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Pyridoxine-dependent epilepsy(EPD)

MedGen UID:
340341
Concept ID:
C1849508
Disease or Syndrome
Synonyms: EPD; Pyridoxine dependency; Pyridoxine dependency with seizures; Pyridoxine-Dependent Seizures; Vitamin B6-dependent seizures
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): ALDH7A1 (5q23.2)
OMIM®: 266100
Orphanet: ORPHA3006

Disease characteristics

Excerpted from the GeneReview: Pyridoxine-Dependent Epilepsy
Pyridoxine-dependent epilepsy is characterized by intractable seizures within the first weeks to months of life that are not controlled with antiepileptic drugs but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent epilepsy. Dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Infants with the classic neonatal presentation begin to experience seizures soon after birth. Atypical features include: late-onset seizures (seizures that begin from late infancy up until age 3 years); seizures that initially respond to antiepileptic drugs and then become intractable; seizures during early life that do not respond to pyridoxine but are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (≤5.5 months) that occur after discontinuation of pyridoxine. Intellectual disability is common. Elevated concentration of α-aminoadipic semialdehyde (α-AASA) in urine and plasma is a strong biomarker of the disorder; pipecolic acid may also be elevated in plasma and cerebrospinal fluid. [from GeneReviews]
Authors:
Sidney M Gospe   view full author information

Additional descriptions

From OMIM
Pyridoxine-dependent epilepsy, characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (Bennett et al., 2005).  http://www.omim.org/entry/266100
From GHR
Pyridoxine-dependent epilepsy is a condition that involves seizures beginning in infancy or, in some cases, before birth. Those affected typically experience prolonged seizures lasting several minutes (status epilepticus). These seizures involve muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures). Additional features of pyridoxine-dependent epilepsy include low body temperature (hypothermia), poor muscle tone (dystonia) soon after birth, and irritability before a seizure episode. In rare instances, children with this condition do not have seizures until they are 1 to 3 years old.Anticonvulsant drugs, which are usually given to control seizures, are ineffective in people with pyridoxine-dependent epilepsy. Instead, people with this type of seizure are medically treated with large daily doses of pyridoxine (a type of vitamin B6 found in food). If left untreated, people with this condition can develop severe brain dysfunction (encephalopathy). Even though seizures can be controlled with pyridoxine, neurological problems such as developmental delay and learning disorders may still occur.  https://ghr.nlm.nih.gov/condition/pyridoxine-dependent-epilepsy

Clinical features

Epilepsies, Myoclonic
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
A clinically diverse group of epilepsy syndromes characterized either by myoclonic seizures or by myoclonus in association with other seizure types. Myoclonic epilepsy syndromes are divided into three subtypes based on etiology: familial, cryptogenic, and symptomatic (i.e., occurring secondary to known disease processes such as infections, hypoxic-ischemic injuries, trauma, etc.).
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Seizures lasting for more than 30 minutes or longer or multiple seizures repeated frequently without regaining consciousness between seizures.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Generalized tonic-clonic seizures
MedGen UID:
141670
Concept ID:
C0494475
Disease or Syndrome
Generalized tonic-clonic seizures are generalized seizures with bilateral symmetrical tonic contraction then bilateral clonic contractions of somatic muscles usually associated with autonomic phenomena.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28)
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Difficulty in breathing. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Neonatal respiratory distress
MedGen UID:
163106
Concept ID:
C0852283
Disease or Syndrome
Respiratory difficulty as newborn.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Prenatal movement abnormality
MedGen UID:
340343
Concept ID:
C1849510
Finding
An abnormality of fetal movement.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPyridoxine-dependent epilepsy
Follow this link to review classifications for Pyridoxine-dependent epilepsy in Orphanet.

Recent clinical studies

Etiology

Gül-Mert G, İncecik F, Hergüner MÖ, Ceylaner S, Altunbaşak Ş
Turk J Pediatr 2015 Jul-Aug;57(4):394-397. PMID: 27186704
Coughlin CR 2nd, van Karnebeek CD, Al-Hertani W, Shuen AY, Jaggumantri S, Jack RM, Gaughan S, Burns C, Mirsky DM, Gallagher RC, Van Hove JL
Mol Genet Metab 2015 Sep-Oct;116(1-2):35-43. Epub 2015 May 23 doi: 10.1016/j.ymgme.2015.05.011. PMID: 26026794
Tamaura M, Shimbo H, Iai M, Yamashita S, Osaka H
Brain Dev 2015 Apr;37(4):442-5. Epub 2014 Aug 7 doi: 10.1016/j.braindev.2014.07.008. PMID: 25123644
Jung S, Tran NT, Gospe SM Jr, Hahn SH
Mol Genet Metab 2013 Nov;110(3):237-40. Epub 2013 Jul 26 doi: 10.1016/j.ymgme.2013.07.017. PMID: 23953072
Bok LA, Halbertsma FJ, Houterman S, Wevers RA, Vreeswijk C, Jakobs C, Struys E, Van Der Hoeven JH, Sival DA, Willemsen MA
Dev Med Child Neurol 2012 Sep;54(9):849-54. Epub 2012 Jul 13 doi: 10.1111/j.1469-8749.2012.04347.x. PMID: 22804844

