Practice Essentials
B6 dependency syndromes are a group of metabolic disorders that respond to large doses of vitamin B6. Although rare, pyridoxine-dependent seizure (PDS) is a recognized cause of intractable seizures in neonates, psychomotor developmental delay, and, sometimes, death in untreated patients. [1, 2, 3, 4, 5, 6] Hunt et al first described PDS in 1954. [7, 1, 8] Since then, fewer than 100 cases have been reported worldwide. [1, 3]
Later onset seizures due to pyridoxine deficiency have been reported. [1, 9] The 2 types of presentations are classic and atypical. The classic presentation consists of intractable seizures that appear within hours of birth and are resistant to conventional anticonvulsants. The seizures rapidly respond to administration of parenteral pyridoxine in doses greater than physiologic doses. [1] A trial of pyridoxine is recommended in all seizures that have no clear etiology and occur before the child is aged 18 months. [9] Atypical forms include those with seizures only partly responsive to pyridoxine, referred to as pyridoxine responsive seizures, and those with late onset of seizures. [2] Despite treatment, children can have intellectual deficits or developmental delays.
PDS is probably an underdiagnosed and underreported condition. All medical specialists should be aware of its existence and potentially favorable outcome. [1] Lifelong supplementation of pyridoxine is required. [1, 3] Despite treatment developmental handicaps especially in expressive language are common.
Vitamin B-6 (pyridoxine)
Pyridoxine is water-soluble. Sources include meat, nuts, and whole-grain products (especially wheat).
Deficiency usually occurs in conjunction with inadequate intake of other B vitamins due to poor diet or malabsorption states.
Isolated pyridoxine dependency can occur during treatment with isoniazid, which is a pyridoxine antagonist. Pyridoxine requirements are increased in the presence of other drugs, including penicillamine, contraceptive steroids, and hydralazine.
Clinical features of deficiency in young infants include abnormal CNS activity (eg, irritability, aggravated startle response, seizures) and GI distress (eg, distension, vomiting, diarrhea). Other manifestations include anemia, peripheral neuropathy, and dermatitis.
Treatment consists of pyridoxine 5 mg intramuscularly followed by 0.5 mg per day orally for 2 weeks. Correct dietary deficiency.
Consider pyridoxine dependency in the differential diagnosis of neonatal seizures when other more common causes have been eliminated. Rapid treatment with pyridoxine, 100 mg intramuscularly, is recommended.
The recommended daily dietary intake for pyridoxine is as follows:
-
Infants aged 0-6 months - 0.25 mg/d
-
Infants aged 7-12 months - 0.45 mg/d
-
Children aged 1-3 years - 0.6-0.9 mg/d
-
Children aged 4-7 years - 0.8-1.3 mg/d
-
Boys aged 8-11 years - 1.1-1.6 mg/d
-
Boys aged 12-15 years - 1.4-2.1 mg/d
-
Boys aged 16-18 years - 1.5-2.2 mg/d
-
Girls aged 8-11 years - 1-1.5 mg/d
-
Girls aged 12-15 years - 1.2-1.8 mg/d
-
Girls aged 16-18 years - 1.1-1.6 mg/d
Pathophysiology
PDS is an autosomal recessive inborn disorder of metabolism. [1, 9, 10] Some studies suggest that, as well as seizure activity, the neurobehavioral phenotype of the defective gene in PDS may include cognitive and other neuropsychologic impairment. [8] Some suggest that PDS is possibly caused by a glutamic acid decarboxylase (GAD) abnormality [11] ; however, genetic analysis of GAD in affected families has not revealed any defects in this gene. [12, 13]
Subsequent studies showed elevated pipecolic acid levels in the plasma and cerebrospinal fluid of affected patients and this led to the recognition of a defect in aaminoadipic semialdehyde (a-AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway, and mutations in the antiquitin gene (ALDH7A1) on chromosome 5q31. [14] These gene defects occur in almost all neonatal onset cases of VB6 dependent seizures,and are also found in some, but not all, late-onset cases. [15] Pipecolic acid and a-AASA have become useful biomarkers for the diagnosis of VB6 dependency. Pipecolic acid acts as a modulator of GABA.
