Vitamin B-6 Dependency Syndromes 

Updated: May 15, 2017
Author: Haritha Reddy Chelimilla, MD; Chief Editor: Jatinder Bhatia, MBBS, FAAP 

Overview

Background

B6 dependency syndromes are a group of metabolic disorders which 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] Atypicalformsinclude 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)

See the list below:

  • 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

Epidemiology

Frequency

United States

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.[16]

International

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.[17]

Mortality/Morbidity

The literature has not reported mortality and morbidity rates.

Race

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]

Sex

The literature has not identified sex differences in susceptibility to PDS.

Age

Most reported cases have been in infants or young children.[1, 2, 9, 3] Outcomes of PDS in older children have rarely been reported.

 

Presentation

History

The 2 forms of pyridoxine (vitamin B-6)–dependent seizure (PDS) are classic PDS and atypical PDS.

  • The classic presentation of PDS consists of intractable seizures that appear within hours of birth and are resistant to conventional anticonvulsants. The seizures respond rapidly to administration of parenteral pyridoxine (vitamin B-6).[1] A history suggestive of intrauterine convulsive movements (reported as a sustained hammering sensation lasting 15-20 min) at 5 months' gestation or later (reported retrospectively), fetal distress during labor, and meconium staining of the amniotic fluid may be present.[1, 2] These symptoms, in addition to flaccidity and early neonatal seizures, frequently lead to the misdiagnosis of perinatal asphyxia (approximately 10% of cases reported early have features of birth asphyxia or suspected hypoxic-ischemic encephalopathy).[1, 18] Typically, seizures begin in the first few days of life.[2]

  • The atypical form is more frequently reported and may be more common than the classic form.[1, 2] Atypical cases were described soon after PDS was recognized and may not appear until later in life, sometimes as late as age 3 years.[2] Atypical presentations described in the literature include the following:

    • An initial response to anticonvulsant therapy

    • Seizures occurring 6 weeks after the successful cessation of phenobarbital used to control neonatal seizures

    • Seizure-free intervals of up to 5.5 months occurring after the discontinuation of pyridoxine

    • Initial failure of pyridoxine used to control neonatal seizures during the first 8 months of life, followed by the successful treatment of seizures with pyridoxine administration[1, 2]

  • Considering the number of atypical presentations of PDS, research has suggested that the diagnosis of PDS should be suspected in all children with convulsions in the first 18 months of life. The clinical features may be misleading, and early treatment appears to be beneficial.[1, 19, 18]

  • Other clinical manifestations include marked irritability, hyperactivity, hyperacusis, or tremulousness which usually appear within 10 days of birth in classic neonatal cases.

  • Wide ranges of neuropsychiatric outcomes have been described with the diagnosis of PDS.

Physical

Physical signs include flaccidity of the limbs at birth and early neonatal seizures.[1]

  • Clinical diagnosis is often delayed, and severe neurologic sequelae are common.

  • Typically, children with PDS experience seizures that are long-lasting, and generalized tonic-clonic seizures often evolve into status. Seizures typical of other conditions have also been described in the literature: brief seizures (both partial and generalized); atonic, myoclonic, and visual seizures; and infantile spasms.[1, 8] External stimuli can also trigger seizures.

  • Associated presenting features include restlessness, irritability, and vomiting. These features may be noted several hours before the seizures occur.[1]

  • Mental development, specifically expressive verbal ability, is usually impaired; however, evidence suggests that appropriate dosing of pyridoxine may prevent or even reverse impairment.[1]

  • Baxter reports an unusual symptom of apparent acute abdominal obstruction or respiratory distress, usually accompanied by irritable behavior in addition to seizure activity.[19]

  • Hydrocephalus is also present in many cases.[8, 19, 18]

  • A history suggestive of intrauterine convulsive movements (reported as a sustained hammering sensation) at 5 months' gestation or later (reported retrospectively), fetal distress during labor, and meconium staining of the amniotic fluid may be present.[1, 2] These symptoms, in addition to flaccidity and early neonatal seizures, frequently lead to the misdiagnosis of perinatal asphyxia (approximately 10% of cases reported early have features of birth asphyxia or hypoxic-ischemic encephalopathy).

  • Pyridoxine dependency remains a clinical diagnosis and is based on the following criteria, which have been deemed simple enough for widespread use and broad enough to recognize both typical and atypical cases:

    • Cessation of clinical seizures with the administration of pyridoxine, either orally or parenterally

    • Complete seizure control on pyridoxine monotherapy

    • A recurrence of seizures caused by the withdrawal of pyridoxine[1, 2, 3, 20]

  • Associated findings supportive of the diagnosis include a typical EEG pattern, seizures resistant to conventional antiepileptic agents, normalization of the EEG after pyridoxine administration, a positive family history, intrauterine seizures, and neonatal onset of seizures. If parents refuse to withdraw pyridoxine therapy, the first 2 criteria alone are sufficient for diagnosis.[1, 8]

  • The parenteral pyridoxine injection test is a highly effective and reproducible test in confirming the diagnosis of PDS.[1]

Causes

PDS is genetically mediated. Researchers have identified defects in the antiquitin gene;[21, 22, 23] however, another unidentified disease-causing gene may also be responsible.[22]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • Perform hematology tests, a sepsis screen, and metabolic (profile) tests.