Diagnosis

Gül-Mert G, İncecik F, Hergüner MÖ, Ceylaner S, Altunbaşak Ş
Turk J Pediatr 2015 Jul-Aug;57(4):394-397. PMID: 27186704
Tincheva S, Todorov T, Todorova A, Georgieva R, Stamatov D, Yordanova I, Kadiyska T, Georgieva B, Bojidarova M, Tacheva G, Litvinenko I, Mitev V
Neurol Sci 2015 Dec;36(12):2209-12. Epub 2015 Aug 1 doi: 10.1007/s10072-015-2338-3. PMID: 26232297
Cirillo M, Venkatesan C, Millichap JJ, Stack CV, Nordli DR Jr
Pediatrics 2015 Jul;136(1):e257-61. doi: 10.1542/peds.2014-2423. PMID: 26101365
Tamaura M, Shimbo H, Iai M, Yamashita S, Osaka H
Brain Dev 2015 Apr;37(4):442-5. Epub 2014 Aug 7 doi: 10.1016/j.braindev.2014.07.008. PMID: 25123644
Oliveira R, Pereira C, Rodrigues F, Alfaite C, Garcia P, Robalo C, Fineza I, Gonçalves O, Struys E, Salomons G, Jakobs C, Diogo L
Epileptic Disord 2013 Dec;15(4):400-6. doi: 10.1684/epd.2013.0610. PMID: 24184718

Therapy

Tincheva S, Todorov T, Todorova A, Georgieva R, Stamatov D, Yordanova I, Kadiyska T, Georgieva B, Bojidarova M, Tacheva G, Litvinenko I, Mitev V
Neurol Sci 2015 Dec;36(12):2209-12. Epub 2015 Aug 1 doi: 10.1007/s10072-015-2338-3. PMID: 26232297
Cirillo M, Venkatesan C, Millichap JJ, Stack CV, Nordli DR Jr
Pediatrics 2015 Jul;136(1):e257-61. doi: 10.1542/peds.2014-2423. PMID: 26101365
Tamaura M, Shimbo H, Iai M, Yamashita S, Osaka H
Brain Dev 2015 Apr;37(4):442-5. Epub 2014 Aug 7 doi: 10.1016/j.braindev.2014.07.008. PMID: 25123644
Nasr E, Mamak E, Feigenbaum A, Donner EJ, Mercimek-Mahmutoglu S
J Child Neurol 2015 Apr;30(5):648-53. Epub 2014 May 1 doi: 10.1177/0883073814531331. PMID: 24789515
Oliveira R, Pereira C, Rodrigues F, Alfaite C, Garcia P, Robalo C, Fineza I, Gonçalves O, Struys E, Salomons G, Jakobs C, Diogo L
Epileptic Disord 2013 Dec;15(4):400-6. doi: 10.1684/epd.2013.0610. PMID: 24184718

Prognosis

Coughlin CR 2nd, van Karnebeek CD, Al-Hertani W, Shuen AY, Jaggumantri S, Jack RM, Gaughan S, Burns C, Mirsky DM, Gallagher RC, Van Hove JL
Mol Genet Metab 2015 Sep-Oct;116(1-2):35-43. Epub 2015 May 23 doi: 10.1016/j.ymgme.2015.05.011. PMID: 26026794
Tamaura M, Shimbo H, Iai M, Yamashita S, Osaka H
Brain Dev 2015 Apr;37(4):442-5. Epub 2014 Aug 7 doi: 10.1016/j.braindev.2014.07.008. PMID: 25123644
Badoe EV
West Afr J Med 2013 Jul-Sep;32(3):231-4. PMID: 24122693
Bok LA, Halbertsma FJ, Houterman S, Wevers RA, Vreeswijk C, Jakobs C, Struys E, Van Der Hoeven JH, Sival DA, Willemsen MA
Dev Med Child Neurol 2012 Sep;54(9):849-54. Epub 2012 Jul 13 doi: 10.1111/j.1469-8749.2012.04347.x. PMID: 22804844
Mercimek-Mahmutoglu S, Horvath GA, Coulter-Mackie M, Nelson T, Waters PJ, Sargent M, Struys E, Jakobs C, Stockler-Ipsiroglu S, Connolly MB
Pediatrics 2012 May;129(5):e1368-72. Epub 2012 Apr 23 doi: 10.1542/peds.2011-0123. PMID: 22529283

Clinical prediction guides

Poliachik SL, Friedman SD, Poliakov AV, Budech CB, Ishak GE, Shaw DW, Gospe SM Jr
Pediatr Neurol 2016 Jan;54:43-8. Epub 2015 Sep 25 doi: 10.1016/j.pediatrneurol.2015.09.012. PMID: 26547255
Xue J, Qian P, Li H, Wu Y, Liu X, Yang Z
Epilepsy Res 2015 Dec;118:1-4. Epub 2015 Oct 19 doi: 10.1016/j.eplepsyres.2015.10.002. PMID: 26555630
Coughlin CR 2nd, van Karnebeek CD, Al-Hertani W, Shuen AY, Jaggumantri S, Jack RM, Gaughan S, Burns C, Mirsky DM, Gallagher RC, Van Hove JL
Mol Genet Metab 2015 Sep-Oct;116(1-2):35-43. Epub 2015 May 23 doi: 10.1016/j.ymgme.2015.05.011. PMID: 26026794
Yusuf IH, Sandford V, Hildebrand GD
J AAPOS 2013 Jun;17(3):315-7. Epub 2013 Apr 18 doi: 10.1016/j.jaapos.2013.01.006. PMID: 23602455
Bok LA, Halbertsma FJ, Houterman S, Wevers RA, Vreeswijk C, Jakobs C, Struys E, Van Der Hoeven JH, Sival DA, Willemsen MA
Dev Med Child Neurol 2012 Sep;54(9):849-54. Epub 2012 Jul 13 doi: 10.1111/j.1469-8749.2012.04347.x. PMID: 22804844

Recent systematic reviews

Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E, Van Hove JL
J Inherit Metab Dis 2010 Oct;33(5):571-81. Epub 2010 Sep 3 doi: 10.1007/s10545-010-9187-2. PMID: 20814824Free PMC Article

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