be considered (35).
High doses carry the risk of developing a reversible peripheral sensory neuropathy. The risk of peripheral neuropathy must be weighed against the potential neurodevelopmental benefits of increased doses of pyridoxine. Adjustment of the dose of pyridoxine might prevent the development of intellectual disability and produce remission of seizures and normalization of CSF glutamate (06). In a patient with pyridoxine-dependent seizures with a partial response to vitamin B6, folinic acid should be added (82). Currently, urinary alpha-aminoadipic semialdehyde is a reliable biomarker of pyridoxine-dependent epilepsy, even under pyridoxine treatment with good evolution; thus, antiquitin gene analysis should be performed (70).
Dietary lysine restriction as an adjunct to pyridoxine therapy was well tolerated with significant decrease of potentially neurotoxic biomarkers and with the potential to improve developmental outcomes and seizure control in children with pyridoxine-dependent epilepsy caused by antiquin deficiency (84; 91; 93; 99; 53). Arginine fortification has proven safe as an add-on treatment to lysine restriction as well as effective in improving outcomes. Arginine supplement of 400 mg/kg/day, together with pyridoxine 200 mg/kg/day, a decrease in CSF alpha-AASA, and improvement in general abilities as well as verbal and motor functions were reported (58; 92; 55). Triple therapy (pyridoxine, lysine-restricted diet, and arginine supplementation) is tried with the aim to improve epilepsy control and neurocognitive development in patients with pyridoxine-dependent epilepsy (55; 65).
It should be taken into account that despite seizure control, neurodevelopment is normal in only 25% of the pyridoxine-treated patients (04; 16). On the other hand, lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients (20; 26; 86). However, if the treatment with pyridoxine and lysine-reduction therapies was started in the first 6 months of life, it was associated with a significant improvement on developmental testing (27).
Mutations in ALDH7A1, MOCS2, and ALDH4A1 are found to lead to build-up of reactive aldehydes (α-aminoadipic semialdehyde, γ-glutamic semialdehyde) that may react nonenzymatically with macromolecules of brain cells. Such reactions may produce "advanced glycation end products" (AGEs). AGEs trigger inflammation in the brain. Development of aldehyde-quenching, anti-AGE, or anti-inflammatory therapies may, therefore, be possible strategies to protect cognitive development and prevent intellectual disability in children with pyridoxine-dependent epilepsy (42).
Vitamin therapy may cause considerable side effects. Some studies report patients presenting with neurologic manifestations and respiratory distress as a result of a pyridoxine challenge. Severity of the side effects of pyridoxine therapy ranges from excessive sleepiness and lethargy to hypotonia, hypotension, hypothermia, bradycardia, and prolonged apnea requiring intubation and assisted ventilation (43; 54; 59; 89; 03; 67).
Prognosis for seizure control is excellent in compliant pyridoxine-dependent patients. However, most children with this disorder have some degree of intellectual disability, regardless of the age of diagnosis and treatment (04; 61). Neurodevelopment is normal in only 25% of pyridoxine-treated patients (04; 16). Early diagnosis and treatment are encouraged.
A small subgroup of patients with pyridoxine-dependent epilepsy is characterized by late-onset beyond 2 months of age. In this subgroup, a relatively good cognitive outcome was observed. de Rooy and colleagues studied four late-onset patients who had a relatively good cognitive outcome (31). No clear association was found between ALDH7A1 mutations, α-AASA and pipecolic acid levels, medication during pregnancy, delivery, treatment delay, number of seizures, pyridoxine dose, adjuvant therapy, and findings on brain MRI. Nevertheless, it was speculated that a less severe genotype may be present in three patients, and maternal medication could be accountable for better outcome in two patients. Therefore, the better outcome may be related to a combination of factors: a yet unknown protective factor, different genetic variations, functional variation and secondarily variation in treatment regimens, and absence of neonatal-seizure-induced brain damage (31).
Each sibling of an individual with pyridoxine-dependent seizures has a 25% risk of intrauterine convulsions (11; 67). Pregnant mothers of infants with pyridoxine dependency should receive 50 to 100 mg pyridoxine daily during the final half of gestation to reduce severity of possible intellectual impairment in a potentially affected fetus (37; 14).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Roberto H Caraballo MD
Dr. Caraballo of Hospital Nacional de Pediatria Juan P Garrahan has no relevant financial relationships to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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