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Pyridoxal phosphate-responsive seizures(PNPOD)

MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
Synonyms: EPILEPTIC ENCEPHALOPATHY, NEONATAL, PNPO-RELATED; PNPOD; Pyridoxal 5'-phosphate-dependent epilepsy; Pyridoxamine 5-Prime-Phosphate Oxidase Deficiency; Pyridoxine-5'-phosphate oxidase deficiency; SEIZURES, PYRIDOXINE-RESISTANT, PLP-SENSITIVE
SNOMED CT: Pyridoxal 5-phosphate dependent epilepsy (724576005); Pyridoxal phosphate-responsive seizures (724576005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PNPO (17q21.32)
 
Monarch Initiative: MONDO:0012407
OMIM®: 610090
Orphanet: ORPHA79096

Disease characteristics

Excerpted from the GeneReview: PNPO Deficiency
Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B6 vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%. About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures. [from GeneReviews]
Authors:
Barbara Plecko  |  Philippa Mills   view full author information

Additional descriptions

From OMIM
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).  http://www.omim.org/entry/610090
From MedlinePlus Genetics
Pyridoxal phosphate-responsive seizures (sometimes called pyridoxamine 5'-phosphate oxidase deficiency or PNPO deficiency) is a condition in which repeated seizures (epilepsy) typically begin within the first two weeks of life. In approximately 10 percent of individuals with PNPO deficiency, the seizures have a later onset, beginning after the first month of life. The seizures typically involve irregular involuntary muscle contractions (myoclonus), abnormal eye movements, or convulsions. In some cases, the seizures may last for several minutes or the seizures may occur too close together to allow for recovery between episodes (status epilepticus). Some babies with PNPO deficiency will experience seizures before birth, and some will experience a slow heart rate and a lack of oxygen before delivery (fetal distress).

Anticonvulsant medications, which are usually given to control seizures, are not effective in people with PNPO deficiency. Instead, individuals with PNPO deficiency require lifelong treatment with one of the following forms of vitamin B6: pyridoxal 5'-phosphate (PLP) or pyridoxine. If untreated, people with this condition can develop severe brain dysfunction (encephalopathy), which can lead to death. Even though seizures can be controlled with PLP or pyridoxine, people with PNPO deficiency may still experience neurological problems such as developmental delays, learning disorders, and uncontrolled movements (dystonia).

Other conditions present with signs and symptoms that are very similar to those seen in people with PNPO deficiency. These include pyridoxine-dependent epilepsy caused by changes in the ALDH7A1 gene and PLPBP deficiency caused by changes in the PLPBP gene. Individuals with these conditions are also typically treated with a form of vitamin B6.  https://medlineplus.gov/genetics/condition/pyridoxal-phosphate-responsive-seizures

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Unsteady gait
MedGen UID:
68544
Concept ID:
C0231686
Finding
A shaky or wobbly manner of walking.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
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.
Decreased CSF homovanillic acid concentration
MedGen UID:
1813045
Concept ID:
C5676596
Finding
Decreased concentration of homovanillic acid (HVA) in the cerebrospinal fluid. HVA is a metabolite of dopamine.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
The birth of a baby of less than 37 weeks of gestational age.
Rotary nystagmus
MedGen UID:
116106
Concept ID:
C0240595
Disease or Syndrome
A form of nystagmus in which the eyeball makes rotary motions around the axis.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPyridoxal phosphate-responsive seizures
Follow this link to review classifications for Pyridoxal phosphate-responsive seizures in Orphanet.

Recent clinical studies

Therapy

Dill P, Schneider J, Weber P, Trachsel D, Tekin M, Jakobs C, Thöny B, Blau N
Mol Genet Metab 2011 Nov;104(3):362-8. Epub 2011 Jun 2 doi: 10.1016/j.ymgme.2011.05.019. PMID: 21752681

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