Table 3.

Selected Disorders of Interest in the Differential Diagnosis of PNPO Deficiency

GeneDisorderLaboratory FeaturesResponse to PN/PLPClinical Features
Pyridoxine (vitamin B6)-dependent epilepsy 1
ALDH7A1 Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) 2↑ α-AASA levels 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).While most newborns have szs soon after birth, some have late onset (i.e., age >2 mos, or as late as adolescence). DD/ID is common, w/more favorable outcome observed in those with late-onset szs.
PLPBP PLPBP (PLPHP) deficiency 2Secondary biochemical abnormalities suggesting abnormal vitamin B6 metabolism may be present, as may lactic acidosis.Szs in affected children respond to supraphysiologic doses of PN (or PLP).Majority have sz onset w/in 1st wk of life; some children present as late as 6 mos. 3 Acquired microcephaly, structural brain abnormalities, & DD/ID are variable.
Pyridoxine (vitamin B6)-responsive seizures 4
PGAP3 Hyperphosphatasia w/ID syndrome 4 2 (OMIM 615716)↑ serum ALPSzs may respond to PN.DD/ID, structural brain anomalies, dysmorphic facies, & szs
ALDH4A1 Hyperprolinaemia type II 2 (OMIM 239510)Markedly ↑ plasma proline levels as well as ↑ P5C in urineSzs may respond to ASM & to PN.Szs usually manifest beyond neonatal period, may occur w/febrile infections, & may respond to common ASM. Persons may have ID or normal intellectual ability.
ALPL Infantile hypophosphatasia 5Using appropriate pediatric normative reference values, this disorder is suspected w/low serum ALP enzyme activity.Vitamin B6-responsive seizures 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 6 (OMIM 617106)No assoc biochemical abnormalitiesA female w/CACNA1A-related absence epilepsy & ataxia responded dramatically to PN. 7
KCNQ2 KCNQ2-related disorders 6No assoc biochemical abnormalities.Some w/neonatal epilepsy are vitamin B6 responsive. 8May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy. Szs are tonic & often asymmetric.
MOCS2 MOSC2-related molybdenum cofactor deficiency 2When present, ↑ 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. 9
PIGA Multiple congenital anomalies-hypotonia-seizures syndrome 2 10 (OMIM 300868)↑ serum ALP in some personsHeterogeneous effect of PN on szsDysmorphic features, hypotonia, early-onset myoclonic seizures, & variable congenital anomalies
PIGL CHIME syndrome 2 (OMIM 280000)↑ 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 2 (OMIM 614749)↑ serum ALPSzs w/variable response to PNModerate-to-severe DD/ID; facial dysmorphism & brachytelephalangy ± szs
PIGS Developmental & epileptic encephalopathy 95 2 (OMIM 618143)Normal serum ALP (except mildly ↑ in 1 person)Szs may be PN responsive.Severe DD/ID, ataxia, hypotonia, coarse facies, & intractable szs
PIGV Hyperphosphatasia w/ID syndrome 1 2 (OMIM 239300)↑ serum ALPVariable neurologic features incl szs that may respond to PN.Distinct facial phenotype, DD, & brachytelephalangy ± anorectal malformations

α-AASA = alpha-aminoadipic semialdehyde; ALP = alkaline phosphatase; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; P5C = pyrroline-5-carboxylate; PLP = pyridoxal 5'-phosphate; PN = pyridoxine; sz = seizures

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.

Autosomal recessive mode of inheritance

3.
4.

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.

5.

Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner.

6.

Autosomal dominant mode of inheritance

7.
8.
9.
10.

X-linked mode of inheritance

From: PNPO Deficiency

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