  • Plecko et al have confirmed pipecolic acid (PA) levels are elevated in the plasma of patients with pyridoxine (vitamin B-6)–dependent seizure (PDS) both before and after treatment with pyridoxine.[21] Furthermore, alpha amino adipic semialdehyde (AASA) levels are also elevated in plasma, urine, and cerebrospinal fluid (CSF).[24] They have recommended PA and AASA levels in plasma and urine be used as markers to select for patients who need molecular analysis of the antiquitin gene.[23]

Imaging Studies

See the list below:

  • Despite several reports about imaging studies, no typical abnormality has been found in PDS.[1, 2]

  • A high prevalence of structural CNS defects has been reported, as well as varying degrees of grey and white matter atrophy, thinning of the corpus callosum, and the presence of mega cisterna magna.[1]

  • Progressive cortical-white matter atrophy and ventricular dilation is also present in inadequately treated patients with PDS.[1, 2]

  • Hydrocephalus of unknown origin can also occur.

  • Baxter reports apparent cysts adjacent to the lateral ventricles in some neonatal-onset ultrasonographic images.

  • CT scanning and MRI reveal structural abnormalities in the brain in addition to white matter abnormalities.[2]

  • CT scanning and MRI do not have a well-established role in the diagnosis of PDS.[1]

Other Tests

See the list below:

  • Following pyridoxine administration, the EEG usually takes 2-6 minutes to normalize. The pattern is typically suggestive of diffuse and focal dysfunction and may show focal discharges; however, some EEG patterns have been normal (ie, bursts or runs of high-voltage, relatively bilateral synchronous sharp and slow [1-4 Hz] wave activity [either ictally or interictally]).[1]

  • EEG does not have a well-established role in the diagnosis of PDS. One report suggests that the abnormal EEG is a result of the administration of anticonvulsants to the patient prior to the diagnosis of PDS.[19]

  • Two case studies by Cirillo et al present the difficulties in diagnosing pyridoxine-dependent seizures by using EEG response to pyridoxine treatment. One patient who was later diagnosed with PDS had no EEG changes while another patient who had extreme EEG changes was not diagnosed with PDS. The study recommended the continuation of oral pyridoxine treatment until laboratory testing confirms the diagnosis.[25]

Procedures

See the list below:

  • Perform a CSF examination (ie, lumbar puncture).

 

Treatment

Medical Care

Recommended maintenance doses of pyridoxine (vitamin B-6) have ranged from 2-300 mg/d.[1, 2] Responses to treatment have included an improvement in the intelligence quotient (IQ) score and reversal of mental retardation in patents with pyridoxine-dependent seizure (PDS), depending on the dose on pyridoxine given. The suggested mechanism of this is normalization of CSF glutamate. Some studies have also found an improvement in the quality of behavior and IQ following an increase in the dose (150-500 mg/d) of pyridoxine given to older children with PDS.[1, 26]

For patients with acute seizures pyridoxine can be administered intravenously, under EEG monitoring if available and with adequate respiratory support in case apnea occurs as an immediate treatment response. A dose of 100 mg of pyridoxine- HCl should be given intravenously with additional doses may be administered over the course of 30 min as needed for response. Clinicians should be aware of possible cardiorespiratory depressive effects of a first pyridoxine administration.

Kuo et al suggested that pyridoxine phosphate should be considered as the drug of choice in atypical cases in children who do not respond to pyridoxine.[11] This is in an attempt to reduce failure rate and further delay in seizure control because pyridoxal phosphate is the active coenzyme for more than 100 enzymes. Further research is needed.

Consultations

See the list below:

  • Neurologist

  • Metabolic physician/Geneticist

  • Eye specialist

  • Rehabilitation specialists - Dietitian, physiotherapist, speech pathologist, and occupational therapist

Diet

Oral supplementation of vitamin B-6 is essential because dietary sources cannot be manipulated to achieve such a high requirement (100 mg/d). No other nutritional support specific to PDS is indicated; however, sequelae of this disease may increase the nutritional risk. According to the Dietary Guidelines for Children and Adolescents, ensuring nutritional adequacy of the diet is essential. This includes adequate vitamin B-6 intake, which meets recommended dietary intake specific to age and sex. Children with mental retardation often cannot achieve sufficient caloric requirements through oral intake alone; thus, supplementary feeding, including enteral feeding, may be indicated. A referral to a dietitian to ensure nutritional adequacy of the diet is recommended initially and then periodically as required.

Activity

Physical activity has not been reported to be of special benefit in children with PDS.

 

Medication

Vitamins

Class Summary

These agents are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Deficiency may result from an inadequate diet, increased requirements, or secondary to disease or drugs. They are used clinically for the prevention and treatment of specific vitamin deficiency states and are considered third-line treatment for both acute and chronic intractable seizure disorders in children younger than 2 years.

Pyridoxine (Vitamin B-6)

Necessary for normal metabolism of proteins, carbohydrates, and fats. Also involved in synthesis of GABA within the CNS. Indicated to treat pyridoxine-dependent disorders caused by enzyme deficiency or deficiency in enzyme activity. These disorders are responsive to pyridoxine administration, typically in high doses.

 

Follow-up

Further Outpatient Care

See the list below:

  • Continue to monitor seizure activity.

Further Inpatient Care

See the list below:

  • Monitor seizure activity in patients with vitamin B-6 dependency syndrome.

Inpatient & Outpatient Medications

See the list below:

  • Pyridoxine (see Medication)

Complications

See the list below:

  • 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.

Prognosis

See the list below:

  • Untreated patients usually die with a severe seizure disorder, and most infants have mental retardation 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, 19, 18] A meta-analysis of the most recent literature 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.[18]

  • 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..[27] 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

Patient Education

See the list below:

  • 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 eMedicineHealth's patient education articles Seizures in Children and Anatomy of the Digestive System.