Table 3.

Other Vitamin B6-Dependent Epilepsies and Selected Disorders with PN- or PLP-Responsive Seizures in the Differential Diagnosis of PLPBP Deficiency

GeneDisorderMOILaboratory FeaturesResponse to PN/PLPClinical Features
Vitamin B6-dependent epilepsy disorders 1
ALDH7A1 Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) 2AR
  • ↑ levels of α-AASA irrespective of treatment w/PN or PLP
  • May also have ↑ levels of pipecolic acid
  • Low PLP levels in plasma & CSF prior to vitamin B6 supplementation
Szs in affected children respond to supraphysiologic doses of PN (or PLP).
  • Although most newborns have szs soon after birth, some have late-onset szs (i.e., age >2 mos or as late as adolescence).
  • ID is common, w/more favorable outcomes observed in those w/late-onset szs.
PNPO PNPO deficiency AR
  • ↓ CSF & plasma levels of PLP when measured prior to administration of PN or PLP
  • ↑ CSF glycine
  • ↑ urinary vanillactic acid. 3
  • ↑ plasma PM, ↑ PM:PA ratio. 4
Szs respond to supraphysiologic doses of PLP (~60% of affected persons) or PN (~40% of affected persons).
  • The vast majority of infants w/classic PNPO deficiency have szs before age 2 wks, w/30% presenting on day 1 of life.
  • As w/other forms of vitamin B6-dependent epilepsy, if untreated, PNPO deficiency is usually fatal.
  • Motor delay has been reported, likely due to long periods of poor sz control before introduction of PLP/PN treatment. 5
Vitamin B6-responsive seizures 6
ALDH4A1 Hyperprolinaemia type IIARMarkedly ↑ plasma proline levels as well as ↑ P5C in urine
  • ~50% of persons develop szs.
  • PN leads to cessation &/or prevention of szs (esp during infection) 2
  • Szs usually manifest after neonatal period, may occur w/febrile infections, & may respond to common ASMs.
  • Persons may have ID or normal intellectual ability.
ALPL Infantile hypophosphatasia (See Hypophosphatasia.)AR 7Using appropriate pediatric normative reference values, this disorder is suspected w/low serum ALP enzyme activity.Vitamin B6-responsive szs may occur.
  • Clinical signs may be recognized between birth & age 6 mos & resemble rickets.
  • Prior to availability of enzyme replacement therapy, ~50% succumbed to respiratory failure caused by undermineralization of ribs.
  • Intractable szs may precede biochemical or radiographic manifestations of rickets.
CACNA1A Developmental & epileptic encephalopathy 42 (OMIM 617106)ADNo assoc biochemical abnormalitiesA female w/CACNA1A-related absence epilepsy & ataxia responded dramatically to PN. 8
GOT2 Developmental & epileptic encephalopathy 82 (OMIM 618721)AR↑ serum lactate & ammoniaCombined PN & serine resulted in clinical improvement & amelioration of sz frequency.
  • Early-onset metabolic epileptic encephalopathy
  • Severely impaired intellectual development w/absent speech & spastic tetraplegia
  • Microcephaly, cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, & white matter abnormalities. 9
KCNQ2 KCNQ2-related disorders ADNo assoc biochemical abnormalitiesSome persons w/neonatal epilepsy are vitamin B6-responsive. 10
  • May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy
  • Szs are tonic & often asymmetric.
MOCS2 MOSC2-related molybdenum cofactor deficiencyARWhen present, ↑ α-AASA is secondary to ALDH7A1 inhibition by accumulated sulfocysteine.A clear but transient response of szs to PN has been observed in 2 affected sibs. 11
PGAP3 Hyperphosphatasia w/ID syndrome 4 (OMIM 615716)AR↑ serum ALPSzs may respond to PN.DD, ID, structural brain anomalies, dysmorphic facies, & szs
PIGA Multiple congenital anomalies-hypotonia-seizures syndrome 2 4 (OMIM 300868)XL↑ serum ALP in some personsHeterogeneous effect of PN on szsDysmorphic features, hypotonia, early-onset myoclonic seizures, & variable congenital anomalies
PIGL CHIME syndrome (OMIM 280000)AR↑ serum ALPSzs may respond to PN (but much more slowly than in PDE-ALDH7A1).Coloboma, congenital heart disease, ichthyosiform dermatosis, ID, & ear anomalies
PIGO Hyperphosphatasia w/ID syndrome 2 (OMIM 614749)AR↑ serum ALPSzs w/variable response to PNModerate-to-severe DD, facial dysmorphism, & brachytelephalangy ± szs
PIGS Developmental & epileptic encephalopathy 95 (OMIM 618143)ARNormal serum ALP (except mildly ↑ in 1 person)Szs may be PN responsive.Severe DD, ataxia, hypotonia, coarse facies, & intractable szs
PIGV Hyperphosphatasia w/ID syndrome 1 (OMIM 239300)AR↑ serum ALPVariable neurologic features incl szs that are ± PN responsive.Distinct facial phenotype, DD, & brachytelephalangy ± anorectal malformations

α-AASA = alpha-aminoadipic semialdehyde; AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; P5C = pyrroline-5-carboxylate; PA = pyridoxic acid; PLP = pyridoxal 5'-phosphate; PM = pyridoxamine; PN = pyridoxine; sz = seizure; XL = X-linked

1.

Epilepsies that respond to treatment with vitamin B6 long term. In this context vitamin dependency indicates a need for lifelong supplementation of supraphysiologic doses of a respective vitamin.

2.

See Mills et al, "Vitamin B6 Metabolism and Inborn Errors," in The Online Metabolic and Molecular Bases of Inherited Disease. Accessed 6-19-22 (registration required).

3.
4.
5.
6.

Epilepsies that may respond to treatment with vitamin B6 transiently. In this context vitamin responsiveness may be a transient effect and may not be directly linked to vitamin B6 metabolism.

7.

Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner.

8.
9.
10.
11.

From: PLPBP Deficiency

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