eMedicine Specialties > Pediatrics: General Medicine > Nutrition

Vitamin B-6 Dependency Syndromes

Author: Anjali Parish, MD, Assistant Professor of Pediatrics, Department of Neonatology, Medical College of Georgia
Coauthor(s): Michael D Nissen, MBBS, BMedSc, FRACP, FRCPA, Associate Professor in Biomolecular, Biomedical Science & Health, Griffith University; Director of Infectious Diseases and Unit Head of Queensland Paediatric Infectious Laboratory, Sir Albert Sakzewski Viral Research Centre, Royal Children's Hospital; Catherine O'Neil, BHlthSc, APD, Clinical Dietician/Nutritionist, Royal Children's Hospital, Australia; Community Nutritionist, Save the Children Fund; Judith A Wilcox, BSc, Director of Nutrition and Dietetics, Royal Children's Hospital, Australia
Contributor Information and Disclosures

Updated: Nov 19, 2008

Introduction

Background

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 Hunt et al first described PDS in 1954.^4,1,5 Since then, fewer than 100 cases have been reported worldwide.^1,3 Later onset seizures due to pyridoxine deficiency have been reported.^1,6 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.¹ A trial of pyridoxine is recommended in all seizures that have no clear etiology and occur before the child is aged 18 months.⁶

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

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.^1,6 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.⁵ Some suggest that PDS is possibly caused by a glutamic acid decarboxylase (GAD) abnormality;⁷ however, genetic analysis of GAD in affected families has not revealed any defects in this gene.^8,9

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.⁵

International

Burd et al reports prevalence data of 1 per 20,000-100,000 live births.⁵ 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.^1,5  In the Netherlands, birth incidence has been reported as 1:396,000 for definite and probable cases of PDS.¹⁰

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.^1,2,6,3 Outcomes of PDS in older children have rarely been reported.

Clinical

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).^1,11 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.^1,12,11
• 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 in 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.^1,5 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.¹²
• Hydrocephalus is also present in many cases.^5,12,11
• 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
• 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.^1,5
• 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;^13,14 however, another unidentified disease-causing gene may also be responsible.¹⁴

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