PDS is genetically mediated. Researchers have identified defects in the antiquitin gene [16, 17, 18] ; however, another unidentified disease-causing gene may also be responsible. [17]
Epidemiology
United States statistics
The frequency of PDS in the United States is unknown. Fewer than 100 cases have been reported in the literature; thus, the full range of symptomatology is unknown. [8] It has an estimated incidence of up to 1:20,000 live births. [19]
International statistics
Burd et al reports prevalence data of 1 per 20,000-100,000 live births. [8] Data from the United Kingdom suggest a very low prevalence. A birth incidence of 1 in 783,000 and a point of prevalence of 1 in 687,000 (for definite and probable cases in children < 16 y) have been reported from the United Kingdom and the Republic of Ireland in 1999. [1, 8] In the Netherlands, birth incidence has been reported as 1:396,000 for definite and probable cases of PDS. [20]
Race-, sex-, and age-related demographics
No particular race has been identified as more or less susceptible to the condition. Studies have mostly come from the United Kingdom because of misdiagnosis in less developed countries. In 2001, Gupta et al reported that PDS is underdiagnosed and underreported in India. [1]
The literature has not identified sex differences in susceptibility to PDS.
Most reported cases have been in infants or young children. [1, 2, 9, 3] Outcomes of PDS in older children have rarely been reported.
Prognosis
Untreated patients usually die with a severe seizure disorder, and most infants have intellectual disability despite the initiation of therapy in utero or during the first hour of life. [1, 8] However, early therapy may decrease the severity of intellectual impairment. [1, 2, 21, 22] A meta-analysis indicates no significant correlation between developmental outcome and the time of diagnosis and institution of pyridoxine therapy. Some studies suggest that the developmental outcome is dependent on the dose of pyridoxine used. [1] Approximately 60% of patients with PDS have delayed developmental milestones for walking and talking. [8] Additionally, one study reports a specific deficit in expressive speech. [22]
Patients presenting older than 1 month have a better prognosis than those presenting younger than 1 month. Infants who have early seizures that are unresponsive to routine anticonvulsants usually have a poor prognosis.
Scharer et al [23] have described three different phenotypes in pyridoxine treated patients: (1) complete seizure control and normal developmental outcome; (2) complete seizure control and developmental delay or intellectual disability; and (3) incomplete seizure control and developmental delay or intellectual disability.
A small Dutch study of adults with PDS found that neurologic symptoms, including tremors, were present in 90% of patients, abnormalities on neuroimaging studies were noted in 80%, and intellectual disability was present in 70%. Seizures were controlled with pyridoxine monotherapy in 70% of the patients in the study; however, 20% required adjunct antiepileptic drug therapy. [24]
Morbidity/mortality
The literature has not reported mortality and morbidity rates.
Complications
Patients who are taking long-term pyridoxine for pyridoxine-dependent seizure (PDS) must be assessed for signs of sensory peripheral neuropathy on follow-up; this should include monitoring of rombergism, ankle jerks, and joint position sense. [1, 2]
The toxic effects of pyridoxine administration are a major concern for patients with PDS. Prolonged depression of neurologic and respiratory function, bradycardia, hypotonia and apnea, and depression of cerebral electrical activity have all been reported in patients receiving oral or parenteral test doses of pyridoxine. A reversible sensory neuropathy has been described in some individuals who have taken high doses of pyridoxine on a long-term basis. In some patients, a chronic painful neuropathy has developed. [1, 2]
In adults, symptoms of adverse effects of megadoses of pyridoxine include unstable gait and feet numbness, followed by numbness and clumsiness of the hands, and then perioral numbness. Signs include gait ataxia, reduced or absent reflexes, decrease position, vibration, pain, and heightened temperature sensation. [2]
Intercurrent illness can precipitate seizures in children whose states are usually well controlled on pyridoxine. Administration of an additional 100 mg of pyridoxine per day is recommended in these cases; [2] however, this is not always effective.
Patient Education
Instruct parents, caregivers, and other relevant parties (eg, relatives, teachers) on the administration of pyridoxine. Compliance in young children can be poor because liquid and tablet preparations of pyridoxine have an unpleasant taste, and breakthrough seizures can occur. [2]
For excellent patient education resources, visit eMedicineHealth's Children's Health Center and Digestive Disorders Center. Also, see WebMD's patient education article Seizures in Children and eMedicineHealth's patient education article Anatomy of the Digestive System.
